BACKGROUND:Antipsychotic drugs are the established treatment for acute schizophrenia but differ in receptor-binding profiles. In 2024, a new-in-class muscarinic receptor agonist (xanomeline-trospium) was licenced, acting upstream of antidopaminergic agents, and providing hope to decrease the adverse effects burden of antipsychotics. We aimed to compare the efficacy and tolerability of antipsychotics by performing network meta-analysis of randomised controlled trials (RCTs). METHODS:This systematic review (PROSPERO, CRD42022380708) included blinded and open RCTs investigating antipsychotic drugs in participants of any age with acute psychotic symptoms of schizophrenia over 3 weeks to 3 months. Included antipsychotics comprised 23 primarily dopamine-receptor blocking medications and the muscarinic receptor agonist xanomeline-trospium in different applications. We searched Cochrane Schizophrenia group's register, previous reviews, and five Chinese databases for trials published from database inception until July 26, 2024 and contacted authors to assess trials' methodological quality; only trials with appropriate randomisation indicated were included. The primary outcome was rating scale-measured overall symptoms of schizophrenia (efficacy) analysed with random-effects frequentist network meta-analysis. Secondary outcomes comprised 32 further efficacy and tolerability outcomes. The confidence in the estimates was assessed using the Confidence in Network Meta-Analysis approach. FINDINGS:After screening 18 859 references and contacting authors of 5428 trials, we included 438 RCTs. Of those, 388 RCTs with 78 193 participants (28 448 women and 49 745 men) provided usable data for at least one outcome. 5117 Chinese trials were identified but most were excluded because authors did not reply or reported serious methodological concerns. 256 double-blind studies with 58 948 participants provided usable data for the primary outcome. All antipsychotics reduced symptoms more than placebo with standardised mean differences ranging from -0·90 (95% CI -1·03 to -0·77) to -0·23 (-0·39 to -0·06). Particularly clozapine, as well as amisulpride, olanzapine, and risperidone were more efficacious than at least three other antipsychotics (confidence in estimates were low-to-moderate). Adverse effects varied across medications. INTERPRETATION:This network meta-analysis provides evidence for small-to-medium clinically relevant differences between antipsychotics in efficacy; this finding warrants stronger and more specific emphasis in clinical guidelines. Nonetheless, important differences in tolerability need to be considered for individualised drug choice, with partial dopamine agonists having overall better tolerability and xanomeline-trospium lacking adverse effects of dopamine-blocking agents but resulting in cholinergic and anticholinergic adverse events. Future research should directly compare xanomeline-trospium with other antipsychotics to confirm its efficacy; modern trials using clozapine early in schizophrenia are needed to establish whether it improves outcomes and prevents chronification. FUNDING:German Research Foundation, German Ministry of Research, Technology and Space, and National Natural Science Foundation of China.

Abstract Antipsychotic dose reduction and discontinuation are increasingly discussed in the management of psychotic disorders, yet clinical decisions remain challenging and evidence on lived experiences is fragmented. This systematic review and meta-synthesis aimed to synthesize qualitative evidence on subjective experiences of antipsychotic dose reduction and discontinuation among people with psychotic disorders, clinicians, and caregivers. A systematic search was performed on PubMed, Scopus, and PsycINFO. Peer-reviewed qualitative studies exploring subjective experiences with antipsychotic dose reduction and/or discontinuation in subjects with affective and non-affective psychotic disorders were included. Findings were integrated using thematic synthesis. A total of 13 studies were included. Eight studies focused on patients (N = 431), three on clinicians (N = 86), and two on caregivers (N = 26). From subjects’ lived experiences, adverse effects were frequently reported as a driver for considering dose reduction, while concerns about relapse and the effort required to maintain stability contributed to ambivalent or cautious attitudes. Caregivers often reported unfavorable views, expressing fear of symptom recurrence, emotional distress, and risks to relational safety. Clinicians highlighted limited evidence and insufficient resources to support safe, long-term tapering and described uncertainty intensified by negative prior experiences and concerns about professional accountability in the event of relapse. Antipsychotic dose reduction and discontinuation are experienced as complex, preference-sensitive processes shaped by competing priorities and high perceived risks. The findings support the need for triadic shared decision-making that includes caregivers and for the development of structured, case-specific tapering protocols supported by adequate clinical resources and long-term monitoring.

Background: The number of randomized-controlled trials (RCTs) originating from China is considerable. However, linguistic barriers and concerns regarding methodological rigor impede their inclusion in meta-analyses. Methods: We searched 5 major Chinese databases for RCTs investigating antipsychotics in schizophrenia and contacted study authors to request information about reliability and methods of randomization and blinding using a semi-structured telephone interview and a specifically-designed online questionnaire in Chinese. Results: Among 11,306 articles, 5117 purported RCTs were eligible. After 1232 telephone calls, 698 emails and 7126 letters, 378 authors responded on 349 studies (response rate: 6.9% of 5117 studies). Of those 29 (8.3%) employed randomization procedures and 35 (10.0%) blinding methods with low risk of bias. 125 (35.8%) used suboptimal randomization methods with high risk of bias. In 83 (23.8%) claimed RCTs clinicians chose the antipsychotic based on patients' symptoms and side effects indicating an observational instead of a randomized study design. For 13 (3.7%) modification of some specific outcome data was revealed and for 15 (4.3%) authors indicated that the study results are not reliable. For 57 (16.3%), authors answered "Not sure" to the direct question whether the trial was conducted in reality. There was no clear improvement of quality from 1998 to 2024. Conclusion: The main limitations of the study are the low response rate, which reduces representativeness, and that many authors answered they cannot recall which introduces uncertainty. From the answers received, it appears that the methodological quality of many RCTs on antipsychotics in schizophrenia published in Chinese language journals is limited despite initiatives of Chinese research institutions. Therefore, it is advisable that systematic reviewers seek direct confirmation of trial methodology before including Chinese studies in evidence synthesis and perform sensitivity analyses. Moreover, further training for Chinese clinical researchers and stricter quality assurance mechanisms by research institutions and publishers appear warranted.

QuestionWhat is the efficacy of psychological and psychosocial interventions for individuals diagnosed with schizophrenia and comorbidity with substance use disorders?FindingsThis systematic review and meta-analysis included 35 studies (4136 participants), with data available from 29 trials involving 3831 participants covered in pairwise meta-analysis. Psychological and psychosocial interventions offered a very small effect on reducing patients' overall symptoms, and no difference was found between intervention and control groups in reduction of all types of substance use intake or when separately analyzed, whereas nicotine use showed a modest improvement.MeaningCurrent psychological and psychological interventions provide limited benefit for symptom reduction and were largely ineffective in decreasing substance use, except for a slight positive effect on nicotine use, indicating that more effective treatment strategies are urgently needed. ImportanceSubstance use disorder (SUD) is commonly found in individuals with schizophrenia, with a high co-occurrence rate of approximately 41.7%. Despite this high prevalence, people with both schizophrenia and SUD are frequently excluded from clinical trials and systematic reviews; this special group is particularly challenging to treat and imposes a significant economic burden on health care systems.ObjectiveTo evaluate the efficacy, acceptability, and tolerability of psychological and psychosocial interventions in patients with schizophrenia and co-occurring SUD.Data SourcesThe Cochrane Schizophrenia Group registry was searched up to January 13, 2025. Data analysis was performed from March to April 2025.Study SelectionRandomized clinical trials (RCTs) examining psychological and psychosocial interventions compared with control groups in adults with schizophrenia and concomitant SUD were identified. No restrictions were applied regarding the type of substance used, including alcohol, cannabis, nicotine, and stimulants, such as amphetamines.Data Extraction and SynthesisA systematic review and random-effect pairwise meta-analyses were conducted to estimate standardized mean differences (SMD) with 95% confidence intervals and were reported following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. Confidence in the estimate was assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.Main Outcomes and MeasuresThe primary outcomes were overall symptoms and substance use reduction measured by validated scales at posttreatment.ResultsA total of 35 RCTs were included (4136 participants), with 29 trials involving 3831 participants contributing to pairwise meta-analyses comparing psychological and psychosocial interventions with control conditions. Among the 3748 participants with reported sex, 951 (25.4%) were female, and mean (range) age was 37.2 (20.6-57.5) years. A very small effect favoring the intervention group was observed in reducing overall symptoms (SMD, -0.11; 95% CI, -0.27 to 0.05; 13 trials; low confidence in the estimate), mainly driven by nicotine studies. No difference was found between intervention and control groups in reducing all types of substance use (SMD, -0.01; 95% CI, -0.21 to 0.18; 8 trials; moderate confidence). When considered separately, alcohol, cannabis, amphetamines, and other stimulants showed similar no-effect results, while nicotine use indicated a small effect.Conclusion and RelevanceThe findings of this systematic review and meta-analysis suggest that current psychological and psychosocial interventions provide limited benefit in reducing symptoms and no effect in reducing substance use in individuals with schizophrenia and SUD compared to control conditions, with the exception of nicotine use, highlighting the urgent need to develop more effective treatment strategies. This systematic review and meta-analysis evaluates the efficacy, acceptability, and tolerability of psychological and psychosocial interventions in patients with schizophrenia and co-occurring substance use disorder.

Importance Auditory hallucinations (AHs) are a hallmark characteristic of schizophrenia spectrum disorders (SSDs) and are often associated with severe distress. Previous research lacks comprehensive evidence on the overall efficacy of approaches targeting AHs in SSDs. Objective To evaluate the efficacy and acceptability of all available psychological and psychosocial interventions targeting AHs in SSDs. Data Sources Embase, MEDLINE, PsycArticles, PsycInfo, PSYNDEX, and the Cochrane library were searched for eligible studies published until August 18, 2025. Study Selection Randomized clinical trials that analyzed psychological interventions targeting AHs compared to controls in adults with SSDs. Data Extraction and Synthesis This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Two independent reviewers screened publications, extracted data, and assessed risk of bias. A random-effects meta-analysis was performed (Hedges g) . Main Outcomes and Measures The main outcomes were between-group differences in AHs and clinical characteristics at posttreatment and follow-up, measured with validated rating scales. Additional number-needed-to-treat (NNT) analyses and rating of evidence certainty (GRADE approach) were conducted. Results A total of 23 studies with 2016 participants were included, with 1081 in the intervention groups across 5 different therapeutic approaches and 935 in the control groups. At posttreatment, targeted interventions reduced the severity of AHs compared with control groups (standardized mean difference [SMD], −0.18; 95% CI, −0.31 to −0.05; P = .007; NNT, 16; GRADE, low evidence). This effect was also observed for numerous secondary outcomes, comprising frequency and distress of AHs, total symptoms, positive symptoms, delusions, depression, and anxiety. Subgroup analysis showed that avatar therapy reduced the severity of AHs with the largest effect size (SMD, −0.37; 95% CI, −0.51 to −0.22; P < .001). Sensitivity analyses indicated robustness of results. Dropout rates and reports on adverse events indicated high tolerability and acceptability of treatments. Conclusion and Relevance Although targeted psychological and psychosocial interventions for AHs in SSDs were found to be effective in reducing the severity and other characteristics of AHs, with effect sizes ranging from small to medium, substantial differences were observed between approaches. In particular, avatar therapy seems to be effective at addressing AH symptoms. These findings could influence future studies and clinical care by advancing the development of targeted, novel approaches for AHs that address relevant treatment characteristics.

Importance:Substance use disorder (SUD) is commonly found in individuals with schizophrenia, with a high co-occurrence rate of approximately 41.7%. Despite this high prevalence, people with both schizophrenia and SUD are frequently excluded from clinical trials and systematic reviews; this special group is particularly challenging to treat and imposes a significant economic burden on health care systems. Objective:To evaluate the efficacy, acceptability, and tolerability of psychological and psychosocial interventions in patients with schizophrenia and co-occurring SUD. Data Sources:The Cochrane Schizophrenia Group registry was searched up to January 13, 2025. Data analysis was performed from March to April 2025. Study Selection:Randomized clinical trials (RCTs) examining psychological and psychosocial interventions compared with control groups in adults with schizophrenia and concomitant SUD were identified. No restrictions were applied regarding the type of substance used, including alcohol, cannabis, nicotine, and stimulants, such as amphetamines. Data Extraction and Synthesis:A systematic review and random-effect pairwise meta-analyses were conducted to estimate standardized mean differences (SMD) with 95% confidence intervals and were reported following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. Confidence in the estimate was assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Main Outcomes and Measures:The primary outcomes were overall symptoms and substance use reduction measured by validated scales at posttreatment. Results:A total of 35 RCTs were included (4136 participants), with 29 trials involving 3831 participants contributing to pairwise meta-analyses comparing psychological and psychosocial interventions with control conditions. Among the 3748 participants with reported sex, 951 (25.4%) were female, and mean (range) age was 37.2 (20.6-57.5) years. A very small effect favoring the intervention group was observed in reducing overall symptoms (SMD, -0.11; 95% CI, -0.27 to 0.05; 13 trials; low confidence in the estimate), mainly driven by nicotine studies. No difference was found between intervention and control groups in reducing all types of substance use (SMD, -0.01; 95% CI, -0.21 to 0.18; 8 trials; moderate confidence). When considered separately, alcohol, cannabis, amphetamines, and other stimulants showed similar no-effect results, while nicotine use indicated a small effect. Conclusion and Relevance:The findings of this systematic review and meta-analysis suggest that current psychological and psychosocial interventions provide limited benefit in reducing symptoms and no effect in reducing substance use in individuals with schizophrenia and SUD compared to control conditions, with the exception of nicotine use, highlighting the urgent need to develop more effective treatment strategies.

Importance:Auditory hallucinations (AHs) are a hallmark characteristic of schizophrenia spectrum disorders (SSDs) and are often associated with severe distress. Previous research lacks comprehensive evidence on the overall efficacy of approaches targeting AHs in SSDs. Objective:To evaluate the efficacy and acceptability of all available psychological and psychosocial interventions targeting AHs in SSDs. Data Sources:Embase, MEDLINE, PsycArticles, PsycInfo, PSYNDEX, and the Cochrane library were searched for eligible studies published until August 18, 2025. Study Selection:Randomized clinical trials that analyzed psychological interventions targeting AHs compared to controls in adults with SSDs. Data Extraction and Synthesis:This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Two independent reviewers screened publications, extracted data, and assessed risk of bias. A random-effects meta-analysis was performed (Hedges g). Main Outcomes and Measures:The main outcomes were between-group differences in AHs and clinical characteristics at posttreatment and follow-up, measured with validated rating scales. Additional number-needed-to-treat (NNT) analyses and rating of evidence certainty (GRADE approach) were conducted. Results:A total of 23 studies with 2016 participants were included, with 1081 in the intervention groups across 5 different therapeutic approaches and 935 in the control groups. At posttreatment, targeted interventions reduced the severity of AHs compared with control groups (standardized mean difference [SMD], -0.18; 95% CI, -0.31 to -0.05; P = .007; NNT, 16; GRADE, low evidence). This effect was also observed for numerous secondary outcomes, comprising frequency and distress of AHs, total symptoms, positive symptoms, delusions, depression, and anxiety. Subgroup analysis showed that avatar therapy reduced the severity of AHs with the largest effect size (SMD, -0.37; 95% CI, -0.51 to -0.22; P < .001). Sensitivity analyses indicated robustness of results. Dropout rates and reports on adverse events indicated high tolerability and acceptability of treatments. Conclusion and Relevance:Although targeted psychological and psychosocial interventions for AHs in SSDs were found to be effective in reducing the severity and other characteristics of AHs, with effect sizes ranging from small to medium, substantial differences were observed between approaches. In particular, avatar therapy seems to be effective at addressing AH symptoms. These findings could influence future studies and clinical care by advancing the development of targeted, novel approaches for AHs that address relevant treatment characteristics.

Background:Antipsychotics are often insufficient for schizophrenia, but the optimal next-step strategies for non-response remain uncertain. Guidelines recommend some pharmacological, psychological, and non-invasive brain stimulation (NIBS) approaches, but we do not know which one works best. We summarized current evidence for schizophrenia non-responsive to antipsychotics. Methods:We searched the Cochrane Schizophrenia Group registry (up till January 13, 2025), and PubMed up till January 8, 2026 for randomized controlled trials (RCTs) of patients non-responsive to prior antipsychotic treatment, with persistent symptoms after at least one adequate 4-week antipsychotic trial. Raters needed to be masked. The primary outcome was change in overall symptoms analyzed using random-effects network meta-analyses of standardized mean differences (SMDs) with 95% confidence intervals (CIs). The protocol was pre-registered (https://osf.io/wcs5d/). Findings:Fifty-nine RCTs (5409 participants; mean age 39.8 years; 3416 men, 1441 women) were included; 5013 contributed to the primary analysis. Antipsychotic combination therapy (k = 18; n = 575; SMD -0.25, 95% CI -0.46 to -0.04; CINeMA: very low) and electroconvulsive therapy (ECT; k = 5; n = 97; SMD -0.51, -0.96 to -0.06; very low) might be more efficacious than continuing the same antipsychotic. Cognitive behavioral therapy for psychosis (CBTp) showed weak evidence of benefit over continuing the same antipsychotic (k = 5; n = 340; SMD -0.23, -0.58 to 0.11; very low). Other strategies-xanomeline-trospium augmentation, dose escalation, transcranial magnetic stimulation, and switching to clozapine or other antipsychotics-were inconclusive. Combination therapy increased adverse events (OR 1.93, 1.26-3.00). We found no evidence of subgroup difference among non-clozapine- and clozapine-non-response. Interpretation:The results were very uncertain. More head-to-head trials are needed. We found no evidence supporting dose-escalation nor switching to clozapine. Very weak evidence suggested efficacy of antipsychotic combination and ECT augmentation and they might be considered, but with substantial caution. Funding:This study was funded by the German Research Foundation (DFG, #468853597) and the Federal Ministry of Research, Technology, and Space (BMTR, #01EE2303B), and partly by a grant from SENSHIN Medical Research Foundation given to YF, DAAD fellowship to NHS and CSC scholarship to YHW.

BACKGROUND:Several medications are available for rapid tranquilisation in psychomotor agitation, but choosing among them varies across local practices and this variation is compounded by inconsistent guidelines. We performed a systematic review with individual participant data network meta-analysis to inform evidence-based recommendations. METHODS:In this systematic review and individual participant data meta-analysis, we searched multiple databases from database inception to Nov 14, 2025, for randomised trials comparing intramuscular or intravenous treatments for rapid tranquilisation (primary outcome defined as sedation within 15-30 min) in patients with psychomotor agitation in general or psychiatric emergency settings. Anonymised individual participant data were collected and harmonised into a common dataset. Risk of bias was assessed using the RoB 2 tool. We performed Bayesian one-stage random-effects individual participant data network meta-regressions, accounting for between-study heterogeneity, drug classes, prognostic factors, and subgroup effects based on agitation severity. We combined individual participant data and aggregate data to evaluate side-effects. Confidence in the evidence was assessed using the Confidence In Network Meta Analysis (CINeMA) framework. People with lived experience were involved in the design and interpretation of the findings. The protocol was registered with PROSPERO (CRD42023402365). FINDINGS:We included 18 trials across eight regions (3411 participants; 1988 [58·3%] men, 1423 [41·7%] women; mean age 36·0 [SD 11·7] years), of which 13 trials (2705 participants) provided individual participant data for antipsychotics, benzodiazepines, and their combination. In moderate agitation, odds of achieving sedation relative to haloperidol monotherapy were higher with antipsychotic-benzodiazepine combinations (odds ratio [OR] 12·93, 95% credible interval [95% CrI] 3·00-50·91; relative risk [RR] 1·58), benzodiazepines (5·52, 1·37-21·02; 1·49), and other antipsychotics (4·54, 1·35-14·45; 1·45). In severe agitation, antipsychotic-benzodiazepine combinations were more effective than haloperidol (4·86, 1·28-17·54; 1·73), whereas results were uncertain for benzodiazepines (2·09, 0·58-6·99; 1·38) and other antipsychotics (1·70, 0·62-4·59; 1·28). Confidence in these estimates was very low, mainly due to imprecision and heterogeneity. Haloperidol monotherapy was associated with higher risk of extrapyramidal side-effects and benzodiazepines, alone or in combination, with hypotension. INTERPRETATION:Antipsychotic-benzodiazepine combinations might be among the most effective options for rapid tranquilisation in patients with psychomotor agitation but carry a risk of hypotension, whereas haloperidol monotherapy appeared among the least effective and is associated with extrapyramidal side-effects. These findings should be contextualised to the specific setting and patient characteristics, including the underlying agitation aetiology. Large trials are needed to provide more precise recommendations. FUNDING:German Ministry of Research, Technology and Space and Swiss National Science Foundation.

Schizophrenia is a challenging and diverse mental health condition with a lifetime prevalence of 0.4%. Schizophrenia usually manifests in late adolescence or early adulthood and is associated with high disability and a reduced life expectancy. Risk factors include genetic predisposition, prenatal and birth complications, infections and immune dysfunction, and cannabis use as well as psychosocial factors such as childhood trauma or migration. The first psychotic episode is often preceded by a long prodromal phase that can last for several years. No markers are yet available for clinical use that allow prediction of disease development or a diagnosis to be established. A leading theory postulates that excitatory-inhibitory (that is, glutamate-GABA) imbalance in the cortex ultimately leads to dysfunction of the dopaminergic system. Schizophrenia is a heterogeneous disease with different manifestations, including psychotic symptoms as well as negative symptoms and global cognitive deficit, that do not respond to antipsychotic drugs, making management very difficult. Pharmacological treatment coupled with psychotherapeutic interventions, such as cognitive behavioural therapy, cognitive remediation and psychoeducation, remains the mainstay of treatment; however, treatment resistance is frequent. The first medication that targets neurotransmitter systems other than dopamine has been approved for use. Current attempts to use virtual reality and avatars to improve psychotic symptoms and smartphone applications to prevent relapses seem promising.

Schizophrenia spectrum disorders significantly impact daily functioning, with antipsychotic medications regarded as the gold standard treatment. However, their efficacy is often limited by side effects and adherence rates. Understanding patient perspectives and subjective experiences, particularly regarding oral versus long-acting injectable (LAI) antipsychotics, is crucial for improving medication outcomes and patient-tailored treatments. A systematic review of qualitative studies was conducted following the ENTREQ guidelines. Data were extracted from PubMed, Scopus, and PsycInfo, with thematic synthesis used to identify key themes in patient-reported experiences. Thirty-nine studies (1.477 patients) were included and analyzed, revealing three core themes: (1) perception and experience of medication, (2) social dynamics and influence, and (3) trust and communication with healthcare providers. Side effects and lack of information were often mentioned by patients. While LAI antipsychotics were linked to symptom stability and functional improvements, many patients lacked adequate information about their effects, contributing to adherence difficulties. Stigma and negative beliefs were common across both oral and LAI formulations, thus determining significant barriers to medication adherence. This review emphasizes that patients’ experiences with antipsychotic medications are shaped by three key factors: the environment, the therapeutic relationship, and the drug itself. Two critical areas warrant particular attention: psychoeducation and stigma. Bridging psychoeducational gaps and addressing stigma could significantly enhance treatment adherence and outcomes. Additionally, greater emphasis on providing comprehensive and accurate information about antipsychotic treatment options is essential to support patient-centred care and informed decision-making.

BACKGROUND:Cognitive behavioral therapy for insomnia (CBT-I) is the first-line treatment for insomnia in general population, but only recently has it begun to be examined among people with schizophrenia. We aimed to summarize the currently available evidence by the systematic review and meta-analysis. DESIGN:Multiple databases, including PubMed, Cochrane Central Register of Controlled Trials and PsycINFO were searched up to 1st October 2024 to include all randomized controlled trials examining CBT-I among adults with insomnia and schizophrenia. We evaluated the certainty of evidence using GRADE. The co-primary outcomes were insomnia severity and overall schizophrenia symptoms at post-treatment. Secondary outcomes included all-cause dropouts, adverse events, other psychotic symptoms and self-reported sleep continuity measures. We conducted frequentist random-effects pairwise meta-analyses. This study was prospectively registered (https://osf.io/ja3cg/). RESULTS:Three trials with 137 randomized participants were identified (mean age, 42.0 [standard deviation, 12.9]; 39.4 % women; mean baseline Positive and Negative Syndrome Scale, 70.7 [16.8]; mean baseline Insomnia Severity Index, 18.9 [4.5]). CBT-I was more beneficial than treatment as usual for insomnia severity (SMD -1.53 [95 % Confidence Interval (CI), -2.04 to -1.02; GRADE certainty of evidence: low), but the effect on overall schizophrenia symptoms remained unclear (SMD -0.29 [95 %CI, -0.70 to 0.12]: low). Most of the secondary outcomes were examined in only a single trial at most, and confidence intervals were very wide. CONCLUSIONS:This meta-analysis found that CBT-I may improve insomnia symptoms among people with schizophrenia but its effect on other schizophrenia-related symptoms remained unclear. Further larger trials are needed.

Background:Non-invasive brain stimulation (NIBS) provides adjunctive therapeutic options for individuals with schizophrenia if medications are insufficient to produce clinical response, but guidelines remain controversial on whether NIBS is effective, and which NIBS methods and targets are preferred. We aimed to compare the efficacy and safety of NIBS for treatment-resistant schizophrenia (TRS). Methods:This systematic review and network meta-analysis of randomised controlled trials investigated NIBS interventions, including electroconvulsive therapy, magnetic seizure therapy (MST), repetitive transcranial magnetic stimulation (rTMS), and transcranial electric stimulation (tES), as adjunctive treatment for TRS. We searched the Cochrane Schizophrenia Group's specialised register from inception to 2025.07.13, and three Chinese databases from inception to 2024.10.30. The primary outcome was overall symptoms, and adverse events were analysed as secondary outcomes. We synthesized the data using random-effects network meta-analysis. Sensitivity analyses examined the robustness of the findings and the effects of the detailed NIBS protocols. The protocol was pre-registered with PROSPERO (CRD42023410645) and published in a scientific journal. Findings:We identified 21710 references and included 78 trials with a total of 3416 participants (1216 women, 1733 men; mean age 37.06 years, range 25.55-48.38; ethnicity data were not recorded). Compared with sham stimulation, rTMS (SMD -0.47, 95% CI [-0.62; -0.31]) was more efficacious in improving overall symptoms; but not in a sensitivity analysis excluding studies from Chinese mainland (-0.19, [-0.38; 0.01]). No clear differences between rTMS specific protocols in terms of stimulation targets and protocols were detected. No clear differences were found for electroconvulsive therapy (-0.20, [-0.78; 0.37]), tES (-0.08, [-0.38; 0.22]), and MST (-0.30, [-1.73; 1.13]) compared to sham stimulation. Treatment as usual might be less efficacious than sham (1.13, [-0.13; 2.38]), based on indirect evidence. NIBS was generally safe (rTMS produced headaches and local reactions), but information about adverse events was rarely reported. Interpretation:rTMS may be efficacious in individuals with TRS, but this finding was driven mainly by studies from Chinese mainland. No clear differences were observed for electroconvulsive therapy, tES, and MST, but the findings were imprecise and inconclusive. Funding:German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung/BMBF; 01KG2206).

Background Muscarinic receptor agonism and positive allosteric modulation is a promising mechanism of action for treating psychosis, not present in most D2R-blocking antipsychotics. Xanomeline, an M1/M4-preferring agonist, has shown efficacy in late-stage clinical trials, with more compounds being investigated. Therefore, we aim to synthesize evidence on the preclinical efficacy of muscarinic receptor agonists and positive allosteric modulators in animal models of psychosis to provide unique insights and evidence-based information to guide drug development. Methods We plan a systematic review and meta-analysis of in vivo animal studies comparing muscarinic receptor agonists or positive allosteric modulators with control conditions and existing D2R-blocking antipsychotics in animals subjected to any method that induces behavioural changes of relevance for psychosis. We will identify eligible studies by searching multiple electronic databases. At least two independent reviewers will conduct the study selection and data extraction using prespecified forms and assess the risk of bias with the SYRCLE’s tool. Our primary outcomes include locomotor activity and prepulse inhibition measured with standardized mean differences. We will examine other behavioural readouts of relevance for psychosis as secondary outcomes, such as social interaction and cognitive function. We will synthesize the data using multi-level meta-analysis with a predefined random-effects structure, considering the non-independence of the data. In meta-regressions we will explore potential sources of heterogeneity from a predefined list of characteristics of the animal population, model, and intervention. We will assess the confidence in the evidence considering a self-developed instrument thatconsiders the internal and external validity of the evidence. Protocol registration PROSPERO-ID: CRD42024520914

BACKGROUND:Clozapine is recommended by national and international guidelines for people with treatment-resistant schizophrenia. However, available meta-analyses of randomised controlled trials have not shown superior efficacy of clozapine when compared with other second-generation antipsychotics, with heterogeneity identified between the original studies. We aimed to use individual patient data (IPD) to account for potential reasons of variability and to synthesise an adjusted estimate for the difference in efficacy between clozapine and other second-generation antipsychotics for treatment-resistant schizophrenia. METHODS:In this systematic review and IPD meta-analysis, we searched the Cochrane Schizophrenia Group's Study-Based Register from inception to Jan 24, 2024, and previous reviews for blinded randomised controlled trials comparing clozapine with other second-generation antipsychotics in participants with treatment-resistant schizophrenia. Trials were eligible if they included patients with treatment-resistant schizophrenia and had a duration of at least 6 weeks. IPD were requested from trial investigators. The primary outcome was change in overall schizophrenia symptoms as measured by the Positive and Negative Syndrome Scale (PANSS) between clozapine and other second-generation antipsychotics after 6-8 weeks of treatment. The effect size measure for the primary outcome was mean difference with 95% credible interval (CrI). We fitted a Bayesian random-effects IPD meta-regression model that included duration of illness, baseline severity, and sex as potential prognostic factors or treatment effect modifiers. Confidence in the evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). People with lived experience of mental illness were involved in this study. This study is registered with PROSPERO, CRD42021254986. FINDINGS:We screened 13 876 references and included 19 studies with data for 1599 participants; IPD were available for 12 of 19 trials (n=1052; mean age 37·67 years [SD 11·24; range 10-66]; 348 [33·08%] women and 704 [66·92%] men). Data on ethnicity were not available. The estimated mean difference in change from baseline PANSS total score was -0·64 points (95% CrI -3·97 to 2·63; τ=2·68) in favour of other second-generation antipsychotics. Shorter duration of illness and higher baseline severity were prognostic factors associated with a larger reduction in symptoms, but neither those factors nor sex were found to modify the relative effect between clozapine and other second-generation antipsychotics. The confidence in the evidence was graded as very low. INTERPRETATION:This IPD meta-analysis found a small and uncertain advantage of other second-generation antipsychotics, mainly olanzapine and risperidone, and so did not provide evidence for superior efficacy of clozapine compared with other second-generation antipsychotics in treatment-resistant schizophrenia. It is limited by unavailability of IPD for some studies, uncaptured sources of variance, and uncertainty due to premature study discontinuation. Given the side-effects of clozapine, the observed uncertainty regarding clozapine's superiority warrants prudent use and further research. FUNDING:German Ministry of Education and Research.

ImportanceCognitive deficits are a substantial part of the symptoms of schizophrenia spectrum disorders (SSDs) and contribute heavily to the burden of disease. Antipsychotic drugs are not cognitive enhancers, but due to their different receptor-binding profiles, they could differ in their effects on cognition. No previous network meta-analysis compared antipsychotics to placebo, which is important to determine whether use of these drugs is associated with cognitive performance in SSDs at all.ObjectiveTo determine the association of treatment with various antipsychotics and cognition in patients with SSDs.Data SourcesCochrane Schizophrenia Trials Register through June 25, 2023.Study SelectionRandomized clinical trials examining the effects on cognition of antipsychotic drugs or placebo in participants with SSD.Data Extraction and SynthesisA systematic review and random-effects frequentist network meta-analysis was performed following Preferred Reporting Items for Systematic Reviews and Meta-analyses–Network Meta-analysis reporting guideline.Main Outcomes and MeasuresThe primary outcome was change in overall cognition score calculated for each study. Secondary outcomes included cognitive domains, quality of life, and functioning.ResultsThis study included 68 studies involving 9525 participants (mean [SD] age, 35.1 [8.9] years; 5878 male [70%] and 2890 [30%] female; some studies did not provide this information). There were few clear differences between antipsychotics, but first-generation dopamine antagonists haloperidol (standardized mean difference [SMD], 0.04; 95% CI, −0.25 to 0.33) and fluphenazine (SMD, 0.15; 95% CI, −0.39 to 0.69) as well as clozapine (SMD, 0.12; 95% CI, −0.23 to 0.48) ranked low. No individual antipsychotic was associated with a clearly better outcome than placebo, but antipsychotics as a group were, with small effect sizes (mean SMDs: adrenergic/low dopamine, −0.21; serotonergic/dopaminergic, −0.26; muscarinic, −0.28; dopaminergic, −0.40).Conclusion and RelevanceAlthough data are relatively sparse, those reviewed in this study suggest that first-generation dopamine antagonists and clozapine should be avoided when cognitive deficits are a concern. Antipsychotics are not procognitive drugs. The overall small superior outcomes compared to placebo may be explained by less disordered thought patterns associated with fewer positive symptoms rather than cognitive deficits in the proper sense. The findings also suggest that harmonizing measurement of cognitive function in randomized clinical trials would be beneficial.

Introduction Treating the early phase of schizophrenia is crucial for preventing further episodes and improving quality of life, functioning, and social inclusion. Pharmacotherapies are first-line treatments, but have limitations. There is consensus on the need for non-pharmacological interventions for individuals in the early phase of schizophrenia. Several psychological interventions have shown promising effects; however, their comparative effectiveness remains largely unknown. To address this issue, a network meta-analysis will be performed. We aim to develop a hierarchy of existing psychological treatments concerning their efficacy and tolerability, which will inform treatment guidelines. Protocol Randomized controlled trials (RCTs) investigating psychological interventions for first-episode psychosis, first-episode schizophrenia, or early phase schizophrenia will be included. The primary outcome will be overall schizophrenia symptoms (measured up to 6 and 12 months, and at the longest follow-up) and relapse as a co-primary outcome. Secondary outcomes are premature discontinuation; change in positive, negative, and depressive symptoms of schizophrenia; response; quality of life; overall functioning; satisfaction with care; adherence; adverse events; and mortality. The study selection and data extraction are performed by two independent reviewers. We will assess the risk of bias of each study using the Cochrane Risk of Bias tool 2 and evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). Subgroup and sensitivity analyses will be conducted to explore heterogeneity and assess the robustness of our findings. Discussion This systematic review and network meta-analysis aims to compare multiple existing psychological interventions, establishing which are best for symptom reduction, relapse prevention, and other important outcomes in early phase schizophrenia. Our results may provide practical guidance concerning the most effective psychological intervention to reduce symptom severity and the societal burden associated with the disorder.

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.