BACKGROUND: In 1993 the Agency for Health Care Policy and Research published guidelines for the treatment of major depression that focused on the efficacy of older antidepressants, particularly second- and third-generation tricyclics and monoamine oxidase inhibitors. Since that time several newer antidepressants have been developed. This report provides further information by including data on newer agents marketed for the treatment of depression.
POPULATION STUDIED: This meta-analysis evaluated more than 300 randomized controlled trials of newer pharmacotherapies for depression, including the selective serotonin reuptake inhibitors (SSRIs) venlafaxine, mirtazapine, nefazodone, and bupropion. Approximately 160 trials were based in outpatient practices. Trials were included if they lasted at least 6 weeks and compared a newer antidepressant with either an older or newer antidepressant or placebo. The most severely depressed patients were often excluded from the studies
STUDY DESIGN AND VALIDITY: Trials for inclusion in the analysis were identified from the Cochrane registry, reference lists from trial articles and meta-analyses, and experts. The Cochrane registry includes trials identified from multiple sources such as MEDLINE, EMBASE, and PsycLIT. A separate search identified more than 200 trials that assessed adverse drug effects. Two trained reviewers independently examined data regarding participant and diagnostic descriptors, intervention characteristics, study designs, and clinical outcomes. Disagreements were resolved by consensus. Publication bias was addressed by using funnel plots and did not suggest missing studies comparing newer antidepressants with older antidepressants. However, an overestimation of treatment effect was suggested for newer antidepressants compared with placebo. Strengths of this meta-analysis include the thorough search and the quality of the review process. A weakness of this report lies not with the meta-analysis itself but in the inconsistency and infrequency of the reporting of the data in the trials. In addition, it is limited by the lack of comparative studies of several of the newer antidepressants with other newer or older antidepressants.
OUTCOME MEASURED: Symptomatic response rate, total discontinuation rates, and discontinuation rates due to adverse events were the primary outcomes. Response rates defined as a 50% or greater improvement in symptoms were assessed by a depression symptoms rating scale or a clinical global assessment rating scale and were calculated using a modified intention-to-treat approach. This approach calculates the response rate as the number of patients who continue treatment and improve divided by the total number of patients randomized. Because some patients who left treatment may have responded, this approach provides a conservative estimate of treatment effect.
RESULTS: Response rates were significantly higher for newer pharmacotherapies than for placebo (50% vs 32%, number needed to treat=6). The new agents were as effective as the first- and second-generation tricyclic antidepressants. No difference was found among the different classes of newer antidepressants, though comparative data were few and use short-term (6-week) outcomes. Fluoxetine and sertraline were effective for treating adults with dysthymia, but information was not available on other newer antidepressants. Hypericum (St John’s wort) was more effective than placebo and similar to low-dose tricyclic antidepressants for short-term treatment of mild to moderate depression. With regard to side effects, diarrhea, nausea, insomnia, and headache were associated with SSRIs, while tricyclics caused the well-known effects of dry mouth, constipation, dizziness, blurred vision, and tremors. Data were insufficient to determine the effects on sexual dysfunction and the common adverse effects of other newer therapies. Overall discontinuation rates due to adverse effects were similar for newer and older antidepressants (4% vs 5%).
The newer antidepressants are as effective as older antidepressants for the treatment of major depression and dysthymia in adults. However, data are insufficient to evaluate the effectiveness of newer therapies in other depressive disorders and populations, such as children and adolescents or postpartum women. Adverse effect profiles differ among the classes of antidepressants, but discontinuation rates are similar. These results are the same as those reported by the clinical guideline on the treatment of acute major depression of the American College of Physicians.1 When choosing treatment, clinicians should consider comorbid disease states and medications, dosing schedule, and cost, and discuss with patients the different side effect profiles of the various antidepressants to determine their preference.