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.

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.

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.

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.

Relapse in clinically stable adult patients with schizophrenia or schizoaffective disorder: evidence-based criteria derived by equipercentile linking and diagnostic test accuracy meta-analysis.

BACKGROUND: There is no consensus on defining relapse in schizophrenia, and scale-derived criteria with unclear clinical relevance are widely used. We aimed to develop an evidence-based scale-derived set of criteria to define relapse in patients with schizophrenia or schizoaffective disorder. METHODS: We searched the Yale University Open Data Access (YODA) for randomised controlled trials (RCTs) in clinically stable adults with schizophrenia or schizoaffective disorder, and obtained individual participant data on Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Severity (CGI-S), Personal and Social Performance (PSP), and Social and Occupational Functioning Assessment Scale (SOFAS). Our main outcomes were PANSS-derived criteria based on worsening in PANSS total score. We examined their relevance using equipercentile linking with CGI-S and functioning scales, and their test-performance in defining relapse with diagnostic test accuracy meta-analysis against CGI-S worsening (≥1-point increase together with a score ≥4 points) and psychiatric hospitalisation. FINDINGS: Based on data from seven RCTs (2354 participants; 1348 men [57·3%] and 1006 women [42·7%], mean age of 39·5 years [SD 12·0, range 17-89]; 303 Asian [12.9%], 255 Black [10.8%], 1665 White [70.7%], and other or unspecified 131 [5.6%]), an increase of 12 points or more in PANSS total (range 30-210 points) corresponded to clinically important deterioration in global severity of illness (≥1 point increase in CGI-S, range 1-7) and functioning (≥10 points decline in PSP or SOFAS, range 1-100). The interpretation of percentage changes varied importantly across different baseline scores. An increase of 12 points or more in PANSS total had good sensitivity and specificity using CGI-S as reference standard (sensitivity 82·1% [95% CI 77·1-86·4], specificity 86·9% [82·9-90·3]), as well as good sensitivity but lower specificity compared to hospitalisation (sensitivity 81·7% [74·1-87·7], specificity 69·2% [60·5-76·9]). Requiring either an increase in PANSS total or in specific items for positive and disorganization symptoms further improved test-performance. Cutoffs for situations where high sensitivity or specificity is needed are presented. INTERPRETATION: An increase of either 12 points or more in the PANSS total score, or worsening of specific positive and disorganisation symptom items could be a reasonable evidence-based definition of relapse in schizophrenia, potentially linking symptoms used to define remission and relapse. Percentage changes should not be used to define relapse because their interpretation depends on baseline scores. FUNDING: German Research Foundation (grant number: 428509362).

Pharmacological treatments in panic disorder in adults: a network meta-analysis.

BACKGROUND: A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as racing heart, chest pain, sweating, shaking, dizziness, flushing, churning stomach, faintness and breathlessness. Other recognised panic attack symptoms involve fearful cognitions, such as the fear of collapse, going mad or dying, and derealisation (the sensation that the world is unreal). Panic disorder is common in the general population with a prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions, including antidepressants and benzodiazepines. OBJECTIVES: To compare, via network meta-analysis, individual drugs (antidepressants and benzodiazepines) or placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia. To rank individual active drugs for panic disorder (antidepressants, benzodiazepines and placebo) according to their effectiveness and acceptability. To rank drug classes for panic disorder (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines (BDZs) and placebo) according to their effectiveness and acceptability. To explore heterogeneity and inconsistency between direct and indirect evidence in a network meta-analysis. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people aged 18 years or older of either sex and any ethnicity with clinically diagnosed panic disorder, with or without agoraphobia. We included trials that compared the effectiveness of antidepressants and benzodiazepines with each other or with a placebo. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles/abstracts and full texts, extracted data and assessed risk of bias. We analysed dichotomous data and continuous data as risk ratios (RRs), mean differences (MD) or standardised mean differences (SMD): response to treatment (i.e. substantial improvement from baseline as defined by the original investigators: dichotomous outcome), total number of dropouts due to any reason (as a proxy measure of treatment acceptability: dichotomous outcome), remission (i.e. satisfactory end state as defined by global judgement of the original investigators: dichotomous outcome), panic symptom scales and global judgement (continuous outcome), frequency of panic attacks (as recorded, for example, by a panic diary; continuous outcome), agoraphobia (dichotomous outcome). We assessed the certainty of evidence using threshold analyses. MAIN RESULTS: Overall, we included 70 trials in this review. Sample sizes ranged between 5 and 445 participants in each arm, and the total sample size per study ranged from 10 to 1168. Thirty-five studies included sample sizes of over 100 participants. There is evidence from 48 RCTs (N = 10,118) that most medications are more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect, with diazepam, alprazolam and clonazepam ranking as the most effective. We found heterogeneity in most of the comparisons, but our threshold analyses suggest that this is unlikely to impact the findings of the network meta-analysis. Results from 64 RCTs (N = 12,310) suggest that most medications are associated with either a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate compared to placebo and were ranked as the most tolerated of all the medications examined. Thirty-two RCTs (N = 8569) were included in the remission outcome. Most medications were more effective than placebo, namely desipramine, fluoxetine, clonazepam, diazepam, fluvoxamine, imipramine, venlafaxine and paroxetine, and their effects were clinically meaningful. Amongst these medications, desipramine and alprazolam were ranked highest. Thirty-five RCTs (N = 8826) are included in the continuous outcome reduction in panic scale scores. Brofaromine, clonazepam and reboxetine had the strongest reductions in panic symptoms compared to placebo, but results were based on either one trial or very small trials. Forty-one RCTs (N = 7853) are included in the frequency of panic attack outcome. Only clonazepam and alprazolam showed a strong reduction in the frequency of panic attacks compared to placebo, and were ranked highest. Twenty-six RCTs (N = 7044) provided data for agoraphobia. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo. For the pooled intervention classes, we examined the two primary outcomes (response and dropout). The classes of medication were: SSRIs, SNRIs, TCAs, MAOIs and BDZs. For the response outcome, all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by BDZs and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked lowest. When we compared classes of medication with each other for the response outcome, we found no difference between classes. Comparisons between MAOIs and TCAs and between BDZs and TCAs also suggested no differences between these medications, but the results were imprecise. For the dropout outcome, BDZs were the only class associated with a lower dropout compared to placebo and were ranked first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo. In terms of ranking, TCAs are on average second to BDZs, followed by SNRIs, then by SSRIs and lastly by MAOIs. BDZs were associated with lower dropout rates compared to SSRIs, SNRIs and TCAs. The quality of the studies comparing antidepressants with placebo was moderate, while the quality of the studies comparing BDZs with placebo and antidepressants was low. AUTHORS' CONCLUSIONS: In terms of efficacy, SSRIs, SNRIs (venlafaxine), TCAs, MAOIs and BDZs may be effective, with little difference between classes. However, it is important to note that the reliability of these findings may be limited due to the overall low quality of the studies, with all having unclear or high risk of bias across multiple domains. Within classes, some differences emerged. For example, amongst the SSRIs paroxetine and fluoxetine seem to have stronger evidence of efficacy than sertraline. Benzodiazepines appear to have a small but significant advantage in terms of tolerability (incidence of dropouts) over other classes.

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.

Antipsychotic drugs and their effects on cognitive function: protocol for a systematic review, pairwise, and network meta-analysis.

BACKGROUND: There is evidence that antipsychotic drugs differ in their effect on the cognitive symptoms of schizophrenia. So far, there is no comprehensive systematic review available that would enable providers and patients to make informed choices regarding this important aspect of treatment. With a large number of substances available, conventional pairwise meta-analyses will not be sufficient to inform this choice. To fill this gap, we will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomized controlled trials (RCTs) to rank antipsychotics according to their effect on cognitive functioning. METHODS: In our NMA, we will include RCTs in patients with schizophrenia or schizophrenia-like psychoses comparing one antipsychotic agent with another antipsychotic agent or placebo that measures cognitive function. We will include studies on patients of every age group, in any phase of illness (e.g., acute or stable, first episode or chronic schizophrenia, in- or outpatients) with an intervention time of at least 3 weeks. The primary outcome will be the composite score of cognitive functioning, preferentially measured with the test battery developed by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. The secondary outcomes include the seven cognitive domains that the composite score is composed of, as well as functioning and quality of life. Study selection and data extraction will be conducted by at least two independent reviewers. We will use the Cochrane Risk of Bias tool 2 to determine the risk of bias in studies, and we will evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). We will perform NMA using R (package netmeta). We will conduct subgroup and sensitivity analyses to explore the heterogeneity and assess the robustness of our findings. DISCUSSION: This systematic review and network meta-analysis aims to inform evidence-based antipsychotic treatment choice for cognitive deficits in schizophrenia patients by analyzing existing RCTs on this subject. The results have the potential to support patients' and physicians' decision-making processes based on the latest available evidence. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022312483.

Efficacy of clozapine compared with other second-generation antipsychotic drugs in patients with treatment-resistant schizophrenia: protocol for a systematic review and individual patient data meta-analysis of randomised controlled trials.

INTRODUCTION: Guidelines recommend clozapine for treatment-resistant schizophrenia. However, meta-analysis of aggregate data (AD) did not demonstrate higher efficacy of clozapine compared with other second-generation antipsychotics but found substantial heterogeneity between trials and variation between participants in treatment effects. Therefore, we will conduct an individual participant data (IPD) meta-analysis to estimate the efficacy of clozapine compared with other second-generation antipsychotics while accounting for potentially important effect modifiers. METHODS AND ANALYSIS: In a systematic review, two reviewers will independently search Cochrane Schizophrenia Group's trial register (without restrictions in date, language or state of publication) and related reviews. We will include randomised controlled trials (RCTs) in participants with treatment-resistant schizophrenia comparing clozapine with other second-generation antipsychotics for at least 6 weeks. We will apply no restrictions in age, gender, origin, ethnicity or setting, but exclude open-label studies, studies from China, experimental studies and phase II of cross-over trials. IPD will be requested from trial authors and cross-check against published results. AD will be extracted in duplicate. Risk of bias will be assessed using Cochrane's Risk of Bias 2 tool.The primary outcome will be overall symptoms of schizophrenia.We will synthesise results using random-effects meta-analysis and meta-regression methods in a 3-level Bayesian model. The model combines IPD with AD when IPD is not available for all studies, and include participant, intervention and study design characteristics as potential effect modifiers. The effect size measures will be mean difference (or standardised mean difference when different scales were used). Confidence in the evidence will be assessed using GRADE. ETHICS AND DISSEMINATION: This project has been approved by the ethics commission of the Technical University of Munich (#612/21 S-NP). The results will be published open-access in a peer-review journal and a plain-language version of the results will be disseminated.If we need to amend this protocol, we will describe the change and give the rationale in a specific section in the resulting publication 'Changes with respect to the protocol'. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (#CRD42021254986).

Metabolic side effects in persons with schizophrenia during mid- to long-term treatment with antipsychotics: a network meta-analysis of randomized controlled trials.

Metabolic side effects of antipsychotic drugs can have serious health consequences and may increase mortality. Although persons with schizophrenia often take these drugs for a long time, their mid- to long-term metabolic effects have been studied little so far. This study aimed to evaluate the mid- to long-term metabolic side effects of 31 antipsychotics in persons with schizophrenia by applying a random-effects Bayesian network meta-analysis. We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (up to April 27, 2020) and PubMed (up to June 14, 2021). We included published and unpublished, open and blinded randomized controlled trials with a study duration >13 weeks which compared any antipsychotic in any form of administration with another antipsychotic or with placebo in participants diagnosed with schizophrenia. The primary outcome was weight gain measured in kilograms. Secondary outcomes included "number of participants with weight gain", fasting glucose, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. We identified 137 eligible trials (with 35,007 participants) on 31 antipsychotics, with a median follow-up of 45 weeks. Chlorpromazine produced the most weight gain (mean difference to placebo: 5.13 kg, 95% credible interval, CrI: 1.98 to 8.30), followed by clozapine (4.21 kg, 95% CrI: 3.03 to 5.42), olanzapine (3.82 kg, 95% CrI: 3.15 to 4.50), and zotepine (3.87 kg, 95% CrI: 2.14 to 5.58). The findings did not substantially change in sensitivity and network meta-regression analyses, although enriched design, drug company sponsorship, and the use of observed case instead of intention-to-treat data modified the mean difference in weight gain to some extent. Antipsychotics with more weight gain were often also among the drugs with worse outcome in fasting glucose and lipid parameters. The confidence in the evidence ranged from low to moderate. In conclusion, antipsychotic drugs differ in their propensity to induce metabolic side effects in mid- to long-term treatment. Given that schizophrenia is often a chronic disorder, these findings should be given more consideration than short-term data in drug choice.

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.

Sex differences in symptomatology in people with schizophrenia and other psychotic disorders: protocol for a systematic review and pairwise meta-analysis of observational studies.

SUMMARY: Sex differences in symptomatology in people with psychosis have been studied extensively in recent decades. Although studies have pointed to such differences, to date there is no review that has performed a systematic search and quantitative synthesis. In this paper, we describe the protocol for a pairwise meta-analysis comparing a range of symptom outcome measures between men and women diagnosed with a psychotic spectrum disorder at different stages of the disorder (PROSPERO registration number CRD42021264942). In August 2021 we conducted systematic searches of PsychInfo, PubMed, Web of Science, Scopus and Dialnet to identify observational studies that report data on symptoms for males and females separately. Two independent reviewers will conduct literature searches, select studies, extract data, assess the risk of bias and assess outcome quality. To assess the effect size of all outcome measures, we will conduct pairwise meta-analysis using random-effects models. The quality of studies will be evaluated using a National Heart, Lung and Blood Institute's quality assessment tool and the confidence in the results will be evaluated using the GRADE tool. Meta-regression and sensitivity analyses will be conducted to assess the robustness of the findings. No ethical problems are foreseen. Results from this study will be published in peer-reviewed journals and presented at relevant conferences.

Antipsychotic dose reduction compared to dose continuation for people with schizophrenia.

BACKGROUND: Antipsychotic drugs are the mainstay treatment for schizophrenia, yet they are associated with diverse and potentially dose-related side effects which can reduce quality of life. For this reason, the lowest possible doses of antipsychotics are generally recommended, but higher doses are often used in clinical practice. It is still unclear if and how antipsychotic doses could be reduced safely in order to minimise the adverse-effect burden without increasing the risk of relapse. OBJECTIVES: To assess the efficacy and safety of reducing antipsychotic dose compared to continuing the current dose for people with schizophrenia. SEARCH METHODS: We conducted a systematic search on 10 February 2021 at 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. We also inspected the reference lists of included studies and previous reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing any dose reduction against continuation in people with schizophrenia or related disorders who were stabilised on their current antipsychotic treatment.  DATA COLLECTION AND ANALYSIS: At least two review authors independently screened relevant records for inclusion, extracted data from eligible studies, and assessed the risk of bias using RoB 2. We contacted study authors for missing data and additional information. Our primary outcomes were clinically important change in quality of life,  rehospitalisations and dropouts due to adverse effects; key secondary outcomes were clinically important change in functioning, relapse, dropouts for any reason, and at least one adverse effect. We also examined scales measuring symptoms, quality of life, and functioning as well as a comprehensive list of specific adverse effects. We pooled outcomes at the endpoint preferably closest to one year. We evaluated the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 25 RCTs, of which 22 studies provided data with 2635 participants (average age 38.4 years old). The median study sample size was 60 participants (ranging from 18 to 466 participants) and length was 37 weeks (ranging from 12 weeks to 2 years). There were variations in the dose reduction strategies in terms of speed of reduction (i.e. gradual in about half of the studies (within 2 to 16 weeks) and abrupt in the other half), and in terms of degree of reduction (i.e. median planned reduction of 66% of the dose up to complete withdrawal in three studies). We assessed risk of bias across outcomes predominantly as some concerns or high risk.  No study reported data on the number of participants with a clinically important change in quality of life or functioning, and only eight studies reported continuous data on scales measuring quality of life or functioning. There was no difference between dose reduction and continuation on scales measuring quality of life (standardised mean difference (SMD) -0.01, 95% confidence interval (CI) -0.17 to 0.15, 6 RCTs, n = 719, I2 = 0%, moderate certainty evidence) and scales measuring functioning (SMD 0.03, 95% CI -0.10 to 0.17, 6 RCTs, n = 966, I2 = 0%, high certainty evidence). Dose reduction in comparison to continuation may increase the risk of rehospitalisation based on data from eight studies with estimable effect sizes; however, the 95% CI does not exclude the possibility of no difference (risk ratio (RR) 1.53, 95% CI 0.84 to 2.81, 8 RCTs, n = 1413, I2 = 59% (moderate heterogeneity), very low certainty evidence). Similarly, dose reduction increased the risk of relapse based on data from 20 studies (RR 2.16, 95% CI 1.52 to 3.06, 20 RCTs, n = 2481, I2 = 70% (substantial heterogeneity), low certainty evidence).   More participants in the dose reduction group in comparison to the continuation group left the study early due to adverse effects (RR 2.20, 95% CI 1.39 to 3.49, 6 RCTs with estimable effect sizes, n = 1079, I2 = 0%, moderate certainty evidence) and for any reason (RR 1.38, 95% CI 1.05 to 1.81, 12 RCTs, n = 1551, I2 = 48% (moderate heterogeneity), moderate certainty evidence). Lastly, there was no difference between the dose reduction and continuation groups in the number of participants with at least one adverse effect based on data from four studies with estimable effect sizes (RR 1.03, 95% CI 0.94 to 1.12, 5 RCTs, n = 998 (4 RCTs, n = 980 with estimable effect sizes), I2 = 0%, moderate certainty evidence).  AUTHORS' CONCLUSIONS: This review synthesised the latest evidence on the reduction of antipsychotic doses for stable individuals with schizophrenia. There was no difference between dose reduction and continuation groups in quality of life, functioning, and number of participants with at least one adverse effect. However, there was a higher risk for relapse and dropouts, and potentially for rehospitalisations, with dose reduction. Of note, the majority of the trials focused on relapse prevention rather potential beneficial outcomes on quality of life, functioning, and adverse effects, and in some studies there was rapid and substantial reduction of doses. Further well-designed RCTs are therefore needed to provide more definitive answers.

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).

Antipsychotic polypharmacy reduction versus polypharmacy continuation for people with schizophrenia.

BACKGROUND: In clinical practice, different antipsychotics can be combined in the treatment of people with schizophrenia (polypharmacy). This strategy can aim at increasing efficacy, but might also increase the adverse effects due to drug-drug interactions. Reducing polypharmacy by withdrawing one or more antipsychotics may reduce this problem, but must be done carefully, in order to maintain efficacy. OBJECTIVES: To examine the effects and safety of reducing antipsychotic polypharmacy compared to maintaining people with schizophrenia on the same number of antipsychotics. SEARCH METHODS: On 10 February 2021, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials, which is based on CENTRAL, CINAHL, ClinicalTrials.Gov, Embase, ISRCTN, MEDLINE, PsycINFO, PubMed and WHO ICTRP. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared reduction in the number of antipsychotics to continuation of the current number of antipsychotics. We included adults with schizophrenia or related disorders who were receiving more than one antipsychotic and were stabilised on their current treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all the identified references for inclusion, and all the full papers. We contacted study authors if we needed any further information. Two review authors independently extracted the data, assessed the risk of bias using RoB 2 and the certainty of the evidence using the GRADE approach. The primary outcomes were: quality of life assessed as number of participants with clinically important change in quality of life; service use assessed as number of participants readmitted to hospital and adverse effects assessed with number of participants leaving the study early due to adverse effects. MAIN RESULTS: We included five RCTs with 319 participants. Study duration ranged from three months to one year. All studies compared polypharmacy continuation with two antipsychotics to polypharmacy reduction to one antipsychotic.  We assessed the risk of bias of results as being of some concern or at high risk of bias. A lower number of participants left the study early due to any reason in the polypharmacy continuation group (risk ratio (RR) 0.44, 95% confidence interval (CI) 0.29 to 0.68; I2 = 0%; 5 RCTs, n = 319; low-certainty evidence), and a lower number of participants left the study early due to inefficacy (RR 0.21, 95% CI 0.07 to 0.65; I2 = 0%; 3 RCTs, n = 201).  Polypharmacy continuation resulted in more severe negative symptoms (MD 3.30, 95% CI 1.51 to 5.09; 1 RCT, n = 35). There was no clear difference between polypharmacy reduction and polypharmacy continuation on readmission to hospital, leaving the study early due to adverse effects, functioning, global state, general mental state and positive symptoms, number of participants with at least one adverse effect, weight gain and other specific adverse effects, mortality and cognition. We assessed the certainty of the evidence as very low or low across measured outcomes. No studies reported quality of life, days in hospital, relapse, depressive symptoms, behaviour and satisfaction with care. Due to lack of data, it was not possible to perform some planned sensitivity analyses, including one controlling for increasing the dose of the remaining antipsychotic. As a result, we do not know if the observed results might be influenced by adjustment of dose of remaining antipsychotic compound. AUTHORS' CONCLUSIONS: This review summarises the latest evidence on polypharmacy continuation compared with polypharmacy reduction. Our results show that polypharmacy continuation might be associated with a lower number of participants leaving the study early, especially due to  inefficacy. However, the evidence is of low and very low certainty and the data analyses based on few study only, so that it is not possible to draw strong conclusions based on the results of the present review. Further high-quality RCTs are needed to investigate this important topic.

Pharmacological and dietary-supplement treatments for autism spectrum disorder: a systematic review and network meta-analysis.

BACKGROUND: There is still no approved medication for the core symptoms of autism spectrum disorder (ASD). This network meta-analysis investigated pharmacological and dietary-supplement treatments for ASD. METHODS: We searched for randomized-controlled-trials (RCTs) with a minimum duration of seven days in ClinicalTrials.gov, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (from inception up to July 8, 2018), CENTRAL and PubMed (up to November 3, 2021). The co-primary outcomes were core symptoms (social-communication difficulties-SCD, repetitive behaviors-RB, overall core symptoms-OCS) measured by validated scales and standardized-mean-differences (SMDs). Associated symptoms, e.g., irritability/aggression and attention-deficit/hyperactivity disorder (ADHD) symptoms, dropouts and important side-effects, were investigated as secondary outcomes. Studies in children/adolescents and adults were analyzed separately in random-effects pairwise and network meta-analyses. RESULTS: We analyzed data for 41 drugs and 17 dietary-supplements, from 125 RCTs (n = 7450 participants) in children/adolescents and 18 RCTs (n = 1104) in adults. The following medications could improve at least one core symptom domain in comparison with placebo: aripiprazole (k = 6 studies in analysis, SCD: SMD = 0.27 95% CI [0.09, 0.44], RB: 0.48 [0.26, 0.70]), atomoxetine (k = 3, RB:0.49 [0.18, 0.80]), bumetanide (k = 4, RB: 0.35 [0.09, 0.62], OCS: 0.61 [0.31, 0.91]), and risperidone (k = 4, SCM: 0.31 [0.06, 0.55], RB: 0.60 [0.29, 0.90]; k = 3, OCS: 1.18 [0.75, 1.61]) in children/adolescents; fluoxetine (k = 1, RB: 1.20 [0.45, 1.96]), fluvoxamine (k = 1, RB: 1.04 [0.27, 1.81]), oxytocin (k = 6, RB:0.41 [0.16, 0.66]) and risperidone (k = 1, RB: 0.97 [0.21,1.74]) in adults. There were some indications of improvement by carnosine, haloperidol, folinic acid, guanfacine, omega-3-fatty-acids, probiotics, sulforaphane, tideglusib and valproate, yet imprecise and not robust. Confidence in these estimates was very low or low, except moderate for oxytocin. Medications differed substantially in improving associated symptoms, and in their side-effect profiles. LIMITATIONS: Most of the studies were inadequately powered (sample sizes of 20-80 participants), with short duration (8-13 weeks), and about a third focused on associated symptoms. Networks were mainly star-shaped, and there were indications of reporting bias. There was no optimal rating scale measuring change in core symptoms. CONCLUSIONS: Some medications could improve core symptoms, although this could be likely secondary to the improvement of associated symptoms. Evidence on their efficacy and safety is preliminary; therefore, routine prescription of medications for the core symptoms cannot be recommended. Trial registration PROSPERO-ID CRD42019125317.