Efficacy and Safety of Second-Generation Antidepressants in the Treatment of Major Depressive Disorder

Context The relative benefits and harms of newer, second-generation antidepressants are sometimes confusing. Contribution In this review of 46 head-to-head randomized trials, the authors generally found no major differences in the numbers of adults with major depression who responded to second-generation antidepressants, such as selective serotonin reuptake inhibitors, bupropion, duloxetine, mirtazapine, and venlafaxine. The overall incidence of adverse events appeared similar across drugs, although types of adverse events varied. Cautions Trials were funded by industry and had variable quality and follow-up duration. Implications Second-generation antidepressants generally have similar benefits but different possible harms for adults with major depression. The Editors Major depressive disorder is a serious disabling illness that affects more than 16% of adults in the United States at some point in their lifetime (1). In 2000, the economic burden of depressive disorders in the United States was estimated to be $83.1 billion (2). Current practice guidelines for the treatment of major depressive disorder recommend pharmacotherapy, psychotherapy, psychotherapy plus pharmacotherapy, or electroconvulsive therapy. In most cases, pharmacotherapy is first-line treatment for major depressive disorder. Moreover, it is a practical tool for primary care physicians, who prescribe the majority of antidepressants in the United States (3). Pharmacologic treatment for major depressive disorder includes first-generation antidepressants (tricyclic antidepressants and monoamine oxidase inhibitors) and second-generation antidepressants. Second-generation medications include selective serotonin reuptake inhibitors (SSRIs); selective norepinephrine reuptake inhibitors; and other drugs that selectively affect the activity of neurotransmitters, such as serotonin, norepinephrine, and dopamine. In general, the efficacy of first- and second-generation antidepressant medications is similar (4-6). However, first-generation antidepressants often cause multiple side effects that many patients find intolerable (7-9), and the risk for harm when taken in overdose or in combination with certain medications is high. Because of their relatively favorable side effect profile, the second-generation antidepressants play a prominent role in the management of patients with major depressive disorder. Reviews have compared the efficacy and tolerability of newer second-generation antidepressants with those of placebo or older treatments (6, 10, 11) but did not evaluate comparative evidence for second-generation antidepressants. We therefore sought to systematically evaluate comparative data on the efficacy, effectiveness, and tolerability of commonly prescribed second-generation antidepressants. Specifically, we conducted a systematic review and meta-analysis of comparative evidence for 6 SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) and 4 other second-generation antidepressants (bupropion, duloxetine, mirtazapine, and venlafaxine). From here on, we refer to these agents collectively as antidepressants. We examine the role of these agents in the initial treatment of ambulatory adult patients with major depressive disorder. Methods Key Questions Key questions designed to address the comparative efficacy, effectiveness, safety, and tolerability of antidepressants guided our research. A consortium of 12 state Medicaid programs, the Canadian Coordinating Office for Health Technology Assessment, the California HealthCare Foundation, and key experts formulated the questions and provided funding for this research. Literature Search To identify articles relevant to each key question, we searched MEDLINE, EMBASE, and PsychLit; the Cochrane Library; and the International Pharmaceutical Abstracts. To capture articles relevant to the scope of our topic, our searches covered 1980 through 28 February 2005. We manually searched reference lists of relevant review articles and letters to the editor. Pharmaceutical manufacturers were invited to submit dossiers, including citations, as outlined by the Drug Effectiveness Review Project (12). We requested unpublished studies from the U.S. Food and Drug Administration, but this agency did not release unpublished data. Study Selection Two persons independently reviewed titles and abstracts. If both reviewers agreed that a trial did not meet preestablished eligibility criteria (Appendix Table), we excluded it. To assess efficacy and effectiveness, we included head-to-head trials comparing one antidepressant with another. We defined effectiveness trials as those that were conducted in primary care settings, had an adequate duration of follow-up (3 months), had minimal inclusion and exclusion criteria (so that participants represented the general population), assessed health outcomes rather than intermediate outcomes, and had an adequate sample size to determine a minimally important difference (from a patient's perspective) on a health-related quality of life instrument (13). To assess safety and tolerability, we included head-to-head trials, placebo-controlled trials, and observational studies with large samples (>100 patients) lasting at least 1 year. We required a larger sample size for observational studies because we wanted primarily to detect adverse events that were not frequent enough to be apparent in smaller trials. Data Abstraction and Quality Assessment Trained reviewers abstracted data from each study, and a senior reviewer read each abstracted article and evaluated completeness of data extraction. We recorded intention-to-treat results if they were available. We assessed the internal validity (quality) of trials by using predefined criteria from the U.S. Preventive Services Task Force (ratings of good, fair, or poor) (14) and the National Health Service Centre for Reviews and Dissemination (15). Elements of internal validity assessment included randomization, allocation concealment, similarity of compared groups at baseline, use of intention-to-treat analysis, and overall and differential loss to follow-up. We defined loss to follow-up as the number of persons who underwent randomization but did not complete the study (16), independent of the reason and whether intention-to-treat analysis was used. We rated studies as poor if they had more than 40% overall loss to follow-up or more than 15 percentage points of differential loss to follow-up between study groups. Data Synthesis We first qualitatively summarized the studies. When more than 3 head-to-head trials compared the same treatments, we did quantitative analyses. In these, the primary outcome measure was treatment response, defined as 50% or greater improvement on the Hamilton Rating Scale for Depression (HAM-D) or the MontgomeryAsberg Depression Rating Scale from baseline to study end. The relative benefit reflects the ratio of benefits or risks in one treatment group compared with another. When treatment effects differed between studies, we explored potential reasons for these differences. For each meta-analysis, we tested for heterogeneity of treatment effects by using I2 statistics. If no heterogeneity was detected, we applied both a random-effects and a fixed-effects model. We report the results of the more conservative random-effects models (17) because the validity of tests of heterogeneity can be limited with a small number of component studies. To estimate possible publication bias caused by the tendency of published studies to be positive, we used funnel plots, the Begg adjusted rank correlation test (18), and the Egger regression approach (19). However, because these tests have low statistical power when the number of trials is small (20), undetected bias may still be present. All statistical analyses were conducted by using StatsDirect Statistical Software, version 2.3. 8 (StatsDirect, Ltd., Sale, United Kingdom). We calculated the mean incidence and 95% CIs for specific adverse events reported in included trials. Because assessment and reporting of adverse events varied greatly among trials, this evidence should be interpreted with caution. Role of the Funding Sources The funding sources contributed to the development of the key questions but had no role in the conduct or reporting of the study or in the decision to submit the manuscript for publication. Results We found 820 unduplicated citations. Manual review of the reference lists of pertinent review articles produced another 74 articles. Although 6 pharmaceutical companies submitted dossiers, no included studies stemmed from the dossiers. Therefore, 894 citations were included in our database (Appendix Figure). Forty-six randomized, controlled trials compared the effectiveness or efficacy of one SSRI or other antidepressant with that of another in the treatment of major depressive disorder (Tables 1 and 2). (Complete evidence tables are available at www.ohsu.edu/drugeffectiveness/reports/final.cfm or from the authors.) Most studies were efficacy trials and received a rating of fair for internal validity; some trials rated fair may have fulfilled all quality criteria but did not report methods to an extent that answered all of our questions. We considered 2 trials from Europe (21, 22) and 1 trial from the United States (23) conducted in primary care settings to be effectiveness trials. Sixty percent of included trials were less than 12 weeks in duration. The samples consisted mostly of persons younger than 60 years of age; samples consisted of persons 60 years of age or older in 6 trials (13%) and children or adolescents younger than 18 years of age in 3 trials (7%). Although sponsorship did not influence our quality rating, it may have influenced reporting. About 85% of trials in our review were sponsored by a pharmaceutical company, and an additional 11% had at least 1 author affiliated with a pharmaceutical company. The remaining 4% of included studies