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.

How well do elderly patients with major depressive disorder respond to antidepressants: a systematic review and single-group meta-analysis.

BACKGROUND: Depression is one of the leading causes of the global burden of disease, and it has particularly negative consequences for elderly patients. Antidepressants are the most frequently used treatment. We present the first single-group meta-analysis examining: 1) the response rates of elderly patients to antidepressants, and 2) the determinants of antidepressants response in this population. METHODS: We searched multiple databases for randomized controlled trials on antidepressants in the elderly with major depressive disorder above 65 years (last search: December 2017). Response was defined as 50% improvement on validated rating scales. We extracted response rates from studies and imputed the missing ones with a validated method. Data were pooled in a single-group meta-analysis. Additionally, several potential moderators of response to antidepressants were examined by subgroup and meta-regression analyses. RESULTS: We included 44 studies with a total of 6373 participants receiving antidepressants. On average, 50.7% of the patients reached a reduction of at least 50% on the Hamilton Depression Scale (HAMD). Subgroup and meta-regression analyses revealed a better response to treatment for patients in antidepressant-controlled trials compared to placebo-controlled trials. Mean age, study duration, percentage of woman, severity of illness at baseline, dose of antidepressants in fluoxetine equivalents, year of publication, setting (in- or out-patients), antidepressant groups (SSRI, TCA, SSNRI, α2-antagonist, SNRI, MAO-inhibitor), ITT (intention-to-treat) analysis vs completer analysis, sponsorship and overall risk of bias were not significant moderators of response. CONCLUSIONS: Our findings suggest an improvement in symptoms can be found in about 50% of the elderly with major depressive disorder treated with antidepressants.

Impact of different types of olive oil on cardiovascular risk factors: A systematic review and network meta-analysis.

BACKGROUND AND AIM: This network meta-analysis (NMA) compares the effects of different types of olive oil (OO) on cardiovascular risk factors. METHODS AND RESULTS: Literature search was conducted on three electronic databases (Medline, Web of Science, and Cochrane Central). INCLUSION CRITERIA: Randomized controlled trials (RCTs) (≥3 weeks duration of intervention) comparing at least two of the following types of OO: refined OO (ROO), mixed OO (MOO), low phenolic (extra) virgin OO (LP(E)VOO), and high phenolic (extra) virgin OO (HP(E)VOO). Random-effects NMA was performed for seven outcomes; and surface under the cumulative ranking curve (SUCRA) was estimated, using an analytical approach (P-score). Thirteen RCTs (16 reports) with 611 mainly healthy participants (mean age: 26-70 years) were identified. No differences for total cholesterol, HDL-cholesterol, triacylglycerols, and diastolic blood pressure were observed comparing ROO, MOO, LP(E)VOO and HP(E)VOO. HP(E)VOO slightly reduce LDL-cholesterol (LDL-C) compared to LP(E)VOO (mean difference [MD]: -0.14 mmol/L, 95%-CI: -0.28, -0.01). Both, HP(E)VOO and LP(E)VOO reduces SBP compared to ROO (range of MD: -2.99 to -2.87 mmHg), and HP(E)VOO may improve oxidized LDL-cholesterol (oxLDL-C) compared to ROO (standardized MD: -0.68, 95%-CI: -1.31, -0.04). In secondary analyses, EVOO may reduce oxLDL-C compared to ROO, and a dose-response relationship between higher intakes of phenolic compounds from OO and lower SBP and oxLDL-C values was detected. HP(E)VOO was ranked as best treatment for LDL-C (P-score: 0.83), oxLDL-C (0.88), and SBP (0.75). CONCLUSIONS: HP(E)VOO may improve some cardiovascular risk factors, however, public health implications are limited by overall low or moderate certainty of evidence.

Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-analysis.

BACKGROUND: Negative symptoms are the core of schizophrenia, but whether antipsychotics are efficacious for their treatment is unclear. Moreover, there is debate whether patients in relevant trials should have predominant negative symptoms or whether prominent negative symptoms are also acceptable. METHODS: We systematically reviewed randomised, blinded antipsychotic drug trials in patients with schizophrenia and either predominant or prominent negative symptoms (last search Dec 12, 2017). Separate pairwise meta-analyses were conducted in these two populations. The primary outcome was negative symptoms. Depressive, symptoms, positive symptoms, and extrapyramidal side-effects were analysed as causes of secondary negative symptoms. FINDINGS: We included 21 randomized-controlled trials with 3451 participants which revealed the following significant differences in the primary outcome: in patients with predominant negative symptoms amisulpride was superior to placebo (N = 4; n = 590, SMD 0.47, CI 0.23, 0.71), olanzapine was superior to haloperidol in a small trial (n = 35) and cariprazine outperformed risperidone (N = 1, n = 456, SMD - 0.29, CI - 0.48, - 0.11). In patients with prominent negative symptoms, olanzapine and quetiapine were superior to risperidone in single trials. Overall, studies in prominent negative symptoms were potentially more confounded by improvements of secondary negative symptoms. INTERPRETATION: Amisulpride is the only antipsychotic that outperformed placebo in the treatment of predominant negative symptoms, but there was a parallel reduction of depression. Cariprazine was better than risperidone in a large trial that was well-controlled for secondary negative symptoms, but the trial was sponsored by its manufacturer. Future trials should apply scientifically developed definitions such as the deficit syndrome and the persistent negative symptoms concept.

Response rates in patients with schizophrenia and positive symptoms receiving cognitive behavioural therapy: a systematic review and single-group meta-analysis.

BACKGROUND: Cognitive behavioural therapy has been used for schizophrenia, but to which extent it is effective is still controversial. Results of existing meta-analyses are of difficult interpretation, because they mainly present effect sizes in the form of standardized mean differences between intervention and control groups based on rating scales, which are of unclear clinical meaning. No meta-analysis has considered the number of patients responding to treatment yet. Based on this ground, we present the first meta-analysis examining the response rates of patients with schizophrenia and positive symptoms to cognitive behavioural therapy. METHODS: We searched multiple databases for randomized controlled trials on psychological interventions of schizophrenia including patients with positive symptoms, and included for this analysis the studies on cognitive behavioural therapy (last search: January 2018). We applied a validated imputation method to calculate the number of responders from rating scales for the outcomes overall symptoms and positive symptoms, based on two criteria, at least 20% and at least 50% reduction from baseline on PANSS or BPRS total scores. Data were pooled in a single-group summary meta-analysis using R software. Additionally, several potential moderators of response to cognitive behavioural therapy were examined by subgroup and meta-regression analyses. The protocol has been registered in PROSPERO (CRD42017067795). RESULTS: We included 33 studies with a total of 1142 participants receiving cognitive behavioural therapy. On average, 44.5 and 13.2% of the patients reached a 20% (minimally improved) and 50% (much improved) reduction of overall symptoms. Similarly, 52.9 and 24.8% of the patients reached a 20%/50% reduction of positive symptoms. Subgroup and meta-regression analyses revealed a better treatment response in overall symptoms for patients that were not treatment resistant and in studies with researchers' allegiance. Of borderline significance was the better response in studies employing expert therapists and in patients that were more severely ill at baseline. Blinding of outcome assessor, number of sessions, treatment duration, age and gender were not significant moderators of response. CONCLUSIONS: Our findings suggest that adding cognitive behavioural therapy to pharmacotherapy brings about a minimal improvement in overall symptoms among 44.5% of its recipients. Several study and patients characteristics can moderate response rates.

Correction to: Effectiveness and safety of vitamin K antagonists and new anticoagulants in the prevention of thromboembolism in atrial fibrillation in older adults - a systematic review of reviews and the development of recommendations to reduce inappropriate prescribing.

CORRECTION: After publication of the original article [1] it was found that author Marc Krause's name had been spelt incorrectly. In the original article it is presented as Mark Krause, rather than Marc Krause. The revised spelling has been included in the author list for this Correction.

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).

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

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

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).

Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis.

BACKGROUND: Placebo response in autism spectrum disorder (ASD) might dilute drug-placebo differences and hinder drug development. Therefore, this meta-analysis investigated placebo response in core symptoms. METHODS: We searched ClinicalTrials.gov , CENTRAL, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (up to July 8, 2018), and PubMed (up to July 4, 2019) for randomized pharmacological and dietary supplement placebo-controlled trials (RCTs) with a minimum of seven days of treatment. Single-group meta-analyses were conducted using a random-effects model. Standardized mean changes (SMC) of core symptoms in placebo arms were the primary outcomes and placebo positive response rates were a secondary outcome. Predictors of placebo response were investigated with meta-regression analyses. The protocol was registered with PROSPERO ID CRD42019125317 . RESULTS: Eighty-six RCTs with 2360 participants on placebo were included in our analysis (87% in children/adolescents). The majority of trials were small, single-center with a duration of 8-12 weeks and published after 2009. Placebo response in social-communication difficulties was SMC = - 0.32, 95% CI [- 0.39, - 0.25], in repetitive behaviors - 0.23[- 0.32, - 0.15] and in scales measuring overall core symptoms - 0.36 [- 0.46, - 0.26]. Overall, 19%, 95% CI [16-22%] of participants were at least much improved with placebo. Caregiver (vs. clinician) ratings, lower risk of bias, flexible-dosing, larger sample sizes and number of sites, less recent publication year, baseline levels of irritability, and the use of a threshold of core symptoms at inclusion were associated with larger placebo response in at least a core symptom domain. LIMITATIONS: About 40% of the trials had an apparent focus on core symptoms. Investigation of the differential impact of predictors on placebo and drug response was impeded by the use of diverse experimental interventions with essentially different mechanisms of action. An individual-participant-data meta-analysis could allow for a more fine-grained analysis and provide more informative answers. CONCLUSIONS: Placebo response in ASD was substantial and predicted by design- and participant-related factors, which could inform the design of future trials in order to improve the detection of efficacy in core symptoms. Potential solutions could be the minimization and careful selection of study sites as well as rigorous participant enrollment and the use of measurements of change not solely dependent on caregivers.

Efficacy and tolerability of pharmacological and non-pharmacological interventions in older patients with major depressive disorder: A systematic review, pairwise and network meta-analysis.

As there is currently no comprehensive evaluation about the efficacy and safety of interventions in elderly patients with major depressive disorder, we did a systematic review and network meta-analysis about all interventions in this population. We searched the specialised register of the Cochrane common mental disorders group, MEDLINE, EMBASE, PsycINFO, CochraneLibrary, ClinicalTrials.gov and the WHO registry until Dec 12, 2017 to identify all randomized controlled trials about the treatment of major depressive disorder in patients over an age of 65. The primary outcome was response defined as reduction of at least 50% on the Hamilton Depression Scale or any other validated depression scale. Secondary outcomes were remission, depressive symptoms, dropouts total, dropouts owing to inefficacy and dropouts due to adverse events, quality of life and social functioning. Additionally, we analysed 116 adverse events. We identified 129 references from 53 RCTs with 9274 participants published from 1990 to 2017. The mean participant age was 73.7 years. In terms of the primary outcome response to treatment the network-meta-analysis showed significant superiority compared to placebo for quetiapine and duloxetine; in addition, agomelatine, imipramine and vortioxetine outperformed placebo in pairwise meta-analyses, and there were also significant superiorities of several antidepressants compared to placebo in secondary efficacy outcomes. Very limited evidence suggests that competitive memory training, geriatric home treatment group and detached mindfulness condition reduce depressive symptoms. Several antidepressants and quetiapine have been shown to be efficacious in elderly patients with major depressive disorder, but due to the comparably few available data, the results are not robust. Differences in the multiple side-effects analysed should also be considered in drug choice. Although there were significant effects for some non-pharmacological treatments, the overall evidence for non-pharmacological treatments in major depressive disorder is insufficient, because it is based on a few trials with usually small sample sizes.

Efficacy, acceptability and tolerability of antipsychotics in patients with schizophrenia and comorbid substance use. A systematic review and meta-analysis.

Patients with schizophrenia and substance related comorbidity or substance induced psychotic disorder are difficult to treat. Although the prevalence of a comorbid substance use is approximately 40% in schizophrenia, such patients are usually excluded from clinical trials. We therefore performed a random-effects meta-analysis of all randomized controlled antipsychotic drug trials in this patient subgroup. We searched multiple databases up to May, 2018. The primary outcome was the reduction of substance user; secondary outcomes were craving, mean reduction of substance use, overall change in schizophrenia symptoms, positive and negative symptoms, response, dropouts, quality of life, social functioning, weight gain, sedation, prolactin, extrapyramidal side effects and use of antiparkinsonian medication. We identified 27 references from 19 RCTs published from 1999 to March 2017 including 1742 participants. The most frequent types of substance abuse were cannabis (8 studies) and cocaine (6 studies) use/dependence. Clozapine was superior to other antipsychotics for reduction of substance use and risperidone to olanzapine for craving. Olanzapine, clozapine and risperidone showed superiority for symptom reduction compared to some other drugs. When reported, results of side-effects followed known patterns. The evidence-base is considerable (19 RCTs), however, firm conclusions cannot be drawn due to small sample sizes of individual studies and insufficient reporting.

Second-generation antipsychotic drugs and short-term somatic serious adverse events: a systematic review and meta-analysis.

BACKGROUND: Antipsychotic drugs might cause acutely occurring, serious side-effects and thus contribute to the increased physical morbidity and mortality observed in patients with severe mental health disorders. We examined this hypothesis by doing a meta-analysis of International Conference on Harmonisation-Good Clinical Practice-defined serious adverse events occurring in placebo-controlled trials of antipsychotics. METHODS: For this systematic review and meta-analysis, we included randomised controlled trials (RCTs) comparing second-generation antipsychotics with placebo. We searched MEDLINE, Embase, Cochrane CENTRAL, BIOSIS, PsycINFO, PubMed, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform for trials published in any language from database inception up until Jan 27, 2017. Trials were included without limitations in population (diagnostic category, age, sex, ethnicity), dosing regimen, blinding status, duration, or publication year. Only psychological studies lasting less than 1 day and trials done in mainland China were excluded. We contacted pharmaceutical companies, drug regulatory authorities, and study investigators for additional data. The primary outcome was the number of patients with at least one somatic serious adverse event. We estimated minimum and maximum numbers of patients with the outcome in each study group and synthesised the results with odds ratios (ORs) in a common-effects meta-analysis. This study is registered with PROSPERO, number CRD42016033930. FINDINGS: We identified 597 RCTs, comprising 108 664 participants, that met the inclusion criteria. 314 trials (67 642 participants) with details on individual serious adverse events available constituted the main dataset for meta-analysis. 88% of these were 13 weeks (approximately 3 months) or shorter in duration (median 6 weeks, IQR 4-9). At least one somatic serious adverse event occurred in 698 (1·63%) to 862 (2·02%) of 42 600 patients on antipsychotics, and in 343 (1·37%) to 419 (1·67%) of 25 042 patients on placebo. The odds ratios (ORs) were 1·24 (95% CI 1·08-1·42) and 1·24 (1·10-1·41) based on the minimum and maximum estimate, respectively. In predefined subgroup analyses we found evidence suggesting a larger effect in older patients (>65 years; OR 1·56, 95% CI 1·22-1·98; 1·58, 1·25-1·99) as compared with adults (18-65 years; 1·09, 0·91-1·29; 1·10, 0·95-1·28); likewise in children or adolescents (<18 years) although the evidence was more uncertain (1·49, 0·81-2·75; 1·54, 0·85-2·77). Of 597 included RCTs, 30 (5%), 358 (60%), and 209 (35%) were rated at high, moderate, or low risk of bias, respectively. τ2 was zero for both analyses of the primary outcome (minimum estimate, maximum estimate). A Bayesian sensitivity analysis using external information on heterogeneity gave similar results. INTERPRETATION: We found evidence that antipsychotics cause short-term somatic serious adverse events on top of somatic serious adverse events occurring independent of treatment. This effect appears to be mainly driven by results in older patients. Hence, clinicians should be aware that antipsychotics are potentially toxic, particularly when treating patients sharing risk factors with the older population. FUNDING: German Ministry of Education and Research.

Antipsychotic drugs for elderly patients with schizophrenia: A systematic review and meta-analysis.

Elderly patients with schizophrenia are a particularly vulnerable group often excluded from clinical trials. Currently there is no evidence-synthesis about the efficacy and safety of antipsychotics in this subgroup. We reviewed all randomized-controlled-trials, about antipsychotics in elderly schizophrenics (last search Dec 12, 2017). Pairwise meta-analyses were conducted. The primary outcome was overall symptoms. Secondary outcomes included positive symptoms, negative symptoms, response, dropouts, quality of life, social functioning and side-effects. We included 29 references from 18 unique randomized-controlled-trials with 1225 participants published from 1958 to 2009. The definition of "elderly" was very heterogeneous across the studies (minimum age 46-65, mean age 57-73). There were evidence gaps for most drugs in many outcomes. In terms of efficacy paliperidone was associated with fewer dropouts due to inefficacy than placebo in the only placebo-controlled-trial. Olanzapine was superior to haloperidol in overall symptoms, negative symptoms and response, and it was associated with fewer dropouts than risperidone. Risperidone and haloperidol produced more prolactin increase than olanzapine, and olanzapine was associated with less use of antiparkinson medication than haloperidol. Although we found no marked differences of the effects of these drugs in the elderly, the evidence presented was based on very few usually small studies. To examine specifically whether there are differences in efficacy and side-effects in elderly, which differs in meaningful ways from the general population, studies in patients who are defined by critiera as truly geriatric, which incorporates older age together with multimorbidity and fraility dimensions, may be more informative.

Efficacy, acceptability, and tolerability of antipsychotics in children and adolescents with schizophrenia: A network meta-analysis.

Children and adolescents with schizophrenia are a particularly vulnerable group. Thus, we integrated all the randomized evidence from the available antipsychotics used for this subgroup by performing a network-meta-analysis and pairwise meta-analysis using a random-effects model. We searched multiple databases up to Nov 17, 2016 (final update search in PubMed: Dec 12, 2017). The primary outcome was efficacy as measured by overall change/endpoint in symptoms of schizophrenia. Secondary outcomes included positive and negative symptoms, response, dropouts, quality of life, social functioning, weight gain, sedation, prolactin, extrapyramidal side effects (EPS) and antiparkinsonian medication. Twenty-eight randomized controlled trials (RCTs) with 3003 unique participants (58% males; mean age 14.41 years) published from 1967 to 2017 were identified. Clozapine was significantly more effective than all other analyzed antipsychotics. Nearly all antipsychotics were more efficacious compared to placebo, but ziprasidone showed no efficacy. In terms of preventing weight gain, molindone, lurasidone and ziprasidone were benign. The highest weight gain was found for clozapine, quetiapine and olanzapine. Most antipsychotics had some sedating effects. Risperidone, haloperidol, paliperidone and olanzapine were associated with prolactin increase. There were evidence gaps for some drugs and many outcomes, especially safety outcomes. Most of the comparisons are based only on one study or just on indirect evidence. Nevertheless, the available direct and indirect evidence showed that the treatment effects were similar compared to findings in adult patients with schizophrenia.

Psychological interventions to reduce positive symptoms in schizophrenia: systematic review and network meta-analysis.

Psychological treatments are increasingly regarded as useful interventions for schizophrenia. However, a comprehensive evaluation of the available evidence is lacking and the benefit of psychological interventions for patients with current positive symptoms is still debated. The present study aimed to evaluate the efficacy, acceptability and tolerability of psychological treatments for positive symptoms of schizophrenia by applying a network meta-analysis approach, that can integrate direct and indirect comparisons. We searched EMBASE, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Library, World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov for randomized controlled trials of psychological treatments for positive symptoms of schizophrenia, published up to January 10, 2018. We included studies on adults with a diagnosis of schizophrenia or a related disorder presenting positive symptoms. The primary outcome was change in positive symptoms measured with validated rating scales. We included 53 randomized controlled trials of seven psychological interventions, for a total of 4,068 participants receiving the psychological treatment as add-on to antipsychotics. On average, patients were moderately ill at baseline. The network meta-analysis showed that cognitive behavioural therapy (40 studies) reduced positive symptoms more than inactive control (standardized mean difference, SMD=-0.29; 95% CI: -0.55 to -0.03), treatment as usual (SMD=-0.30; 95% CI: -0.45 to -0.14) and supportive therapy (SMD=-0.47; 95% CI: -0.91 to -0.03). Cognitive behavioural therapy was associated with a higher dropout rate compared with treatment as usual (risk ratio, RR=0.74; 95% CI: 0.58 to 0.95). Confidence in the estimates ranged from moderate to very low. The other treatments contributed to the network with a lower number of studies. Results were overall consistent in sensitivity analyses controlling for several factors, including the role of researchers' allegiance and blinding of outcome assessor. Cognitive behavior therapy seems to be effective on positive symptoms in moderately ill patients with schizophrenia, with effect sizes in the lower to medium range, depending on the control condition.

Second-generation antipsychotic drugs and short-term mortality: a systematic review and meta-analysis of placebo-controlled randomised controlled trials.

BACKGROUND: Acutely occurring, life-threatening side-effects of antipsychotic drugs might contribute to the reduced life expectancy observed in patients with severe mental disorders. We aimed to assess this hypothesis by doing a systematic review and meta-analysis of deaths occurring in placebo-controlled trials of antipsychotic drugs. METHODS: For this systematic review and meta-analysis, we included randomised controlled trials comparing second-generation antipsychotics with placebo across several diagnostic categories. We searched MEDLINE, EMBASE, Cochrane CENTRAL, BIOSIS, PsycINFO, PubMed, ClinicalTrials.gov, and WHO ICTRP from inception (the last search was done on Jan 21, 2017), and contacted pharmaceutical companies and regulatory authorities for further eligible trials. We examined mortality from any cause (the primary outcome) and mortality from natural causes, suicide, and other non-natural causes. We synthesised the results with odds ratios (ORs) in a common-effects meta-analysis. We investigated the effects of age, diagnostic category, sex, study duration, antipsychotic drug used, drug dose, and polypharmacy in subgroup and meta-regression analyses. This study is registered with PROSPERO, number CRD42016033930. FINDINGS: We identified 596 randomised controlled trials published between 1978 and 2017, comprising 108 747 participants. 352 studies (comprising 84 988 participants) with mortality data available constituted the main dataset for our meta-analysis. 207 (0·4%) deaths were reported in 53 804 patients on an antipsychotic drug and 99 (0·3%) deaths in 31 184 patients on placebo. 300 (85%) of 352 trials were 13 weeks (3 months) or shorter in duration (median 6 weeks; IQR 4-10). We found no evidence of a difference between antipsychotic drugs and placebo in mortality by any cause (OR 1·19; 95% CI 0·93-1·53), from natural causes (1·29; 0·85-1·94), from suicide (1·15; 0·47-2·81), and from other non-natural causes (1·55; 0·66-3·63). Most subgroup and meta-regression analyses did not indicate any important effect moderators. The exceptions were increased mortality in patients with dementia (OR 1·56; 95% CI 1·10-2·21), in elderly patients (1·38; 1·01-1·89), in aripiprazole-treated patients (2·20; 1·00-4·86), and in studies with a higher proportion of women (regression coefficient 0·025; 95% credible interval 0·010-0·040). However, the effects in elderly patients, aripiprazole-treated patients, and women were mainly based on the included dementia trials. For patients with schizophrenia there was no evidence of an increased mortality risk (OR 0·69; 95% CI 0·35-1·35). INTERPRETATION: Overall, and for the main indication of schizophrenia, there is no evidence from randomised trials that antipsychotic drugs increase mortality. However, vulnerable populations (particularly patients with dementia) might be at increased risk. This meta-analysis could only address acute treatment effects leading to death in the short-term, and not long-term effects of antipsychotic drugs on mortality. FUNDING: German Ministry of Education and Research.

How well do patients with a first episode of schizophrenia respond to antipsychotics: A systematic review and meta-analysis.

It is often stated that first-episode patients tend to respond better to antipsychotics than chronic patients, but the exact numbers and moderators of response in this population are unclear. We, therefore, present the first systematic review on response rates of first episode patients with schizophrenia in randomized trials. We searched multiple databases for randomized-controlled trials of antipsychotics in acutely ill patients with a first episode of schizophrenia (last search: November 17, 2016). The outcomes were response rate based on two criteria, at least 50% PANSS or BPRS total score reduction from baseline and at least 20% reduction. Data were pooled in a single-group summary meta-analysis using Comprehensive Meta-Analysis software. Moreover, several potential moderators of response to antipsychotics were examined by meta-regression. We included 17 studies with a total of 3156 participants. On the average, 81.3%/51.9% of the first-episode patients reached an at least 20%/50% PANSS or BPRS reduction from baseline, respectively. Meta-regressions revealed a better treatment response in female patients, in more severely ill patients at baseline, in antipsychotic naïve patients, in patients with a shorter illness duration and in open studies. Study duration and dosage were no significant moderators of response. Our finding suggest that more than 80% of first-episode patients achieved 20% PANSS/BPRS reduction from baseline and around 50% achieved a 50% PANSS/BPRS reduction. Several patient characteristics moderated response rates.

Antipsychotic drugs for the acute treatment of patients with a first episode of schizophrenia: a systematic review with pairwise and network meta-analyses.

BACKGROUND: The first episode of schizophrenia is a pivotal phase of this debilitating illness. Which drug to use remains controversial without a summary of all direct or indirect comparisons of drugs. We did a systematic review with pairwise and network meta-analyses of efficacy and tolerability. METHODS: We searched MEDLINE, Embase, PsycINFO, Cochrane Library, PubMed, Biosis, and ClinicalTrials.gov for randomised controlled trials of antipsychotics for the acute treatment of first-episode schizophrenia, published up to Nov 17, 2016. Our primary outcome was overall change in symptoms. Secondary outcomes were change in positive and negative symptoms, categorical response to treatment, study dropout for any reason and for inefficacy of treatment, use of drugs to treat parkinsonian symptoms, weight gain, sedation, increase in prolactin release, overall functioning, and quality of life. We did the meta-analyses with a random-effects model to calculate standardised mean differences (SMDs) or odds ratios (ORs) with 95% CIs. FINDINGS: We identified 19 relevant randomised controlled trials of 12 antipsychotic drugs that involved 2669 participants. 13 of the studies presented data on the primary outcome. For overall reduction of symptoms, amisulpride (SMD -0·37, 95% CI -0·61 to -0·14), olanzapine (-0·25, -0·39 to -0·12), ziprasidone (-0·25, -0·48 to -0·01), and risperidone (-0·14, -0·27 to -0·01) were significantly more efficacious than haloperidol, but the evidence was very low to moderate quality. Amisulpride was superior for reduction of symptoms to quetiapine (SMD -0·25, 95% CI -0·50 to -0·01). Olanzapine was superior to haloperidol and risperidone for reduction of negative symptoms. Several second-generation antipsychotics were superior to haloperidol in terms of all-cause discontinuation. Olanzapine was associated with at least one use of drugs to treat parkinsonian symptoms and quetiapine with less akathisia than haloperidol, aripiprazole, risperidone, and olanzapine, but, again, evidence was very low to low quality. Molindone was superior to risperidone, haloperidol, and olanzapine in terms of weight gain, and superior to risperidone in terms of increase in prolactin release. INTERPREATION: Haloperidol seems to be a suboptimum treatment option for acute treatment of first-episode schizophrenia, but we found little difference between second-generation antipsychotics. The evidence was generally of low quality and the numbers of patients for each drug were small. Thus, the choice of treatment should be guided primarily by side-effects. FUNDING: German Federal Ministry of Education and Research.