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.

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.

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.

Psychosocial and psychological interventions for relapse prevention in schizophrenia: a systematic review and network meta-analysis.

BACKGROUND: Many psychosocial and psychological interventions are used in patients with schizophrenia, but their comparative efficacy in the prevention of relapse is not known. We aimed to evaluate the efficacy, acceptability, and tolerability of psychosocial and psychological interventions for relapse prevention in schizophrenia. METHODS: To conduct this systematic review and network meta-analysis we searched for published and unpublished randomised controlled trials that investigated psychosocial or psychological interventions aimed at preventing relapse in patients with schizophrenia. We searched EMBASE, MEDLINE, PsycINFO, BIOSIS, Cochrane Library, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov up to Jan 20, 2020, and searched PubMed up to April 14, 2020. We included open and masked studies done in adults with schizophrenia or related disorders. We excluded studies in which all patients were acutely ill, had a concomitant medical or psychiatric disorder, or were prodromal or "at risk of psychosis". Study selection and data extraction were done by two reviewers independently based on published and unpublished reports, and by contacting study authors. Data were extracted about efficacy, tolerability, and acceptability of the interventions; potential effect moderators; and study quality and characteristics. The primary outcome was relapse measured with operationalised criteria or psychiatric hospital admissions. We did random-effects network meta-analysis to calculate odds ratios (ORs) or standardised mean differences (SMDs) with 95% CIs. The study protocol was registered with PROSPERO, CRD42019147884. FINDINGS: We identified 27 765 studies through the database search and 330 through references of previous reviews and studies. We screened 28 000 records after duplicates were removed. 24 406 records were excluded by title and abstract screening and 3594 full-text articles were assessed for eligibility. 3350 articles were then excluded for a variety of reasons, and 244 full-text articles corresponding to 85 studies were included in the qualitative synthesis. Of these, 72 studies with 10 364 participants (3939 females and 5716 males with sex indicated) were included in the network meta-analysis. The randomised controlled trials included compared 20 psychological interventions given mainly as add-on to antipsychotics. Ethnicity data were not available. Family interventions (OR 0·35, 95% CI 0·24-0·52), relapse prevention programmes (OR 0·33, 0·14-0·79), cognitive behavioural therapy (OR 0·45, 0·27-0·75), family psychoeducation (OR 0·56, 0·39-0·82), integrated interventions (OR 0·62, 0·44-0·87), and patient psychoeducation (OR 0·63, 0·42-0·94) reduced relapse more than treatment as usual at 1 year. The confidence in the estimates ranged from moderate to very low. We found no indication of publication bias. INTERPRETATION: We found robust benefits in reducing the risk of relapse for family interventions, family psychoeducation, and cognitive behavioral therapy. These treatments should be the first psychosocial interventions to be considered in the long-term treatment for patients with schizophrenia. FUNDING: German Ministry for Education and Research.

Metabolic side effects of antipsychotic drugs in individuals with schizophrenia during medium- to long-term treatment: protocol for a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Antipsychotic drugs and especially the newer compounds are known to cause metabolic side effects. However, a comprehensive comparison of the different substances regarding their propensity to cause metabolic side effects in medium- to long-term treatment of schizophrenia is lacking. METHODS: We will conduct a systematic review and network meta-analysis (NMA). We will include randomized controlled trials (RCTs) in which participants received either placebo or an antipsychotic (i.e. placebo-controlled trials and head-to-head comparisons of drugs). We will include studies in individuals with schizophrenia or related disorders (such as schizophreniform or schizoaffective disorders) at any stage of the disease (acute episode; maintenance phase). We will include studies with a duration of more than 3 months (medium- to long-term treatment). The primary outcome will be the change in body weight. Secondary outcomes will be the further metabolic parameters: fastening glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides. We will search for eligible studies (independent of the publication status) in Cochrane Schizophrenia Group's Study-Based Register of Trials, which is compiled by regular searches in trial registries and multiple electronic databases from their inception onwards including MEDLINE, EMBASE and PsycINFO. Additionally, we will search previously published systematic reviews and websites of pharmaceutical companies for eligible studies. At least two reviewers will independently conduct the process of study selection and data extraction. We will use the Cochrane Risk of Bias 2 tool to evaluate the risk of bias in studies. We will conduct random-effects NMA within a Bayesian framework to synthesize all evidence for each outcome. We will conduct sensitivity and subgroup analyses to assess the robustness of the findings and to explore heterogeneity. The confidence in the results will be evaluated using the Confidence in Network Meta-Analysis (CINeMA) framework. DISCUSSION: This systematic review and network meta-analysis will provide a synthesis of the existing evidence from RCTs how antipsychotic drugs differ in terms of metabolic side effects during medium- to long-term treatment. The findings have the potential to influence the choice of antipsychotic medication made by individuals with schizophrenia and their physicians. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020175414.

Psychosocial treatments for relapse prevention in schizophrenia: study protocol for a systematic review and network meta-analysis of randomised evidence.

INTRODUCTION: There is evidence that different psychosocial interventions could reduce the risk of relapse in schizophrenia, but a comprehensive evidence based on their relative efficacy is lacking. We will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomised controlled trials (RCTs) to rank psychosocial treatments for relapse prevention in schizophrenia according to their efficacy, acceptability and tolerability. METHODS AND ANALYSIS: We will include all RCTs comparing a psychosocial treatment aimed at preventing relapse in patients with schizophrenia with another psychosocial intervention or with a no treatment condition (waiting list, treatment as usual). We will include studies on adult patients with schizophrenia, excluding specific subpopulations (eg, acutely ill patients). Primary outcome will be the number of patients experiencing a relapse. Secondary outcomes will be acceptability (dropout), change in overall, positive, negative and depressive symptoms, quality of life, adherence, functioning and adverse events. Published and unpublished studies will be sought through database searches, trial registries and websites. Study selection and data extraction will be conducted by at least two independent reviewers. We will conduct random-effects NMA to synthesise all evidence for each outcome and obtain a comprehensive ranking of all treatments. NMA will be conducted in R within a frequentist framework. The risk of bias in studies will be evaluated using the Cochrane Risk of Bias tool and the credibility of the evidence will be evaluated using Confidence in Network Meta-Analysis (CINeMA). Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. ETHICS AND DISSEMINATION: No ethical issues are foreseen. Results from this study will be published in peer-reviewed journals and presented at relevant conferences. PROSPERO REGISTRATION NUMBER: CRD42019147884.

Peer-counseling in schizophrenia: patients consult patients.

OBJECTIVE: To evaluate whether peer-counseling, common in non-psychiatric medical fields, is feasible and useful for inpatients with schizophrenia. METHODS: The participants of a one-to-one peer-counseling were given the opportunity to present all questions related to their illness to a peer-counselor, who had himself been living with a schizoaffective disorder for over 20 years. The peer-counseling was evaluated by the participants (STEPP-questionnaire), by the counselor (structured protocol) and by a physician (supervision). Descriptive methods were used for statistical analyses. RESULTS: Eighty-eight patients (mean age 37 years, 35% female, hospitalized for 5 weeks) took part. The main topics addressed were 'symptoms of schizophrenia'; main suggestions were 'taking medication for symptom control and relapse prevention', 'having patience' and providing 'emotional support'. The mean ratings in the STEPP-subscales were: relationship-perspective 18.6 out of 21, problem-solving 19.8 out of 28, clarification-perspective 24.9 out of 35. Ninety-six percent of the participants would recommend this peer-counseling to others. CONCLUSIONS: The results of this pilot-study show that peer-counseling is feasible in schizophrenia. The peer-counselor was able to answer the questions adequately; patients felt well understood and obtained support and encouragement. PRACTICE IMPLICATIONS: The data suggest that peer-counseling is a potentially useful, additional tool for inpatients with schizophrenia as it appears to meet as yet unattended needs.

Peer-to-peer psychoeducation in schizophrenia: a new approach.

OBJECTIVE: To evaluate the feasibility of the first peer-to-peer psychoeducation program in schizophrenia. METHOD: We developed a 5-step curriculum for structured training of peer moderators. In step 1, peer moderators participate in regular psychoeducation, and in step 2, they participate in workshops on knowledge about schizophrenia and moderation techniques. In step 3, peer moderators conduct peer-to-peer groups in the presence of a mental health professional, and in step 4, they conduct the groups independently with regular supervision. Further peer moderators are recruited in step 5. Psychoeducation by trained peer moderators comprises 8 60-minute group sessions (warm-up, symptoms, diagnosis, causes, medication, psychosocial therapy, warning signs, coping with schizophrenia) with 6 to 10 patients per group. The feasibility of the 5-step curriculum was evaluated by conducting a pilot study of 7 peer groups with 2 peer moderators. Evaluation of peer-moderated groups was done from January 2003 to July 2004 using inpatients of a university hospital who had schizophrenia or schizoaffective disorder according to ICD-10. The primary outcomes of interest were change in knowledge and concept of illness from baseline to endpoint. RESULTS: Two peer moderators conducted psychoeducational groups with a total of 49 patients in the presence of a physician (step 3). On the whole, conduction of peer-moderated groups worked well. Knowledge of illness increased significantly (N = 44, p < .001), and concept of illness changed significantly in 3 subscales: trust in physician (N = 40, p = .002) and trust in medication (N = 40, p = .001) increased, and negative treatment expectations decreased (N = 40, p = .001). Subjective assessments of peer moderators by participating patients were positive. CONCLUSION: First results suggest that peer-to-peer psychoeducation in schizophrenia according to the 5-step curriculum is feasible and may be comparable to professional psychoeducation in regard to short-term outcomes.