Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis

GENDER DIFFERENCES IN PREMORBID, ENTRY, TREATMENT, AND OUTCOME CHARACTERISTICS IN A TREATED EPIDEMIOLOGICAL SAMPLE OF 661 PATIENTS WITH FIRST EPISODE PSYCHOSIS

C.15.05 Schizophrenia: antipsychotics in the acute phase and beyond

SummaryBackgroundThe question of which antipsychotic drug should be preferred for the treatment of schizophrenia is controversial, and conventional pairwise meta-analyses cannot provide a hierarchy based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs.MethodsWe did a Bayesian-framework, multiple-treatments meta-analysis (which uses both direct and indirect comparisons) of randomised controlled trials to compare 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia. We searched the Cochrane Schizophrenia Group’s specialised register, Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for reports published up to Sept 1, 2012. Search results were supplemented by reports from the US Food and Drug Administration website and by data requested from pharmaceutical companies. Blinded, randomised con...

SummaryBackgroundSchizophrenia 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.MethodsWe 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.FindingsWe 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.InterpretationThere 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.FundingGerman Ministry of Education and Research and National Institute for Health Research

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

BackgroundThere is rising awareness about the need of multi-disciplinary approaches integrating psychological treatments for schizophrenia, but a comprehensive evidence base on their relative efficacy is lacking. Conventional pairwise meta-analyses cannot provide a hierarchy based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, acceptability and tolerability of psychological interventions for schizophrenia.MethodsWe performed a network meta-analysis (which uses both direct and indirect comparisons) of randomized controlled trials on psychological treatments aimed at positive symptoms in the acute treatment of schizophrenia, compared with another psychological intervention or with a no treatment condition (waiting list, treatment as usual). We excluded trials done in patients with predominant negative symptoms, concomitant psychiatric disorders or medical illnesses, and those done in first episode or stable patients. Published and unpublished studies were sought through database searches, trial registries and websites. Study selection and data extraction were conducted by at least two independent reviewers. Our primary outcome is the change in positive symptoms on a validated rating scale. Secondary outcomes include number of dropouts, overall and negative symptoms of schizophrenia, response, relapse, adherence, depression, quality of life, functioning and adverse events. Analyses were conducted in R within a frequentist framework. The risk of bias in studies has been evaluated using the Cochrane Risk of Bias tool and the credibility of the evidence will be evaluated using an adaptation of the GRADE framework to NMA, recommended by the Cochrane guidance. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. The protocol of this review has been registered in Prospero (registration number: CRD42017067795).ResultsAfter screening 20196 references for title and abstract and 2555 full text articles, we identified 58 suitable trials, for a total of 3956 participants.Regarding primary outcome positive symptoms, only Cognitive Behavioural Therapy was significantly more effective than treatment as usual, with a standardised mean difference of -0.59 [95% credible interval -1.03; -0.16].The standardised mean differences with 95% credible intervals for other interventions were: Acceptance and Commitment Therapy -0.07 [-2.12; 1.98], Cognitive Therapy -0.18 [-1.92; 1.55], Hallucination Treatment -0.69 [-2.40; 1.01], Metacognitive Therapy -0.26 [-1.16; 0.64], Mindfulness -0.26 [-2.14; 1.62], with heterogeneity tau2 = 0.6942.Data analyses on other outcomes are ongoing.DiscussionWe are going to investigate the possible sources of heterogeneity with the pre-planned subgroup analyses: number of sessions, study duration, individual versus group setting, expertise of the therapist and baseline severity.A network meta-analysis is the only methodology that allows the production of hierarchies of interventions for treatment of schizophrenia. Such hierarchies, saying which treatment is likely to be the best, the second best and so on, are essential for guideline development. The results of this study are therefore likely to provide knowledge of great impact for treatment decisions.This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 701717.

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

Comparative efficacy and acceptability of antidepressant treatment in patients with post-stroke depression: a multiple-treatments meta-analysis

Combined use of electroconvulsive therapy (ECT) and antipsychotics in acute phases of schizophrenia remains controversial and inadequately investigated. This study tried to examine whether the ECT-antipsychotic combination was more efficacious than antipsychotic drugs used alone in the acute phase treatment of schizophrenia, by way of an open review and an exploratory meta-analysis of the Indian studies on the subject. Eleven studies (n = 651) and 4 controlled trials (n = 113) were selected for the open review and the meta-analysis, respectively. For the meta-analysis, a standard chi analysis was undertaken to check for heterogeneity. Brief Psychiatric Rating Scale scores were used to estimate treatment effects. The open review suggested that the ECT-antipsychotic combination was more efficacious than antipsychotic drugs used alone in the first few weeks of treatment of schizophrenia. The meta-analysis, using the Inverse Weighted Variance Model, showed that the ECT-antipsychotic combination provides an advantage of approximately 5 Brief Psychiatric Rating Scale points over antipsychotic drugs, in the first 4 to 5 weeks of treatment of schizophrenia (mean treatment effect, 4.89; 95% confidence intervals, 0.50-9.38). The studies reviewed thus indicated that ECT-antipsychotic combinations might be better than antipsychotic drugs used alone in the first few weeks of treatment of schizophrenia; the main benefit seemed to be an acceleration of treatment response. Although the evidence was not conclusive because of several methodological difficulties, it does suggest that further research is required to determine the usefulness of the ECT-antipsychotic combination in the acute treatment of schizophrenia.

Pharmacotherapy remains the mainstay of treatment for acute bipolar mania, but there are many choices, including mood stabilizers (MSs) and antipsychotics (APs). To provide an up-to-date and comprehensive review of the efficacy, acceptability and adverse effects of MSs and APs as combination or augmentation therapy versus monotherapy with either drug class for the treatment of acute mania. The Cochrane Central Register of Controlled Trials, MEDLINE, PsycINFO, Scopus, and clinical trial databases were searched for articles published between the inception of the databases and July 1, 2014. The following keywords were used: [bipolar disorder, mania, manic, mixed bipolar, schizoaffective] combined with the names of MSs and APs. The reference lists of all the identified randomized controlled trials (RCTs), articles that cited the identified trials, and recent systematic reviews were also checked. Double-blind RCTs comparing MS and AP as combination or augmentation therapy with either monotherapy during the acute phase treatment of mania were included in the present study. The electronic search yielded 6,445 potential articles in September 2013 and 264 new references in an updated search performed in July 2014. Finally, 19 RCTs were considered eligible for our meta-analyses: MS plus AP combination or augmentation therapy was compared with MS monotherapy in 14 trials (n = 3,651) and with AP monotherapy in 6 trials (n = 606) [one study compared combination therapy versus both MS monotherapy and AP monotherapy]. The primary outcomes were the mean change scores on validated rating scales for mania and all-cause discontinuation at 3 weeks. The secondary outcomes included response, remission, the mean change scores for depression, dropouts due to adverse events and to inefficacy, and adverse events at 3 weeks and mean change scores on validated rating scales at 1 week. Using random-effects models, standardized mean difference (SMD), risk ratio (RR) and numbers needed to treat with their 95 % confidence intervals (CIs) were calculated. Most patients included in trials comparing combination/augmentation therapy versus MS monotherapy had prior treatment with an MS, while more than 70 % of participants in trials comparing combination/augmentation therapy versus AP monotherapy had not been on medications or were washed out from their previous medication before randomization. MS plus AP combination/augmentation therapy was more effective than MS monotherapy in terms of change in scores on mania rating scales at 3 weeks (SMD -0.26; 95 % CI -0.36 to -0.15) and at 1 week (SMD -0.17, -0.29 to -0.04). MS plus AP combination/augmentation therapy was more effective than AP monotherapy at 3 weeks (SMD -0.31, -0.50 to -0.12), but not at 1 week (SMD -0.22, -0.84 to 0.40). No significant differences were seen between the combination/augmentation therapy and either monotherapy group in study withdrawal for any reason (MS + AP vs. MS monotherapy: RR 0.99, 0.88-1.12; MS + AP vs. AP monotherapy: RR 0.70, 0.47-1.04) or adverse events (MS + AP vs. MS monotherapy: RR 1.39, 0.97-1.99; MS + AP vs. AP monotherapy: RR 0.62, 0.27-1.40). The combination/augmentation therapy was associated with more side effects, especially with somnolence, while it did not increase treatment-emergent depression. Combining MS and AP is more efficacious and more burdensome than, but overall as acceptable as, the continuation of MS or AP monotherapy, when either monotherapy has not been successful. There is currently no robust evidence to judge whether MS and AP combination therapy is more efficacious than MS monotherapy as the initial therapy for acutely manic patients without prior medication.

Short-term efficacy and tolerability of lurasidone in the treatment of acute schizophrenia: A meta-analysis of randomized controlled trials

Alpha-2 Agonists for Attention-Deficit/Hyperactivity Disorder in Youth: A Systematic Review and Meta-Analysis of Monotherapy and Add-On Trials to Stimulant Therapy

Background Treatment using add-on antidepressants with antipsychotic drugs in negative symptoms of schizophrenia has been reviewed recently in comprehensive meta-analyses. Tranylcypromine (TCP), an irreversible monoamine oxidase (MAO)-A/B inhibitor applied in treatment resistant depression, was not included because of strict requirements for quality of study design. To get a clear picture of available evidence for this resource in the treatment of schizophrenia, we conducted a review and meta-analysis of add-on TCP in the treatment of predominant negative symptoms of schizophrenia (negative schizophrenia). Methods Seven controlled studies of add-on TCP in schizophrenia with predominant negative symptoms were found in a search of multiple databases. A subset of four studies of the prospective and parallel comparison of add-on TCP with antipsychotic drugs vs. antipsychotic drug monotherapy and meeting minimum quality criteria formed the primary meta-analysis. The effect size was calculated as the natural logarithm of the odds ratio (logOR) of responders and non-responders. Results In the primary meta-analysis, a pooled logOR = 1.092 with 95%CI 0.410–1.774 (I 2 = 43.4%, moderate heterogeneity) was calculated according to a fixed-effect model. Heterogeneity was reduced for three double-blind studies of add-on TCP with trifluoperazine (TFP) vs. TFP-monotherapy and resulted a pooled logOR = 0.916 with 95%CI 0.216–1.616 (I 2 negative, no heterogeneity). A significant logOR = 1.558 with 95%CI 0.340–2.776 was found for TCP/TFP compared to placebo in one study. In a meta-analysis of extrapyramidal adverse effects, studies were very heterogeneous and revealed no significant differences between treatments. The risk of exacerbation of positive symptoms with add-on TCP was found to be very low for a duration of treatment of 12–16 weeks. No cases of hypertensive crisis were reported. The main methodical limitations were insufficient description of randomization or matching of patients without randomization. The main clinical limitation is a gap of data for add-on TCP with second-generation antipsychotics. Conclusion New studies are needed for add-on TCP with antipsychotic drugs in schizophrenia with predominant negative symptoms. Trials of this treatment may be possible in rare and selected cases. The therapeutic effect of add-on TCP may be explained by a strong dopaminergic activity.

We examined whether memantine add-on to antipsychotic treatment is beneficial in schizophrenia treatment. This systematic review and meta-analysis aimed to achieve stronger evidence on the efficacy and safety of memantine add-on for treating schizophrenia. We analyzed double-blind, randomized, placebo-controlled trials of memantine add-on treatment in schizophrenia patients receiving antipsychotics. The primary outcomes were amelioration of negative symptoms and all-cause discontinuation. Dichotomous outcomes are presented as risk ratios (RRs), and continuous outcomes are presented as mean differences (MDs) or standardized mean differences (SMDs). Eight studies (n=448) were included. Although memantine add-on treatment was superior to placebo for ameliorating negative symptoms (SMD=-0.96, p=0.006, I 2=88%; N=7, n=367) in the Positive and Negative Syndrome Scale general subscale (MD=-1.62, p=0.002, I 2=0%; N=4, n=151) and Mini-Mental Status Examination score (MD=-3.07, p<0.0001, I 2=21%; N=3, n=83), there were no statistically significant differences in the amelioration of overall (SMD=-0.75, p=0.06, I 2 =86%; N=5, n=271), positive (SMD=-0.46, p=0.07, I 2=80%; N=7, n=367), and depressive symptoms (SMD=-0.127, p=0.326, I 2=0%; N=4, n=201); all-cause discontinuation (RR=1.34, p=0.31, I 2=0%; N=8, n=448); and individual adverse events (fatigue, dizziness, headache, nausea, constipation) between the groups. For negative symptoms, the significant heterogeneity disappeared when risperidone studies alone were considered (I 2=0%). However, memantine add-on treatment remained superior to placebo (SMD=-1.29, p=0.00001). Meta-regression analysis showed that patient age was associated with memantine-associated amelioration of negative symptoms (slope=0.171, p=0.0206). Memantine add-on treatment may be beneficial for treating psychopathological symptoms (especially negative symptoms) in schizophrenia patients. The negative-symptom effect size may be associated with younger adult schizophrenia patients.