Relationship between quality of reports of antidepressant randomized controlled trials and treatment estimates: systematic review, meta-analysis, and meta-regression analysis.

In the field of meta-analyses of antidepressant randomized controlled trials (RCTs), it is unclear whether a relationship exists between study quality, treatment estimates, and different quality measures. In this systematic review, we investigated whether quality of RCTs allocating patients with major depression to fluoxetine versus any other antidepressant agent influenced treatment estimates. We designed a systematic review and meta-regression analysis of RCTs, obtaining data from the Cochrane Collaboration Depressive Anxiety and Neurosis Controlled Trials Register, Cochrane Controlled Trials Register, MEDLINE, EMBASE, reference lists, and specialist textbooks, with no language restriction. Two reviewers independently extracted data. Efficacy and tolerability outcomes were calculated for the overall sample and for the subgroup of high-quality trials. Quality was assessed using the Jadad scale, the Cochrane Collaboration Depressive Anxiety and Neurosis quality assessment instrument and 3 items of the CONSORT statement. A meta-regression analysis was also carried out. Thirty-nine RCTs contributed to efficacy and 74 to tolerability analyses. We found no correlation between the methodological quality of reports of RCTs and treatment estimates of efficacy and tolerability. Subgroup analyses of high-quality trials provided treatment estimates that did not materially change from overall estimates. This finding was further confirmed by the meta-regression analysis. Quality is an important issue and meta-analyses should take quality into consideration to provide less biased treatment estimates. However, current quality measures are not related with treatment estimates in antidepressant trials and may not be useful weighting tools when meta-analyses of data extracted from antidepressant RCTs are carried out

Validity of the impact factor of journals as a measure of randomized controlled trial quality.

OBJECTIVE: To assess whether the impact factor, a measure of the frequency with which journal articles are cited in the scientific literature, is a proxy measure of the quality of articles reporting the results of randomized controlled trials. METHOD: The quality of trials included in an ongoing Cochrane review concerned with the antidepressant fluoxetine was assessed using the Cochrane Collaboration Depression, Anxiety, and Neurosis quality assessment instrument, the Jadad scale, and the quality criterion of the Cochrane Collaboration Handbook. Journal impact factors were extracted from the Journal Citation Report. RESULTS: A total of 131 articles reported results from 132 clinical trials comparing fluoxetine with other antidepressants. The relationship between trial quality and the impact factor of journals where these studies were published, stratified by period of publication, revealed that journals with impact factors above 4 points published only trials with above-average overall quality ratings, while journals with impact factors below 4 points published both high- and low-quality trials. The Jadad scale revealed similar quality in trials published in journals with high, medium, and low impact factors (Pearson chi(2) = 0.298, p = .861), and the quality criterion of the Cochrane Collaboration Handbook showed unclear randomization in the majority of trials and in all 15 trials published in high-impact factor journals (Pearson chi(2) = 4.678, p = .096). CONCLUSION: The impact factor of journals is not a valid measure of randomized controlled trial quality

Fluoxetine versus other types of pharmacotherapy for depression

Background: Depression is common in primary care and it is associated with marked personal, social and economic morbidity, and creates significant demands on service providers in terms of workload. Treatment is predominantly pharmaceutical or psychological. Fluoxetine, the first of a group of antidepressant (AD) agents known as selective serotonin reuptake inhibitors (SSRIs), has been studied in many randomised controlled trials (RCTs) in comparison with tricyclic (TCA), heterocyclic and related ADs, and other SSRIs. These comparative studies provided contrasting findings. In addition, systematic reviews of RCTs have always considered the SSRIs as a group, and evidence applicable to this group of drugs might not be applicable to fluoxetine alone. The present systematic review assessed the efficacy and tolerability profile of fluoxetine in comparison with TCAs, SSRIs and newer agents. Objectives: To determine the efficacy of fluoxetine, compared with other ADs, in alleviating the acute symptoms of depression, and to review its acceptability. Search strategy: Relevant studies were located by searching the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), the Cochrane Central Register of Controlled Trials (CENTRAL), Medline (1966-2004) and Embase (1974-2004). Non-English language articles were included. Selection criteria: Only RCTs were included. For trials which have a crossover design only results from the first randomisation period were considered. Data collection and analysis: Data were independently extracted by two reviewers using a standard form. Responders to treatment were calculated on an intentionto-treat basis: drop-outs were always included in this analysis. When data on drop-outs were carried forward and included in the efficacy evaluation, they were analysed according to the primary studies; when dropouts were excluded from any assessment in the primary studies, they were considered as treatment failures. Scores from continuous outcomes were analysed including patients with a final assessment or with the last observation carried forward. Tolerability data were analysed by calculating the proportion of patients who failed to complete the study and who experienced adverse reactions out of the total number of randomised patients. The primary analyses used a fixed effects approach, and presented Peto Odds Ratio (Peto OR) and Standardised Mean Difference (SMD). Main results: On a dichotomous outcome fluoxetine was less effective than dothiepin (Peto OR: 2.09, 95% CI 1.08 to 4.05), sertraline (Peto OR: 1.40, 95% CI 1.11 to 1.76), mirtazapine (Peto OR: 1.64, 95% CI 1.01 to 2.65) and venlafaxine (Peto OR: 1.40, 95% CI 1.15 to 1.70). On a continuous outcome, fluoxetine was more effective than ABT-200 (Standardised Mean Difference (SMD) random effects: - 1.85, 95%CI - 2.25 to - 1.45) and milnacipran (SMD random effects: - 0.38, 95% CI - 0.71 to - 0.06); conversely, it was less effective than venlafaxine (SMD random effect: 0.11, 95% CI 0.00 to 0.23), however these figures were of borderline statistical significance. Fluoxetine was better tolerated than TCAs considered as a group (Peto OR: 0.78, 95% CI 0.68 to 0.89), and was better tolerated in comparison with individual ADs, in particular than amitriptyline (Peto OR: 0.64, 95% CI 0.47 to 0.85) and imipramine (Peto OR: 0.79, 95% CI 0.63 to 0.99), and among newer ADs than ABT-200 (Peto OR: 0.21, 95% CI 0.10 to 0.41), pramipexole (Peto OR: 0.20, 95% CI 0.08 to 0.47) and reboxetine (Peto OR: 0.61, 95% CI 0.40 to 0.94). Authors' conclusions There are statistically significant differences in terms of efficacy and tolerability between fluoxetine and certain ADs, but the clinical meaning of these differences is uncertain, and no definitive implications for clinical practice can be drawn. From a clinical point of view the analysis of antidepressants' safety profile (adverse effect and suicide risk) remains of crucial importance and more reliable data about these outcomes are needed. Waiting for more robust evidence, treatment decisions should be based on considerations of clinical history, drug toxicity, patient acceptability, and cost.We need for large, pragmatic trials, enrolling heterogeneous populations of patients with depression to generate clinically relevant information on the benefits and harms of competitive pharmacological options. A metaanalysis of individual patient data from the randomised trials is clearly necessary. Copyright © 2009 The Cochrane Collaboration. Published by John Wiley and Sons, Ltd

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