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Gartlehner G, Hansen RA, Reichenpfader U, et al. Drug Class Review: Second-Generation Antidepressants: Final Update 5 Report [Internet]. Portland (OR): Oregon Health & Science University; 2011 Mar.

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Drug Class Review: Second-Generation Antidepressants

Drug Class Review: Second-Generation Antidepressants: Final Update 5 Report [Internet].

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Methods

A. Literature Search

To identify articles relevant to each key question we searched PubMed, Embase, The Cochrane Library, CINAHL, PsycINFO, and the International Pharmaceutical Abstracts. We used either Medical Subject Headings (MeSH or MH) as search terms when available or key words when appropriate. We combined terms for selected indications (MDD, dysthymia, subsyndromal depression, seasonal affective disorder, general anxiety disorder, PTSD, OCD, panic disorder, social anxiety disorder, PMDD), drug interactions, and adverse events with a list of 12 specific second-generation antidepressants (citalopram, desvenlafaxine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, mirtazapine, duloxetine, venlafaxine, bupropion, and nefazodone). We limited the electronic searches to “human” and “English language.” Sources were searched from 1980 to 2010 (September) to capture literature relevant to the scope of our topic. See Appendix A for complete search strategy.

We manually searched reference lists of pertinent and relevant review articles and letters to the editor. All citations were imported into an electronic database (Endnote® v. X.04). Additionally, we handsearched the Center for Drug Evaluation and Research (CDER) database to identify unpublished research submitted to the FDA. The search strategy is summarized in Appendix A.

Furthermore the Center for Evidence-based Policy at the Oregon Health and Science University (OHSU) contacted pharmaceutical manufacturers and invited them to submit dossiers, including citations, using a protocol issued by the Center for Evidence-based Policy (http://www.ohsu.edu/drugeffectiveness/pharma/Final_Submission_Protocol_Ver1_1.pdf). We received dossiers from six pharmaceutical companies.

B. Study Selection

Two persons independently reviewed abstracts. If both reviewers agreed that the trial did not meet eligibility criteria, we excluded it. We obtained the full text of all remaining articles. Records were considered for exclusion if they did not meet pre-established eligibility criteria with respect to study design or duration, patient population, interventions, outcomes, and comparisons to antidepressant medications outside our scope of interest.

For this review, results from well-conducted, valid head-to-head trials provide the strongest evidence to compare drugs with respect to effectiveness, efficacy, and adverse events. RCTs of at least 6 weeks’ duration and an outpatient study population with a sample size greater than 40 participants were eligible for inclusion. We defined head-to-head trials as those comparing one second-generation antidepressant with another.

We did not examine placebo-controlled trials in detail if head-to-head trials were available. We viewed FDA approval as evidence for general efficacy; therefore, we did not review placebo-controlled trials for FDA-approved indications except when outcome measures assessed quality of life or other health outcomes that are not generally required for FDA approval.

If no head-to-head evidence was published, we reviewed placebo-controlled trials for indications of interest that had not already been approved by the FDA. We reviewed all placebo-controlled trials for indications without FDA approval to provide an overview of efficacy without taking drug equivalency into account. In other words, we did not evaluate the dosage of one drug relative to the dosage of an alternative drug in a different trial. High dosages may yield greater treatment effects compared to placebo than do low or medium dosages. Comparisons of treatment effects across trials must, therefore, be made cautiously.

For adverse events we included both experimental and observational studies. For observational studies, we included those with large sample sizes (≥100 patients), lasting at least 1 year that reported an included outcome.

Initially, we reviewed studies with health outcomes as primary outcome measures. Outcomes for efficacy or effectiveness were response, remission, speed of response, relapse, functional capacity, and hospitalization. If no study measuring health outcomes was available for a particular indication or population subgroup, we included intermediate outcomes (e.g., changes in depression scores). Safety outcomes included overall and specific adverse events (e.g., suicide, sexual side effects, hyponatremia, weight change, seizures, gastrointestinal symptoms), withdrawals attributable to adverse events, serious adverse events, and drug interactions.

We included meta-analyses in our evidence report if we found them to be relevant for a key question and of good or fair methodological quality.10 We did not review individual studies if they were included in a high-quality meta-analysis. We excluded meta-analyses that were not based on a comprehensive systematic literature search or did not maintain the units of the studies in their statistical analyses. We checked our database to guarantee that our literature search had detected trials included in any meta-analyses that we discarded, and we then obtained any missing articles.

C. Data Abstraction

We designed and used a structured data abstraction form to ensure consistency of appraisal for each study. Trained reviewers abstracted data from each study and assigned an initial quality rating. A senior reviewer read each abstracted article, evaluated the completeness of the data abstraction, and confirmed the quality rating. We abstracted the following data from included trials: study design, eligibility criteria, intervention (drugs, dose, duration), additional medications allowed, methods of outcome assessment, population characteristics, sample size, loss to follow-up, withdrawals due to adverse events, results, and adverse events reported. We recorded intention-to-treat results if available.

D. Quality Assessment

We assessed the internal validity (quality) of trials based on predefined criteria (Appendix B). These criteria are based on those developed by the US Preventive Services Task Force (ratings: good-fair-poor)11 and the National Health Service Centre for Reviews and Dissemination.12 External validity (generalizability) was assessed and reported but did not influence quality ratings.

Two independent reviewers assigned quality ratings; they resolved any disagreements by discussion and consensus or by consulting a third, independent party. Elements of internal validity assessment included, among others, randomization and allocation concealment, similarity of compared groups at baseline, use of intention-to-treat analysis, and overall and differential loss to follow-up.

Loss to follow-up was defined as the number of persons randomized who did not reach the endpoint of the study,13 independent of the reason and the use of intention-to-treat analysis. We adopted a cut-off point of 20 percent loss to follow-up as a limit beyond which bias was likely to be introduced because of missing endpoint assessments. Trials with more than 20 percent but less than 40 percent loss to follow-up were eligible for a quality rating of fair (but not good). Studies with more than 40 percent overall loss to follow-up or more than 15 percentage points differential loss to follow-up between study groups were rated as poor. These cut-off points took into consideration that loss to follow-up appears to be higher in psychiatric populations than in other study populations.

Trials that had a fatal flaw in one or more categories were rated poor quality and not included in the analysis of the evidence report (Appendix C) unless the evidence was severely lacking for an indication. Trials that met all criteria were rated good quality. The majority of trials received a quality rating of fair. This includes studies that presumably fulfilled all quality criteria but did not report their methodologies to an extent that answered all our questions. Thus, the “fair quality” category includes trials with quite different strengths and weaknesses. The results of some fair quality studies are likely to be valid; others are probably valid.

E. Data Synthesis

We conducted meta-analyses of data for head-to-head comparisons for trials that were fairly homogenous in study populations and outcome assessments. Our outcome measure of choice was the relative risk (RR) of being a responder on the Hamilton Rating Scale for Depression (HAM-D) or the Montgomery-Asberg Depression Rating Scale (MADRS) (more than 50 percent improvement from baseline) at study endpoint. We chose this outcome measure because response to treatment can be viewed as a close proxy to health outcomes. Therefore, such an outcome measure has more clinical significance than a comparison of mean changes of scores on rating scales.

For each meta-analysis, we conducted a test of heterogeneity and applied both a random and a fixed effects model. We report the random effects model results because, in all three meta-analyses, the results from random and fixed effects models were very similar. If the RR was statistically significant, we then conducted a meta-analysis of the risk differences to calculate the number needed to treat (NNT) on the pooled risk difference.

We assessed publication bias using funnel plots and Kendell’s tests. However, given the small number of component studies in our meta-analyses results of these tests must be viewed cautiously. All statistical analyses were conducted using StatsDirect, version 2.3.8.

Copyright © 2011 Oregon Health & Science University.
Bookshelf ID: NBK54357

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