Loukia M. Spineli

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

BACKGROUND The 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. METHODS We 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 Groups 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 controlled trials of patients with schizophrenia or related disorders were eligible. We excluded trials done in patients with predominant negative symptoms, concomitant medical illness, or treatment resistance, and those done in stable patients. Data for seven outcomes were independently extracted by two reviewers. The primary outcome was efficacy, as measured by mean overall change in symptoms. We also examined all-cause discontinuation, weight gain, extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation. FINDINGS We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0·88, 0·73-1·03; amisulpride 0·66, 0·53-0·78; olanzapine 0·59, 0·53-0·65; risperidone 0·56, 0·50-0·63; paliperidone 0·50, 0·39-0·60; zotepine 0·49, 0·31-0·66; haloperidol 0·45, 0·39-0·51; quetiapine 0·44, 0·35-0·52; aripiprazole 0·43, 0·34-0·52; sertindole 0·39, 0·26-0·52; ziprasidone 0·39, 0·30-0·49; chlorpromazine 0·38, 0·23-0·54; asenapine 0·38, 0·25-0·51; lurasidone 0·33, 0·21-0·45; and iloperidone 0·33, 0·22-0·43. Odds ratios compared with placebo for all-cause discontinuation ranged from 0·43 for the best drug (amisulpride) to 0·80 for the worst drug (haloperidol); for extrapyramidal side-effects 0·30 (clozapine) to 4·76 (haloperidol); and for sedation 1·42 (amisulpride) to 8·82 (clozapine). Standardised mean differences compared with placebo for weight gain varied from -0·09 for the best drug (haloperidol) to -0·74 for the worst drug (olanzapine), for prolactin increase 0·22 (aripiprazole) to -1·30 (paliperidone), and for QTc prolongation 0·10 (lurasidone) to -0·90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses. INTERPRETATION Antipsychotics differed substantially in side-effects, and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients. These findings should be considered by mental health policy makers and in the revision of clinical practice guidelines. FUNDING None.

Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis

BACKGROUND Conventional meta-analyses have shown inconsistent results for efficacy of pharmacological treatments for acute mania. We did a multiple-treatments meta-analysis, which accounted for both direct and indirect comparisons, to assess the effects of all antimanic drugs. METHODS We systematically reviewed 68 randomised controlled trials (16,073 participants) from Jan 1, 1980, to Nov 25, 2010, which compared any of the following pharmacological drugs at therapeutic dose range for the treatment of acute mania in adults: aripiprazole, asenapine, carbamazepine, valproate, gabapentin, haloperidol, lamotrigine, lithium, olanzapine, quetiapine, risperidone, topiramate, and ziprasidone. The main outcomes were the mean change on mania rating scales and the number of patients who dropped out of the allocated treatment at 3 weeks. Analysis was done by intention to treat. FINDINGS Haloperidol (standardised mean difference [SMD] -0·56 [95% CI -0·69 to -0·43]), risperidone (-0·50 [-0·63 to -0·38), olanzapine (-0·43 [-0·54 to -0·32], lithium (-0·37 [-0·63 to -0·11]), quetiapine (-0·37 [-0·51 to -0·23]), aripiprazole (-0·37 [-0·51 to -0·23]), carbamazepine (-0·36 [-0·60 to -0·11], asenapine (-0·30 [-0·53 to -0·07]), valproate (-0·20 [-0·37 to -0·04]), and ziprasidone (-0·20 [-0·37 to -0·03]) were significantly more effective than placebo, whereas gabapentin, lamotrigine, and topiramate were not. Haloperidol had the highest number of significant differences and was significantly more effective than lithium (SMD -0·19 [95% CI -0·36 to -0·01]), quetiapine (-0·19 [-0·37 to 0·01]), aripiprazole (-0·19 [-0·36 to -0·02]), carbamazepine (-0·20 [-0·36 to -0·01]), asenapine (-0·26 [-0·52 to 0·01]), valproate (-0·36 [-0·56 to -0·15]), ziprasidone -0·36 [-0·56 to -0·15]), lamotrigine (-0·48 [-0·77 to -0·19]), topiramate (-0·63 [-0·84 to -0·43]), and gabapentin (-0·88 [-1·40 to -0·36]). Risperidone and olanzapine had a very similar profile of comparative efficacy, being more effective than valproate, ziprasidone, lamotrigine, topiramate, and gabapentin. Olanzapine, risperidone, and quetiapine led to significantly fewer discontinuations than did lithium, lamotrigine, placebo, topiramate, and gabapentin. INTERPRETATION Overall, antipsychotic drugs were significantly more effective than mood stabilisers. Risperidone, olanzapine, and haloperidol should be considered as among the best of the available options for the treatment of manic episodes. These results should be considered in the development of clinical practice guidelines. FUNDING None.

Efficacy of Pharmacotherapy and Psychotherapy for Adult Psychiatric Disorders: A Systematic Overview of Meta-analyses

IMPORTANCE There is debate about the effectiveness of psychiatric treatments and whether pharmacotherapy or psychotherapy should be primarily used. OBJECTIVES To perform a systematic overview on the efficacy of pharmacotherapies and psychotherapies for major psychiatric disorders and to compare the quality of pharmacotherapy and psychotherapy trials. EVIDENCE REVIEW We searched MEDLINE, EMBASE, PsycINFO, and the Cochrane Library (April 2012, with no time or language limit) for systematic reviews on pharmacotherapy or psychotherapy vs placebo, pharmacotherapy vs psychotherapy, and their combination vs either modality alone. Two reviewers independently selected the meta-analyses and extracted efficacy effect sizes. We assessed the quality of the individual trials included in the pharmacotherapy and psychotherapy meta-analyses with the Cochrane risk of bias tool. FINDINGS The search yielded 45,233 results. We included 61 meta-analyses on 21 psychiatric disorders, which contained 852 individual trials and 137,126 participants. The mean effect size of the meta-analyses was medium (mean, 0.50; 95% CI, 0.41-0.59). Effect sizes of psychotherapies vs placebo tended to be higher than those of medication, but direct comparisons, albeit usually based on few trials, did not reveal consistent differences. Individual pharmacotherapy trials were more likely to have large sample sizes, blinding, control groups, and intention-to-treat analyses. In contrast, psychotherapy trials had lower dropout rates and provided follow-up data. In psychotherapy studies, wait-list designs showed larger effects than did comparisons with placebo. CONCLUSIONS AND RELEVANCE Many pharmacotherapies and psychotherapies are effective, but there is a lot of room for improvement. Because of the multiple differences in the methods used in pharmacotherapy and psychotherapy trials, indirect comparisons of their effect sizes compared with placebo or no treatment are problematic. Well-designed direct comparisons, which are scarce, need public funding. Because patients often benefit from both forms of therapy, research should also focus on how both modalities can be best combined to maximize synergy rather than debate the use of one treatment over the other.

Evaluating the impact of imputations for missing participant outcome data in a network meta-analysis

Background In a meta-analysis of trials with missing outcome data, a parameter known as informative missing odds ratio (IMOR) can be used to quantify the relationship between informative missingness and a binary outcome. IMORs also account for the increased uncertainty due to missingness in the meta-analysis results. Purpose To extend the idea of IMOR into a network meta-analysis (NMA) setting in order to explore the impact of missing outcome data on the inferences about the relative effectiveness of several competing treatments in psychiatric trials. Methods IMORs were estimated in two datasets comparing anti-manic treatments and antidepressants. The outcome was response to treatments. In the original meta-analyses, missing participants were assumed to have failed regardless the treatment they were allocated to. To evaluate the robustness of this assumption in each dataset, several imputations of the missing outcomes were studied by an IMOR parameter in the NMA model. By comparing the odds ratios for efficacy under the initial analysis and under several assumptions about the missingness, we assessed the consistency of the conclusions. The missing data mechanism was studied by comparing the prior with the posterior IMOR distribution. Models were fitted using Markov chain Monte Carlo (MCMC) in WinBUGS. Results In both datasets, the relative effectiveness of the treatments seems to be affected only by the two extreme imputation scenarios of worst- and best-case analyses. Moreover, heterogeneity increases in both datasets under these two extreme scenarios. Overall, there is a non-significant change on the ranking of the anti-manic and antidepressant treatments. The posterior and prior IMOR distributions are very similar showing that the data do not provide any information about the true outcome in missing participants. There is a very weak indication that missing participants tend to fail in placebo and paroxetine, while the opposite occurs for sertraline, fluoxetine, and fluvoxamine. Limitations Investigation of informative missingness was limited two classes of treatments and for dichotomous outcome measures. The proportion of missing outcomes was very low overall, and hence, the power of detecting any differences in effectiveness estimated under the various imputation methods is small. Conclusions Sensitivity analysis to account for missing outcome data and their uncertainty in the NMA can be undertaken by extending the idea of IMOR. In two case examples, we found no differences between the various models due to low missing data rate. In line with previous observations, data carry little information about the reason of missingness.

Reporting and Handling Missing Outcome Data in Mental Health: A Systematic Review of Cochrane Systematic Reviews and Meta-Analyses.

OBJECTIVES The purpose of the study was to provide empirical evidence about the reporting of methodology to address missing outcome data and the acknowledgement of their impact in Cochrane systematic reviews in the mental health field. METHODS Systematic reviews published in the Cochrane Database of Systematic Reviews after January 1, 2009 by three Cochrane Review Groups relating to mental health were included. RESULTS One hundred ninety systematic reviews were considered. Missing outcome data were present in at least one included study in 175 systematic reviews. Of these 175 systematic reviews, 147 (84%) accounted for missing outcome data by considering a relevant primary or secondary outcome (e.g., dropout). Missing outcome data implications were reported only in 61 (35%) systematic reviews and primarily in the discussion section by commenting on the amount of the missing outcome data. One hundred forty eligible meta-analyses with missing data were scrutinized. Seventy-nine (56%) of them had studies with total dropout rate between 10 and 30%. One hundred nine (78%) meta-analyses reported to have performed intention-to-treat analysis by including trials with imputed outcome data. Sensitivity analysis for incomplete outcome data was implemented in less than 20% of the meta-analyses. CONCLUSIONS Reporting of the techniques for handling missing outcome data and their implications in the findings of the systematic reviews are suboptimal.

Initial orthodontic alignment effectiveness with self-ligating and conventional appliances: A network meta-analysis in practice

Systematic reviews of well-designed trials constitute a high level of scientific evidence and are important for medical decision making. Meta-analysis facilitates integration of the evidence using a transparent and systematic approach, leading to a broader interpretation of treatment effectiveness and safety than can be attained from individual studies. Traditional meta-analyses are limited to comparing just 2 interventions concurrently and cannot combine evidence concerning multiple treatments. A relatively recent extension of the traditional meta-analytical approach is network meta-analysis, which allows, under certain assumptions, the quantitative synthesis of all evidence under a unified framework and across a network of all eligible trials. Network meta-analysis combines evidence from direct and indirect information via common comparators; interventions can therefore be ranked in terms of the analyzed outcome. In this article, the network meta-analysis approach is introduced in a nontechnical manner using a worked example on the treatment effectiveness of conventional and self-ligating appliances.

The gender gap: discrepant human T-cell reconstitution after cord blood stem cell transplantation in humanized female and male mice

The gender gap: discrepant human T-cell reconstitution after cord blood stem cell transplantation in humanized female and male mice

Clinical outcome of brain metastases differs significantly among breast cancer subtypes

Brain metastases in patients with breast cancer are associated with a poor survival rate. A small number of studies have challenged this premise, suggesting that survival times following brain metastasis differ significantly between breast cancer subtypes. In the current study, overall survival (OS), brain metastases-free survival (BMFS) and survival following brain metastases (SFBM) were found to be associated with the intrinsic breast cancer subtype. A total of 1,147 patients with invasive breast cancer who were treated at the Hannover Medical School between January 2004 and December 2010 were included, from which 54 patients with brain metastases were identified. The Kaplan-Meier method or Cox regression analyses were performed for analysis of survival. OS was found to differ significantly between breast cancer subtypes: OS was significantly shorter in patients with triple-negative (TN) cancer compared with patients with human epidermal growth factor receptor (HER2)-enriched tumors (P<0.001). In addition, median BMFS times differed significantly between luminal (1,003 days), HER2-enriched (514 days) and TN breast cancer patients (460 days) (P=0.045). The median durations of SFBM were 386 days in luminal, 310 days in HER2-enriched and 147 days in TN breast cancer patients (P=0.029). The results suggested that patients with luminal breast cancer have a lower risk of brain metastases and the most favorable outcome with regard to BMFS, whereas patients with HER2-positive or TN breast cancer have a significantly higher risk of developing brain metastases. Compared with TN breast cancer, the duration of SFBM was doubled in HER2-enriched cancers. These findings may have important implications for treatment and follow-up strategies in patients with breast cancer.

Measuring in vivo cerebral maturation using age-related T2 relaxation times at 3 T

OBJECTIVE To examine age-related changes in T2 relaxation times during infancy and childhood in order to assess T2 values obtained from routine MRI as a biomarker. METHODS From our pool of clinical pediatric MRI examinations at 3T all patients with normal conventional MRI scans were retrospectively selected. Depending on their clinical findings the identified 99 patients (0-199months) were divided into 43 healthy controls and 56 diseased children with various clinical abnormalities (developmental delay, epilepsy, prematurity, and deafness). T2 maps based on routinely performed triple echo turbo spin echo sequences were created. T2 values were measured in 22 brain regions to determine age-related changes. We also investigated whether such changes differ between healthy and diseased children. RESULTS Age significantly reduced T2 relaxation times across all regions (p<0.05), but health status had no impact. With increasing age, T2 values decreased continuously, with declines faster over the first 10months and slower thereafter. Early rapid and later slow decline was similar in healthy and diseased groups. CONCLUSIONS Using T2 maps based on clinical MRI data we could determine age-related T2 relaxation times in 22 brain regions during infancy and childhood. Our data have relevance for future investigator independent T2 relaxation time measurements in determining whether T2 values are within the normal range or should be considered as potentially pathologic.

Addressing missing participant outcome data in dental clinical trials

Missing outcome data are common in clinical trials and despite a well-designed study protocol, some of the randomized participants may leave the trial early without providing any or all of the data, or may be excluded after randomization. Premature discontinuation causes loss of information, potentially resulting in attrition bias leading to problems during interpretation of trial findings. The causes of information loss in a trial, known as mechanisms of missingness, may influence the credibility of the trial results. Analysis of trials with missing outcome data should ideally be handled with intention to treat (ITT) rather than per protocol (PP) analysis. However, true ITT analysis requires appropriate assumptions and imputation of missing data. Using a worked example from a published dental study, we highlight the key issues associated with missing outcome data in clinical trials, describe the most recognized approaches to handling missing outcome data, and explain the principles of ITT and PP analysis.