Antipsychotic Drugs and Cognitive Function: A Systematic Review and Pairwise Network Meta-Analysis.

Importance: Cognitive 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. Objective: To determine the association of treatment with various antipsychotics and cognition in patients with SSDs. Data Sources: Cochrane Schizophrenia Trials Register through June 25, 2023. Study Selection: Randomized clinical trials examining the effects on cognition of antipsychotic drugs or placebo in participants with SSD. Data Extraction and Synthesis: A 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 Measures: The primary outcome was change in overall cognition score calculated for each study. Secondary outcomes included cognitive domains, quality of life, and functioning. Results: This 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 Relevance: Although 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.

Changes in the prevalence of mental health problems during the first year of the pandemic: a systematic review and dose-response meta-analysis.

AIM: To describe the pattern of the prevalence of mental health problems during the first year of the COVID-19 pandemic and examine the impact of containment measures on these trends. METHODS: We identified articles published until 30 August 2021 that reported the prevalence of mental health problems in the general population at two or more time points. A crowd of 114 reviewers extracted data on prevalence, study and participant characteristics. We collected information on the number of days since the first SARS-CoV-2 infection in the study country, the stringency of containment measures and the number of cases and deaths. We synthesised changes in prevalence during the pandemic using a random-effects model. We used dose-response meta-analysis to evaluate the trajectory of the changes in mental health problems. RESULTS: We included 41 studies for 7 mental health conditions. The average odds of symptoms increased during the pandemic (mean OR ranging from 1.23 to 2.08). Heterogeneity was very large and could not be explained by differences in participants or study characteristics. Average odds of psychological distress, depression and anxiety increased during the first 2 months of the pandemic, with increased stringency of the measures, reported infections and deaths. The confidence in the evidence was low to very low. CONCLUSIONS: We observed an initial increase in the average risk of psychological distress, depression-related and anxiety-related problems during the first 2 months of the pandemic. However, large heterogeneity suggests that different populations had different responses to the challenges imposed by the pandemic.

Single-arm meta-analysis of drug response in placebo-controlled versus active-controlled antipsychotic drug trials in schizophrenia.

Antipsychotic drug efficacy may vary in placebo-controlled and active-controlled trials. The study aims to investigate the performance of antipsychotics in these two different study designs using single-arm meta-analysis. We included randomized controlled trials (RCTs) comparing second-generation antipsychotics with placebo or other antipsychotics from our previous systematic reviews and updated the results with the search on Cochrane Schizophrenia Group register until March 06, 2022. The outcomes were the differences in the change of overall, positive and negative symptoms of schizophrenia, and the difference in study discontinuation between placebo-controlled and head-to-head trials. Random-effects single-arm meta-analysis and subgroup test were conducted to examine the differences in each outcome. A total of 208 RCTs (n = 42,159) were included in the analysis. Of these, 85 trials with 17,056 participants were placebo-controlled, while the remaining were head-to-head trials. Antipsychotics in head-to-head trials demonstrated a significantly greater improvement in overall symptoms (MC -23.58; 95 % CI -25.33, -21.83) compared to antipsychotics in placebo-controlled trials (MC -16.74; 95 % CI -17.80, -15.69; p < 0.0001). Similar findings were observed for positive symptoms, negative symptoms, study discontinuation and sensitivity analyses. Notably, when assessing antipsychotics individually, the same antipsychotic consistently demonstrated superior performance in head-to-head trials compared to placebo-controlled trials. In conclusion, antipsychotics in head-to-head trials presented a considerable efficacy superiority compared to those in placebo-controlled trials. Moreover, the efficacy of the same antipsychotics varied depending on the study design. Future trials should carefully consider the methodology and employ strategies to mitigate the potential for overestimation or underestimation of treatment efficacy.

Tool to assess risk of bias in studies estimating the prevalence of mental health disorders (RoB-PrevMH).

OBJECTIVE: There is no standard tool for assessing risk of bias (RoB) in prevalence studies. For the purposes of a living systematic review during the COVID-19 pandemic, we developed a tool to evaluate RoB in studies measuring the prevalence of mental health disorders (RoB-PrevMH) and tested inter-rater reliability. METHODS: We decided on items and signalling questions to include in RoB-PrevMH through iterative discussions. We tested the reliability of assessments by different users with two sets of prevalence studies. The first set included a random sample of 50 studies from our living systematic review. The second set included 33 studies from a systematic review of the prevalence of post-traumatic stress disorders, major depression and generalised anxiety disorder. We assessed the inter-rater agreement by calculating the proportion of agreement and Kappa statistic for each item. RESULTS: RoB-PrevMH consists of three items that address selection bias and information bias. Introductory and signalling questions guide the application of the tool to the review question. The inter-rater agreement for the three items was 83%, 90% and 93%. The weighted kappa scores were 0.63 (95% CI 0.54 to 0.73), 0.71 (95% CI 0.67 to 0.85) and 0.32 (95% CI -0.04 to 0.63), respectively. CONCLUSIONS: RoB-PrevMH is a brief, user-friendly and adaptable tool for assessing RoB in studies on prevalence of mental health disorders. Initial results for inter-rater agreement were fair to substantial. The tool's validity, reliability and applicability should be assessed in future projects.

Long-term efficacy of antipsychotic drugs in initially acutely ill adults with schizophrenia: systematic review and network meta-analysis.

Most acute phase antipsychotic drug trials in schizophrenia last only a few weeks, but patients must usually take these drugs much longer. We examined the long-term efficacy of antipsychotic drugs in acutely ill patients using network meta-analysis. We searched the Cochrane Schizophrenia Group register up to March 6, 2022 for randomized, blinded trials of at least 6-month duration on all second-generation and 18 first-generation antipsychotics. The primary outcome was change in overall symptoms of schizophrenia; secondary outcomes were all-cause discontinuation; change in positive, negative and depressive symptoms; quality of life, social functioning, weight gain, antiparkinson medication use, akathisia, serum prolactin level, QTc prolongation, and sedation. Confidence in the results was assessed by the CINeMA (Confidence in Network Meta-Analysis) framework. We included 45 studies with 11,238 participants. In terms of overall symptoms, olanzapine was on average more efficacious than ziprasidone (standardized mean difference, SMD=0.37, 95% CI: 0.26-0.49), asenapine (SMD=0.33, 95% CI: 0.21-0.45), iloperidone (SMD=0.32, 95% CI: 0.15-0.49), paliperidone (SMD=0.28, 95% CI: 0.11-0.44), haloperidol (SMD=0.27, 95% CI: 0.14-0.39), quetiapine (SMD=0.25, 95% CI: 0.12-0.38), aripiprazole (SMD=0.16, 95% CI: 0.04-0.28) and risperidone (SMD=0.12, 95% CI: 0.03-0.21). The 95% CIs for olanzapine versus aripiprazole and risperidone included the possibility of trivial effects. The differences between olanzapine and lurasidone, amisulpride, perphenazine, clozapine and zotepine were either small or uncertain. These results were robust in sensitivity analyses and in line with other efficacy outcomes and all-cause discontinuation. Concerning weight gain, the impact of olanzapine was higher than all other antipsychotics, with a mean difference ranging from -4.58 kg (95% CI: -5.33 to -3.83) compared to ziprasidone to -2.30 kg (95% CI: -3.35 to -1.25) compared to amisulpride. Our data suggest that olanzapine is more efficacious than a number of other antipsychotic drugs in the longer term, but its efficacy must be weighed against its side effect profile.

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.

A tool to assess risk of bias in studies estimating the prevalence of mental health disorders (RoB-PrevMH).

Objective: Biases affect how certain we are about the available evidence, however no standard tool for assessing the risk of bias (RoB) in prevalence studies exists. For the purposes of a living systematic review on prevalence of mental health disorders during the COVID-19 pandemic, we developed a RoB tool to evaluate prevalence studies in mental health (RoB-PrevMH) and tested interrater reliability. Methods: We reviewed existing RoB tools for prevalence studies until September 2020, to develop a tool for prevalence studies in mental health. We tested the reliability of assessments by different users of RoB-PrevMH in 83 studies stemming from two systematic reviews of prevalence studies in mental health. We assessed the interrater agreement by calculating the proportion of agreement and Kappa statistic for each item. Results: RoB-PrevMH consists of three items that address selection bias and information bias. Introductory and signaling questions guide the application of the tool to the review question. The interrater agreement for the three items was 83%, 90% and 93%. The weighted kappa was 0.63 (95% CI 0.54 to 0.73), 0.71 (95% CI 0.67 to 0.85) and 0.32 (95% CI -0.04 to -0.63), respectively. Conclusions: We developed a brief, user friendly, and adaptable tool for assessing RoB in studies on prevalence of mental health disorders. Initial results for interrater agreement were fair to substantial. The tool's validity, reliability, and applicability should be assessed in future projects.

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).

The response of subgroups of patients with schizophrenia to different antipsychotic drugs: a systematic review and meta-analysis.

BACKGROUND: As comparatively few trials in subgroups of patients with schizophrenia have been done, clinicians need to know whether they can rely on the results of randomised controlled trials (RCTs) in the general population of patients with schizophrenia. We aimed to compare the efficacy and side-effects of antipsychotic drugs in different subgroups. METHODS: In this systematic review and meta-analysis, we searched reference lists of previous systematic reviews and meta-analyses, the Cochrane Schizophrenia Group's Study-Based Register (from database inception to April 27, 2020), and PubMed (from April 1, 2020 to June 14, 2021). We excluded studies in patients with stable schizophrenia (ie, relapse prevention studies), studies with a high risk of bias, and studies from mainland China due to quality concerns concerning allocation and masking methods. We included single-blind RCTs or better that assessed one or more of 16 second-generation and 18 first-generation antipsychotics in the general population of patients with schizophrenia or in one or more of the subgroups: children and adolescents (age range as defined in the original studies), patients with a first episode, patients with predominant or prominent negative symptoms, patients with comorbid substance use, patients with treatment-resistant schizophrenia, or older patients (age range as defined in the original studies). Two authors independently screened the results of the search, retrieved full-text articles, and checked the inclusion criteria. Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline, all parameters were extracted in duplicate. The primary outcome was change in overall symptoms. We compared drug efficacy between subgroups, by sex, schizoaffective disorder versus schizophrenia, and study origin using random-effects, inverse variance meta-analyses and random-effects subgroup tests, and meta-regression. FINDINGS: We included 537 RCTs with 76 382 participants, 26 627 (34·9%) women, 49 755 (65·1%) men, mean age 37·3 years (range of means 7·9-80·2; ethnicity data not available). 412 RCTs included patients in the general population of patients with schizophrenia, 42 included patients with treatment-resistant schizophrenia, 25 included children and adolescents, 20 included patients with their first episode, 20 included patients with predominant or prominent negative symptoms, 13 included patients with comorbid substance use, and 11 included older patients. Of 507 random-effects subgroup tests done, 46 (9%) showed a significant difference (p<0·05) between subgroups, but there was no clear indication as to which drug should be used in which subgroup. INTERPRETATION: The effects of antipsychotics in various patient subgroups were usually similar to those in the general population of patients with schizophrenia, but comparably few studies contributed to the subgroups, in particular in terms of side-effects. If the evidence for treatment in a given subgroup is small, guideline makers and clinicians should consider using the results in the much better studied group of the general population of patients with schizophrenia. FUNDING: German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung; FKZ 01KG1508).

Comparative Efficacy and Tolerability of 32 Oral Antipsychotics for the Acute Treatment of Adults With Multi-Episode Schizophrenia: A Systematic Review and Network Meta-Analysis.

(Reprinted with permission from the Lancet 2019; 394: 939-51).

Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis.

BACKGROUND: Schizophrenia is one of the most common, burdensome, and costly psychiatric disorders in adults worldwide. Antipsychotic drugs are its treatment of choice, but there is controversy about which agent should be used. We aimed to compare and rank antipsychotics by quantifying information from randomised controlled trials. METHODS: We did a network meta-analysis of placebo-controlled and head-to-head randomised controlled trials and compared 32 antipsychotics. We searched Embase, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Central Register of Controlled Trials (CENTRAL), WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from database inception to Jan 8, 2019. Two authors independently selected studies and extracted data. We included randomised controlled trials in adults with acute symptoms of schizophrenia or related disorders. We excluded studies in patients with treatment resistance, first episode, predominant negative or depressive symptoms, concomitant medical illnesses, and relapse-prevention studies. Our primary outcome was change in overall symptoms measured with standardised rating scales. We also extracted data for eight efficacy and eight safety outcomes. Differences in the findings of the studies were explored in metaregressions and sensitivity analyses. Effect size measures were standardised mean differences, mean differences, or risk ratios with 95% credible intervals (CrIs). Confidence in the evidence was assessed using CINeMA (Confidence in Network Meta-Analysis). The study protocol is registered with PROSPERO, number CRD42014014919. FINDINGS: We identified 54 417 citations and included 402 studies with data for 53 463 participants. Effect size estimates suggested all antipsychotics reduced overall symptoms more than placebo (although not statistically significant for six drugs), with standardised mean differences ranging from -0·89 (95% CrI -1·08 to -0·71) for clozapine to -0·03 (-0·59 to 0·52) for levomepromazine (40 815 participants). Standardised mean differences compared with placebo for reduction of positive symptoms (31 179 participants) varied from -0·69 (95% CrI -0·86 to -0·52) for amisulpride to -0·17 (-0·31 to -0·04) for brexpiprazole, for negative symptoms (32 015 participants) from -0·62 (-0·84 to -0·39; clozapine) to -0·10 (-0·45 to 0·25; flupentixol), for depressive symptoms (19 683 participants) from -0·90 (-1·36 to -0·44; sulpiride) to 0·04 (-0·39 to 0·47; flupentixol). Risk ratios compared with placebo for all-cause discontinuation (42 672 participants) ranged from 0·52 (0·12 to 0·95; clopenthixol) to 1·15 (0·36 to 1·47; pimozide), for sedation (30 770 participants) from 0·92 (0·17 to 2·03; pimozide) to 10·20 (4·72 to 29·41; zuclopenthixol), for use of antiparkinson medication (24 911 participants) from 0·46 (0·19 to 0·88; clozapine) to 6·14 (4·81 to 6·55; pimozide). Mean differences compared to placebo for weight gain (28 317 participants) ranged from -0·16 kg (-0·73 to 0·40; ziprasidone) to 3·21 kg (2·10 to 4·31; zotepine), for prolactin elevation (21 569 participants) from -77·05 ng/mL (-120·23 to -33·54; clozapine) to 48·51 ng/mL (43·52 to 53·51; paliperidone) and for QTc prolongation (15 467 participants) from -2·21 ms (-4·54 to 0·15; lurasidone) to 23·90 ms (20·56 to 27·33; sertindole). Conclusions for the primary outcome did not substantially change after adjusting for possible effect moderators or in sensitivity analyses (eg, when excluding placebo-controlled studies). The confidence in evidence was often low or very low. INTERPRETATION: There are some efficacy differences between antipsychotics, but most of them are gradual rather than discrete. Differences in side-effects are more marked. These findings will aid clinicians in balancing risks versus benefits of those drugs available in their countries. They should consider the importance of each outcome, the patients' medical problems, and preferences. FUNDING: German Ministry of Education and Research and National Institute for Health Research.