Association of symptom severity and cerebrospinal fluid alterations in recent onset psychosis in schizophrenia-spectrum disorders - An individual patient data meta-analysis.

Neuroinflammation and blood-cerebrospinal fluid barrier (BCB) disruption could be key elements in schizophrenia-spectrum disorders(SSDs) etiology and symptom modulation. We present the largest two-stage individual patient data (IPD) meta-analysis, investigating the association of BCB disruption and cerebrospinal fluid (CSF) alterations with symptom severity in first-episode psychosis (FEP) and recent onset psychotic disorder (ROP) individuals, with a focus on sex-related differences. Data was collected from PubMed and EMBASE databases. FEP, ROP and high-risk syndromes for psychosis IPD were included if routine basic CSF-diagnostics were reported. Risk of bias of the included studies was evaluated. Random-effects meta-analyses and mixed-effects linear regression models were employed to assess the impact of BCB alterations on symptom severity. Published (6 studies) and unpublished IPD from n = 531 individuals was included in the analyses. CSF was altered in 38.8 % of individuals. No significant differences in symptom severity were found between individuals with and without CSF alterations (SMD = -0.17, 95 %CI -0.55-0.22, p = 0.341). However, males with elevated CSF/serum albumin ratios or any CSF alteration had significantly higher positive symptom scores than those without alterations (SMD = 0.34, 95 %CI 0.05-0.64, p = 0.037 and SMD = 0.29, 95 %CI 0.17-0.41p = 0.005, respectively). Mixed-effects and simple regression models showed no association (p > 0.1) between CSF parameters and symptomatic outcomes. No interaction between sex and CSF parameters was found (p > 0.1). BCB disruption appears highly prevalent in early psychosis and could be involved in positive symptoms severity in males, indicating potential difficult-to-treat states. This work highlights the need for considering BCB breakdownand sex-related differences in SSDs clinical trials and treatment strategies.

Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: a systematic review and dose-response meta-analysis.

Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic review and dose-response meta-analysis. We searched multiple electronic databases up to 20.02.2023 for fixed-dose studies investigating 16 second-generation antipsychotics and haloperidol (all formulations and administration routes) in adults with acute exacerbations of schizophrenia. The primary outcome was the number of participants receiving antiparkinsonian medication, and if not available, the number of participants with extrapyramidal side-effects (EPS) and the mean scores of EPS rating scales were used as proxies. The effect-size was odds ratio (ORs) compared with placebo. One-stage random-effects dose-response meta-analyses with restricted cubic splines were conducted to estimate the dose-response curves. We also examined the relationship between dopamine D2 receptor (D2R) occupancy and ORs by estimating occupancies from administrated doses. We included data from 110 studies with 382 dose arms (37193 participants). Most studies were short-term with median duration of 6 weeks (range 3-26 weeks). Almost all antipsychotics were associated with dose-dependent EPS with varied degrees and the maximum ORs ranged from OR = 1.57 95%CI [0.97, 2.56] for aripiprazole to OR = 7.56 95%CI [3.16, 18.08] for haloperidol at 30 mg/d. Exceptions were quetiapine and sertindole with negligible risks across all doses. There was very low quality of findings for cariprazine, iloperidone, and zotepine, and no data for clozapine. The D2R occupancy curves showed that the risk increased substantially when D2R occupancy exceeded 75-85%, except for D2R partial agonists that had smaller ORs albeit high D2R occupancies. In conclusion, we found that the risk of EPS increases with rising doses and differs substantially in magnitude among antipsychotics, yet exceptions were quetiapine and sertindole with negligible risks. Our data provided additional insights into the current D2R therapeutic window for EPS.

Negative symptoms, striatal dopamine and model-free reward decision-making in schizophrenia.

Negative symptoms, such as lack of motivation or social withdrawal, are highly prevalent and debilitating in patients with schizophrenia. Underlying mechanisms of negative symptoms are incompletely understood, thereby preventing the development of targeted treatments. We hypothesized that in patients with schizophrenia during psychotic remission, impaired influences of both model-based and model-free reward predictions on decision-making ('reward prediction influence', RPI) underlie negative symptoms. We focused on psychotic remission, because psychotic symptoms might confound reward-based decision-making. Moreover, we hypothesized that impaired model-based/model-free RPIs depend on alterations of both associative striatum dopamine synthesis and storage (DSS) and executive functioning. Both factors influence RPI in healthy subjects and are typically impaired in schizophrenia. Twenty-five patients with schizophrenia with pronounced negative symptoms during psychotic remission and 24 healthy controls were included in the study. Negative symptom severity was measured by the Positive and Negative Syndrome Scale negative subscale, model-based/model-free RPI by the two-stage decision task, associative striatum DSS by 18F-DOPA positron emission tomography and executive functioning by the symbol coding task. Model-free RPI was selectively reduced in patients and associated with negative symptom severity as well as with reduced associative striatum DSS (in patients only) and executive functions (both in patients and controls). In contrast, model-based RPI was not altered in patients. Results provide evidence for impaired model-free reward prediction influence as a mechanism for negative symptoms in schizophrenia as well as for reduced associative striatum dopamine and executive dysfunction as relevant factors. Data suggest potential treatment targets for patients with schizophrenia and pronounced negative symptoms.

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.

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.

Sharing information across patient subgroups to draw conclusions from sparse treatment networks.

Network meta-analysis (NMA) usually provides estimates of the relative effects with the highest possible precision. However, sparse networks with few available studies and limited direct evidence can arise, threatening the robustness and reliability of NMA estimates. In these cases, the limited amount of available information can hamper the formal evaluation of the underlying NMA assumptions of transitivity and consistency. In addition, NMA estimates from sparse networks are expected to be imprecise and possibly biased as they rely on large-sample approximations that are invalid in the absence of sufficient data. We propose a Bayesian framework that allows sharing of information between two networks that pertain to different population subgroups. Specifically, we use the results from a subgroup with a lot of direct evidence (a dense network) to construct informative priors for the relative effects in the target subgroup (a sparse network). This is a two-stage approach where at the first stage, we extrapolate the results of the dense network to those expected from the sparse network. This takes place by using a modified hierarchical NMA model where we add a location parameter that shifts the distribution of the relative effects to make them applicable to the target population. At the second stage, these extrapolated results are used as prior information for the sparse network. We illustrate our approach through a motivating example of psychiatric patients. Our approach results in more precise and robust estimates of the relative effects and can adequately inform clinical practice in presence of sparse networks.

[Deprescribing in DGPPN S3 guidelines-a systematic analysis]. / "Deprescribing" in DGPPN-S3-Leitlinien ­ eine systematische Analyse.

BACKGROUND: Deprescribing of medication or psychotherapy represents a critical phase in treatment. The aim of the work is to systematically analyze recommendations for deprescribing medication and discontinuation of psychotherapy in the evidence- and consensus-based S3 guidelines of the German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN) to identify potential research gaps. METHODS: A systematic analysis of the DGPPN S3 guidelines to investigate and compare information and recommendations on deprescribing. RESULTS: Regarding deprescribing of medication, our analysis showed that eight of the 20 included S3 guidelines contain information both in the form of recommendations and background information. Regarding psychotherapy, only two guidelines provided information on deprescribing. CONCLUSION: Our results highlight the need to expand guidelines to include evidence-based recommendations for deprescribing medication or discontinuation of psychotherapy. Future research should focus on the development of specific, generic, and evidence-based guidelines that support both medical staff and patients during these critical phases of therapy.

Comparative efficacy and tolerability of 32 oral and long-acting injectable antipsychotics for the maintenance treatment of adults with schizophrenia: a systematic review and network meta-analysis.

BACKGROUND: Schizophrenia is a common, severe, and usually chronic disorder. Maintenance treatment with antipsychotic drugs can prevent relapse but also causes side-effects. We aimed to compare the efficacy and tolerability of antipsychotics as maintenance treatment for non-treatment resistant patients with schizophrenia. METHODS: In this systematic review and network meta-analysis, we searched, without language restrictions, the Cochrane Schizophrenia Group's specialised register between database inception and April 27, 2020, PubMed from April 1, 2020, to Jan 15, 2021, and the lists of included studies from related systematic reviews. We included randomised controlled trials (RCTs; ≥12 weeks of follow-up) that recruited adult participants with schizophrenia or schizoaffective disorder with stable symptoms who were treated with antipsychotics (monotherapy; oral or long-acting injectable) or placebo. We excluded RCTs of participants with specific comorbidities or treatment resistance. In duplicate, two authors independently selected eligible RCTs and extracted aggregate data. The primary outcome was the number of participants who relapsed and was analysed by random-effects, Bayesian network meta-analyses. The study was registered on PROSPERO, CRD42016049022. FINDINGS: We identified 4157 references through our search, from which 501 references on 127 RCTs of 32 antipsychotics (comprising 18 152 participants) were included. 100 studies including 16 812 participants and 30 antipsychotics contributed to our network meta-analysis of the primary outcome. All antipsychotics had risk ratios (RRs) less than 1·00 when compared with placebo for relapse prevention and almost all had 95% credible intervals (CrIs) excluding no effect. RRs ranged from 0·20 (95% CrI 0·05-0·41) for paliperidone oral to 0·65 (0·16-1·14) for cariprazine oral (moderate-to-low confidence in estimates). Generally, we interpret that there was no clear evidence for the superiority of specific antipsychotics in terms of relapse prevention because most comparisons between antipsychotics included a probability of no difference. INTERPRETATION: As we found no clear differences between antipsychotics for relapse prevention, we conclude that the choice of antipsychotic for maintenance treatment should be guided mainly by their tolerability. FUNDING: The German Ministry of Education and Research and Oxford Health Biomedical Research Centre.

Optimizing subjective wellbeing with amisulpride in first episode schizophrenia or related disorders.

BACKGROUND: Subjective response (SR) to antipsychotic medication is relevant for quality of life, adherence and recovery. Here, we evaluate (1) the extent of variation in SR in patients using a single antipsychotic; (2) the association between subjective and symptomatic response; and (3) predictors of SR. METHODS: Open-label, single treatment condition with amisulpride in 339 patients with a first episode of a schizophrenia spectrum disorder, at most minimally treated before inclusion. Patients were evaluated at baseline, before start with amisulpride and after four weeks of treatment with the Subjective Wellbeing under Neuroleptic scale, the Positive and Negative Syndrome Scale, and the Calgary Depression Scale for Schizophrenia. RESULTS: (1) 26.8% of the patients had a substantial favorable SR, and 12.4% of the patients experienced a substantial dysphoric SR during treatment with amisulpride. (2) Modest positive associations were found between SR and 4 weeks change on symptom subscales (r = 0.268-0.390, p values < 0.001). (3) Baseline affective symptoms contributed to the prediction of subjective remission, demographic characteristics did not. Lower start dosage of amisulpride was associated with a more favorable SR (r = -0.215, p < 0.001). CONCLUSIONS: We conclude that variation in individual proneness for an unfavorable SR is substantial and only modestly associated with symptomatic response. We need earlier identification of those most at risk for unfavorable SR and research into interventions to improve SR to antipsychotic medication in those at risk.

Effects of psychological treatments on functioning in people with Schizophrenia: a systematic review and meta-analysis of randomized controlled trials.

Functioning is recognized as a key treatment goal in alleviating the burden of schizophrenia. Psychological interventions can play an important role in improving functioning in this population, but the evidence on their efficacy is limited. We therefore aimed to evaluate the effect of psychological interventions in functioning for patients with schizophrenia. To conduct this systematic review and meta-analysis, we searched for published and unpublished randomized controlled trials (RCTs) in EMBASE, MEDLINE, PsycINFO, BIOSIS, Cochrane Library, WHO International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov and the Study register of the Cochrane Schizophrenia Group. The outcome functioning was measured with validated scales. We performed random-effects pairwise meta-analysis to calculate standardized mean differences (SMDs) with 95% confidence intervals (CIs). We included 58 RCTs (5048 participants). Psychological interventions analyzed together (SMD = - 0.37, 95% CI - 0.49 to - 0.25), cognitive behavioral therapy (30 RCTs, SMD = - 0.26, 95% CI - 0.39 to - 0.12), and third wave cognitive-behavioral therapies (15 RCTs, SMD = - 0.60, 95% CI - 0.83 to - 0.37) were superior to control in improving functioning, while creative therapies (8 RCTs, SMD = 0.01, 95% CI - 0.38 to 0.39), integrated therapies (4 RCTs, SMD = - 0.21, 95% CI - 1.20 to 0.78) and other therapies (4 RCTs, SMD = - 0.74, 95% CI - 1.52 to 0.04) did not show a benefit. Psychological interventions, in particular cognitive behavioral therapy and third wave cognitive behavioral therapies, have shown a therapeutic effect on functioning. The confidence in the estimate was evaluated as very low due to risk of bias, heterogeneity and possible publication bias.

A network meta-analysis of efficacy, acceptability, and tolerability of antipsychotics in treatment-resistant schizophrenia.

OBJECTIVE: Clozapine is considered as the standard treatment for this subgroup, but the evidence is not unequivocal. There are several potential alternatives being used because of the possible adverse effects of clozapine. We aimed to examine the efficacy and adverse events of different antipsychotics in treatment-resistant schizophrenia by performing a network meta-analysis. METHODS: We searched the Cochrane Schizophrenia Group register for randomized-controlled trials (up to March 06, 2022) and MEDLINE (up to January 20, 2023). We included blinded and open studies and participants with a broad definition of treatment resistance. The primary outcome was overall symptoms of schizophrenia; secondary outcomes were response to treatment, positive and negative symptoms of schizophrenia, discontinuation, side effects, quality of life, and functioning. The study was registered in Open Science Framework ( https://osf.io/9nf2y/ ). RESULTS: We included 60 studies involving 6838 participants in the network meta-analysis. In the primary outcome, clozapine and olanzapine were more efficacious than risperidone, haloperidol, fluphenazine, sertindole, chlorpromazine, and quetiapine (range of mean SMDs, - 0.11 to - 0.48). The difference between clozapine and olanzapine was trivial and uncertain (SMD - 0.05, 95% CI, - 0.21 to 0.11). The result of other efficacy outcomes as well as subgroup and sensitivity analyses were consistent with the primary analysis. Clozapine and olanzapine were associated with more weight gain, and clozapine was associated with more sedation events compared to many other antipsychotics. CONCLUSIONS: Clozapine remains the gold standard for patients with treatment-resistant schizophrenia. Olanzapine seems to be second-best and could be tried before switching to clozapine.

Guideline for schizophrenia: implementation status and attitude toward an upcoming living guideline.

The implementation status of clinical guidelines is, despite their important role in connecting research with practice, frequently not satisfactory. This study aims to investigate the implementation status of the current German guideline for schizophrenia. Moreover, the attitude toward a living guideline has been explored for the first time by presenting screenshots of the German schizophrenia guideline transferred to a digital living guideline format called MAGICapp. A cross-sectional online survey was performed under the participation of 17 hospitals for psychiatry and psychosomatic medicine in Southern Germany and one professional association for German neurologists and psychiatrists. 439 participants supplied sufficient data for analysis. 309 provided complete data sets. Regarding the current guideline for schizophrenia and key recommendations, a large awareness-to-adherence gap was found. Group comparisons between different professions (caregivers, medical doctors, psychologists/psychotherapists, psychosocial therapists) detected differences in the implementation status showing higher awareness and agreement with the schizophrenia guideline and its key recommendations among medical doctors compared to psychosocial therapists and caregivers. Moreover, we detected differences in the implementation status of the guideline as a whole and its key recommendations between specialist and assistant doctors. The attitude toward an upcoming living guideline was mostly positive, especially among younger healthcare professionals. Our findings confirm an awareness-to-adherence gap, not only for the current schizophrenia guideline in general but also for its key recommendations with apparent differences between professions. Overall, our results show promising positive attitudes toward the living guideline for schizophrenia among healthcare providers, suggesting that a living guideline may be a supportive tool in everyday clinical practice.

Conventional and living guideline for schizophrenia: barriers and facilitating factors in guideline implementation.

This study aims to investigate the barriers and facilitators to guideline adherence for the print format of the German schizophrenia guideline as well as for the concept of a digital living guideline for the first time. For this purpose, the schizophrenia guideline was transferred to a digital guideline format within the web-based tool MAGICapp. An online survey was performed under participation of mental healthcare professionals (medical doctors, psychologists/psychotherapists, psychosocial therapists, caregivers) in 17 hospitals for psychiatry in Southern Germany and a professional association for German neurologists and psychiatrists. 524 participants opened the survey, 439 completed the demographic questions and commenced the content-related survey and 309 provided complete data sets. Results indicate a higher occurrence of knowledge-related barriers for the living guideline. The print version is associated with more attitude-related and external barriers. Older professionals reported more attitude-related barriers to a living guideline compared to younger professionals. Differences between professions regarding barriers were found for both formats. Various barriers exist for both guideline formats and a need for facilitators was expressed across professions. Many of the mentioned obstacles and facilitators can be more easily addressed with living guidelines. However, also living guidelines face barriers. Thus, the introduction of these new formats alone cannot lead to sustainable behavior change regarding guideline adherence. Yet, living guidelines seem to be a cornerstone to improved and tailored guideline implementation as they facilitate to keep recommendations up to date and to address the need of individual professional groups.

Linkage of Young Mania Rating Scale to Clinical Global Impression Scale to Enhance Utility in Clinical Practice and Research Trials.

INTRODUCTION: The Young Mania Rating Scale (YMRS) is the gold standard to assess manic symptoms of bipolar disorder, yet the clinical meaning of scores is unknown. To clinically understand and interpret YMRS scores, we examined linkages between the total and change scores of YMRS with the Clinical Global Impression (CGI) ratings. METHODS: Individual participant data (N=2,988) from eight randomized, double-blind, placebo-controlled trials were included. Data were collected at baseline and subsequent visits. Spearman's correlation coefficients ρ were computed, and equipercentile linking was implemented. RESULTS: A YMRS score of 6 points corresponded approximately to 'borderline mentally ill,' 12 points to 'mildly ill,' 20 points to 'moderately ill,' 30 points to 'markedly ill,' 40 points to 'severely ill,' and 52 points to 'among the most extremely ill' patients on the CGI-S. A reduction of CGI-S by one point as well as 'minimally improved' on the CGI-I corresponded approximately to an absolute decrease of 4 to 8 YMRS points or a 21% to 29% reduction of YMRS baseline score whereas a reduction of CGI-S by two points and 'much improved' on the CGI-I corresponded to an absolute decrease of 10 to 15 points or a 42% to 53% reduction of YMRS baseline score. DISCUSSION: The current study findings offer clinicians meaningful cutoff values to interpret YMRS scores. Moreover, these values contribute to the definition of treatment targets, response, remission, and entry criteria in mania trials.

Effects of Early Clozapine Treatment on Remission Rates in Acute Schizophrenia (The EARLY Trial): Protocol of a Randomized-Controlled Multicentric Trial.

BACKGROUND: Quick symptomatic remission after the onset of psychotic symptoms is critical in schizophrenia treatment, determining the subsequent disease course and recovery. In this context, only every second patient with acute schizophrenia achieves symptomatic remission within three months of initiating antipsychotic treatment. The potential indication extension of clozapine-the most effective antipsychotic-to be introduced at an earlier stage (before treatment-resistance) is supported by several lines of evidence, but respective clinical trials are lacking. METHODS: Two hundred-twenty patients with acute non-treatment-resistant schizophrenia will be randomized in this double-blind, 8-week parallel-group multicentric trial to either clozapine or olanzapine. The primary endpoint is the number of patients in symptomatic remission at the end of week 8 according to international consensus criteria ('Andreasen criteria'). Secondary endpoints and other assessments comprise a comprehensive safety assessment (i. e., myocarditis screening), changes in psychopathology, global functioning, cognition, affective symptoms and quality of life, and patients' and relatives' views on treatment. DISCUSSION: This multicentre trial aims to examine whether clozapine is more effective than a highly effective second-generation antipsychotics (SGAs), olanzapine, in acute schizophrenia patients who do not meet the criteria for treatment-naïve or treatment-resistant schizophrenia. Increasing the likelihood to achieve symptomatic remission in acute schizophrenia can improve the overall outcome, reduce disease-associated burden and potentially prevent mid- and long-term disease chronicity.

Informing the development of a decision aid: Expectations and wishes from service users and psychiatrists towards a decision aid for antipsychotics in the inpatient setting.

OBJECTIVES: Decision aids (DAs) are promising tools to foster evidence-based shared decision-making between practitioners and service users. Nevertheless, it is still obscure how an evidence-based DA for people with severe mental illness, especially psychosis, should look in an inpatient treatment setting to be useful and feasible. Therefore, we conducted focus groups with psychiatrists and service users to collect and assess their expectations and wishes regarding an evidence-based DA. From these findings, we derived immediate recommendations for the future development of DAs. METHODS: We held two group interviews with service users (n = 8) and three group interviews with psychiatrists (n = 10). We used an open, large-scale topic guide. First, we presented data from a current meta-analysis on antipsychotics to the interviewees and, in a second step, asked for their expectations and wishes towards a DA that integrates these data. RESULTS: Our thematic analysis revealed six key themes addressed by the respondents: (1) general considerations on the importance and usefulness of such a DA, (2) critical comments on psychiatry and psychopharmacotherapy, (3) communicative prerequisites for the use of a DA, (4) form and content of the DA, (5) data input, data processing and output as well as (6) application of the DA and possible obstacles. CONCLUSIONS: Participants identified several important features for the development of DAs for selecting antipsychotics in inpatient psychiatric treatment. The digital format was met with the greatest approval. Especially the adaptability to different needs, users and psychopathologies and the possibility to outsource information dissemination via app seemed to be a decisive convincing argument. Further research is required to test specific features of DAs to be developed in clinical settings.

The Impact of the COVID-19 Pandemic and Associated Control Measures on the Mental Health of the General Population : A Systematic Review and Dose-Response Meta-analysis.

BACKGROUND: To what extent the COVID-19 pandemic and its containment measures influenced mental health in the general population is still unclear. PURPOSE: To assess the trajectory of mental health symptoms during the first year of the pandemic and examine dose-response relations with characteristics of the pandemic and its containment. DATA SOURCES: Relevant articles were identified from the living evidence database of the COVID-19 Open Access Project, which indexes COVID-19-related publications from MEDLINE via PubMed, Embase via Ovid, and PsycInfo. Preprint publications were not considered. STUDY SELECTION: Longitudinal studies that reported data on the general population's mental health using validated scales and that were published before 31 March 2021 were eligible. DATA EXTRACTION: An international crowd of 109 trained reviewers screened references and extracted study characteristics, participant characteristics, and symptom scores at each timepoint. Data were also included for the following country-specific variables: days since the first case of SARS-CoV-2 infection, the stringency of governmental containment measures, and the cumulative numbers of cases and deaths. DATA SYNTHESIS: In a total of 43 studies (331 628 participants), changes in symptoms of psychological distress, sleep disturbances, and mental well-being varied substantially across studies. On average, depression and anxiety symptoms worsened in the first 2 months of the pandemic (standardized mean difference at 60 days, -0.39 [95% credible interval, -0.76 to -0.03]); thereafter, the trajectories were heterogeneous. There was a linear association of worsening depression and anxiety with increasing numbers of reported cases of SARS-CoV-2 infection and increasing stringency in governmental measures. Gender, age, country, deprivation, inequalities, risk of bias, and study design did not modify these associations. LIMITATIONS: The certainty of the evidence was low because of the high risk of bias in included studies and the large amount of heterogeneity. Stringency measures and surges in cases were strongly correlated and changed over time. The observed associations should not be interpreted as causal relationships. CONCLUSION: Although an initial increase in average symptoms of depression and anxiety and an association between higher numbers of reported cases and more stringent measures were found, changes in mental health symptoms varied substantially across studies after the first 2 months of the pandemic. This suggests that different populations responded differently to the psychological stress generated by the pandemic and its containment measures. PRIMARY FUNDING SOURCE: Swiss National Science Foundation. (PROSPERO: CRD42020180049).

Scalability of the Positive and Negative Syndrome Scale in first-episode schizophrenia assessed by Rasch models.

OBJECTIVE: Historically, assessment of the psychometric properties of the Positive and Negative Syndrome Scale (PANSS) has had several foci: (1) calculation of reliability indexes, (2) extraction of subdimensions from the scale, and (3) assessment of the validity of the total score. In this study, we aimed to examine the scalability and to assess the clinical performance of the 30-item PANSS total score as well as the scalability of a shorter version (PANSS-6) of the scale. METHODS: A composite data set of 1073 patients with first-episode schizophrenia or schizophrenia spectrum disorder was subjected to Rasch analysis of PANSS data from baseline and 4-6 weeks follow-up. RESULTS: The central tests of fit of the Rasch model failed to satisfy the statistical requirements behind item homogeneity for the PANSS-30 as well as the PANSS-6 total score. For the PANSS-30, Differential Item Functioning was pronounced both for the 7-point Likert scale rating categories and when dichotomizing the rating categories. Subsequently, the Rasch structure analysis in the context of dichotomized items was used to isolate and estimate a systematic error because of item inhomogeneity, as well as a random error. The size of the combined sources of error for the PANSS-30 total score approximated 20% which is often regarded as clinical cut-off between response versus no-response. CONCLUSION: The results demonstrate the operational consequences of a lack of statistical fit of the Rasch model and suggest that the calculated measure of uncertainty needs to be considered when using the PANSS-30 total score.

Evidence-based Shared-Decision-Making Assistant (SDM-assistant) for choosing antipsychotics: protocol of a cluster-randomized trial in hospitalized patients with schizophrenia.

BACKGROUND: Choosing an antipsychotic medication is an important medical decision in the treatment of schizophrenia. This decision requires risk-benefit assessments of antipsychotics, and thus, shared-decision making between physician and patients is strongly encouraged. Although the efficacy and side-effect profiles of antipsychotics are well-established, there is no clear framework for the communication of the evidence between physicians and patients. For this reason, we developed an evidence-based shared-decision making assistant (SDM-assistant) that presents high-quality evidence from network meta-analysis on the efficacy and side-effect profile of antipsychotics and can be used as a basis for shared-decision making between physicians and patients when selecting antipsychotic medications. METHODS: The planned matched-pair cluster-randomised trial will be conducted in acute psychiatric wards (n = 14 wards planned) and will include adult inpatients with schizophrenia or schizophrenia-like disorders (N = 252 participants planned). On the intervention wards, patients and their treating physicians will use the SDM-assistant, whenever a decision on choosing an antipsychotic is warranted. On the control wards, antipsychotics will be chosen according to treatment-as-usual. The primary outcome will be patients' perceived involvement in the decision-making during the inpatient stay as measured with the SDM-Q-9. We will also assess therapeutic alliance, symptom severity, side-effects, treatment satisfaction, adherence, quality of life, functioning and rehospitalizations as secondary outcomes. Outcomes could be analysed at discharge and at follow-up after three months from discharge. The analysis will be conducted per-protocol using mixed-effects linear regression models for continuous outcomes and logistic regression models using generalised estimating equations for dichotomous outcomes. Barriers and facilitators in the implementation of the intervention will also be examined using a qualitative content analysis. DISCUSSION: This is the first trial to examine a decision assistant specifically designed to facilitate shared-decision making for choosing antipsychotic medications, i.e., SDM-assistant, in acutely ill inpatients with schizophrenia. If the intervention can be successfully implemented, SDM-assistant could advance evidence-based medicine in schizophrenia by putting medical evidence on antipsychotics into the context of patient preferences and values. This could subsequently lead to a higher involvement of the patients in decision-making and better therapy decisions. TRIAL REGISTRATION: German Clinical Trials Register (ID: DRKS00027316 , registration date 26.01.2022).

Pharmacological Treatment of Early-Onset Schizophrenia: A Critical Review, Evidence-Based Clinical Guidance and Unmet Needs.

Early-onset schizophrenia (EOS) - onset before age 18 - is linked with great disease burden and disability. Decision-making for EOS pharmacological treatment may be challenging due to conflicting information from evidence and guidelines and unidentified care needs may remain unmet.We searched for systematic reviews, meta-analyses and umbrella reviews of EOS pharmacological treatment published in PubMed over the past 10 years and selected five clinical guidelines from Europe, North-America and Australia. Based on predefined outcomes, we critically compared the evidence supporting EOS-approved drugs in Europe and/or North-America with guidelines recommendations. We also evaluated the coverage of these outcomes to identify unmet needs.One systematic review, nine meta-analyses and two umbrella reviews (k=203 trials, N=81,289 participants, including duplicated samples across selected articles) were retrieved. Evidence supported the efficacy of aripiprazole, clozapine, haloperidol, lurasidone, molindone, olanzapine, quetiapine, risperidone and paliperidone in EOS, all of which obtained approval for EOS either in Europe and/or in North-America. Cognition, functioning and quality of life, suicidal behaviour and mortality and services utilisation and cost-effectiveness were poorly covered/uncovered.Among the antipsychotics approved for EOS, aripiprazole, lurasidone, molindone, risperidone, paliperidone and quetiapine emerged as efficacious and comparably safe options. Olanzapine is known for a high risk of weight gain and haloperidol for extrapyramidal side-effects. Treatment-resistant patients should be offered clozapine. Future long-term trials looking at cognition, functioning, quality of life, suicidal behaviour, mortality, services utilisation and cost-effectiveness are warranted. Closer multi-agency collaboration may bridge the gap between evidence, guidelines and approved drugs.