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Objectives: To report the comparative benefits and harms of exercise and complementary and alternative medicine (CAM) treatments with second-generation antidepressants (SGA) for major depressive disorder (MDD). Design: Systematic review and meta-analysis. Settings: Outpatient clinics. Subjects: Adults, aged 18 years and older, with MDD receiving an initial treatment attempt with SGA. Interventions: Any CAM or exercise intervention compared with an SGA. Outcome measures: Treatment response, remission, change in depression rating, adverse events, treatment discontinuation, and treatment discontinuation due to adverse events. Results: We found 22 randomized controlled trials for direct comparisons and 127 trials for network meta-analyses, including trials of acupuncture, omega-3 fatty acids, S-adenosyl methionine, St. John's wort, and exercise. For most treatment comparisons, we found no differences between treatment groups for response and remission. However, the risk of bias of these studies led us to conclude that the strength of evidence for these findings was either low or insufficient. The risk of treatment harms and treatment discontinuation attributed to adverse events was higher for selective serotonin receptor inhibitors than for St. John's wort. Conclusions: Although we found little difference in the comparative efficacy of most CAM therapies or exercise and SGAs, the overall poor quality of the available evidence base tempers any conclusions that we might draw from those trials. Future trials should incorporate patient-oriented outcomes, treatment expectancy, depressive severity, and harms assessments into their designs; antidepressants should be administered over their full dosage ranges; and larger trials using methods to reduce sampling bias are needed. [ABSTRACT FROM AUTHOR]

Background: Primary care patients and clinicians may prefer options other than second-generation antidepressants for the treatment of major depressive disorder (MDD). The comparative benefits and harms of antidepressants and alternative treatments are unclear.Purpose: To compare the benefits and harms of second-generation antidepressants and psychological, complementary and alternative medicine (CAM), and exercise treatments as first- and second-step interventions for adults with acute MDD.Data Sources: English-, German-, and Italian-language studies from multiple electronic databases (January 1990 to September 2015); trial registries and gray-literature databases were used to identify unpublished research.Study Selection: Two investigators independently selected comparative randomized trials of at least 6 weeks' duration on health outcomes of adult outpatients; nonrandomized studies were eligible for harms.Data Extraction: Reviewers abstracted data on study design, participants, interventions, and outcomes; rated the risk of bias; and graded the strength of evidence. A senior reviewer confirmed data and ratings.Data Synthesis: 45 trials met inclusion criteria. On the basis of moderate-strength evidence, cognitive behavioral therapy (CBT) and antidepressants led to similar response rates (relative risk [RR], 0.90 [95% CI, 0.76 to 1.07]) and remission rates (RR, 0.98 [CI, 0.73 to 1.32]). In trials, antidepressants had higher risks for adverse events than most other treatment options; no information from nonrandomized studies was available. The evidence was too limited to make firm conclusions about differences in the benefits and harms of antidepressants compared with other treatment options as first-step therapies for acute MDD. For second-step therapies, different switching and augmentation strategies provided similar symptom relief.Limitation: High dropout rates, dosing inequalities, small sample sizes, and poor assessment of adverse events limit confidence in the evidence.Conclusion: Given their similar efficacy, CBT and antidepressants are both viable choices for initial treatment of MDD.Primary Funding Source: Agency for Healthcare Research and Quality. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What are the benefits and harms of second generation antidepressants and cognitive behavioral therapies (CBTs) in the initial treatment of a current episode of major depressive disorder in adults? METHODS This was a systematic review including qualitative assessment and meta-analyses using random and fixed effects models. Medline, Embase, the Cochrane Library, the Allied and Complementary Medicine Database, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature were searched from January1990 through January 2015. The 11 randomized controlled trials included compared a second generation antidepressant CBT. Ten trials compared antidepressant monotherapy with CBT alone; three compared antidepressant monotherapy with antidepressant plus CBT. SUMMARY ANSWER AND LIMITATIONS Meta-analyses found no statistically significant difference in effectiveness between second generation antidepressants and CBT for response (risk ratio 0.91, 0.77 to 1.07), remission (0.98, 0.73 to 1.32), or change in 17 item Hamilton Rating Scale for Depression score (weighted mean difference, -0.38, -2.87 to 2.10). Similarly, no significant differences were found in rates of overall study discontinuation (risk ratio 0.90, 0.49 to 1.65) or discontinuation attributable to lack of efficacy (0.40, 0.05 to 2.91). Although more patients treated with a second generation antidepressant than receiving CBT withdrew from studies because of adverse events, the difference was not statistically significant (risk ratio 3.29, 0.42 to 25.72). No conclusions could be drawn about other outcomes because of lack of evidence. Results should be interpreted cautiously given the low strength of evidence for most outcomes. The scope of this review was limited to trials that enrolled adult patients with major depressive disorder and compared a second generation antidepressant with CBT, and many of the included trials had methodological shortcomings that may limit confidence in some of the findings. WHAT THIS STUDY ADDS Second generation antidepressants and CBT have evidence bases of benefits and harms in major depressive disorder. Available evidence suggests no difference in treatment effects of second generation antidepressants and CBT, either alone or in combination, although small numbers may preclude detection of small but clinically meaningful differences. FUNDING, COMPETING INTERESTS, DATA SHARING This project was funded under contract from the Agency for Healthcare Research and Quality by the RTI-UNC Evidence-based Practice Center. Detailed methods and additional information are available in the full report, available at http://effectivehealthcare.ahrq.gov/. [ABSTRACT FROM AUTHOR]

Background Patients with major depressive disorder (MDD) often suffer from accompanying symptoms that influence the choice of pharmacotherapy with second-generation antidepressants (SGAs). We conducted a systematic review to determine the comparative effectiveness of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, desvenlafaxine, duloxetine, venlafaxine, bupropion, mirtazapine, nefazodone, and trazodone, for accompanying anxiety, insomnia, and pain in patients with MDD. Methods We conducted searches in multiple databases including MEDLINE®, Embase, the Cochrane Library, International Pharmaceutical Abstracts, and PsycINFO, from 1980 through August 2011 and reviewed reference lists of pertinent articles. We dually reviewed abstracts, full-text articles, and abstracted data. We included randomized, head-to-head trials of SGAs of at least 6 weeks' duration. We grouped SGAs into three classes for the analysis: selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors, and others. We graded the strength of the evidence as high, moderate, low, or very low based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group (GRADE) approach. Results We located 19 head-to-head trials in total: 11 on anxiety, six on insomnia, and four on pain. For the majority of comparisons, the strength of the evidence was moderate or low: evidence is weakened by inconsistency and imprecision. For treating anxiety, insomnia, and pain moderate evidence suggests that the SSRIs do not differ. Conclusions Evidence guiding the selection of an SGA based on accompanying symptoms of depression is limited. Very few trials were designed and adequately powered to answer questions about accompanying symptoms; analyses were generally of subgroups in larger MDD trials. [ABSTRACT FROM AUTHOR]

Background: Second-generation antidepressants dominate the management of major depressive disorder (MDD), but evidence on the comparative benefits and harms of these agents is contradictory. Purpose: To compare the benefits and harms of second-generation antidepressants for treating MDD in adults. Data Sources: English-language studies from PubMed, Embase, the Cochrane Library, PsycINFO, and International Pharmaceutical Abstracts from 1980 to August 2011 and reference lists of pertinent review articles and gray literature. Study Selection: 2 independent reviewers identified randomized trials of at least 6 weeks' duration to evaluate efficacy and observational studies with at least 1000 participants to assess harm. Data Extraction: Reviewers abstracted data about study design and conduct, participants, and interventions and outcomes and rated study quality. A senior reviewer checked and confirmed extracted data and quality ratings. Data Synthesis: Meta-analyses and mixed-treatment comparisons of response to treatment and weighted mean differences were conducted on specific scales to rate depression. On the basis of 234 studies, no clinically relevant differences in efficacy or effectiveness were detected for the treatment of acute, continuation, and maintenance phases of MDD. No differences in efficacy were seen in patients with accompanying symptoms or in subgroups based on age, sex, ethnicity, or comorbid conditions. Individual drugs differed in onset of action, adverse events, and some measures of healthrelated quality of life. Limitations: Most trials were conducted in highly selected populations. Publication bias might affect the estimates of some comparisons. Mixed-treatment comparisons cannot conclusively exclude differences in efficacy. Evidence within subgroups was limited. Conclusion: Current evidence does not warrant recommending a particular second-generation antidepressant on the basis of differences in efficacy. Differences in onset of action and adverse events may be considered when choosing a medication. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The objective of this study was to determine the effect of industry bias in a systematically reviewed body of evidence of head-to-head trials. Study Design and Setting: We limited our analysis to published head-to-head randomized controlled trials of selective serotonin reuptake inhibitors (SSRIs) identified in a comparative effectiveness review. Two reviewers independently determined the status of funding for each trial. We classified drugs into one of two groups: (1) drugs associated with the funding source and (2) drugs not associated with the funding source. To determine the effect of any underlying industry bias, we conducted relative-benefit meta-analyses comparing the response rates of drugs when associated with the funding source with response rates of the same drugs when not associated with the funding source. Results: Thirteen out of 20 studies (65%) numerically favored drugs associated with the funding source over drugs used as controls. The pooled response rates of SSRIs, when associated with the funding source, are significantly greater than those of the same SSRIs when not associated with the sponsor (relative benefit=1.07; 95% confidence interval=1.02–1.11). The difference, however, is likely to be not of clinical importance. Conclusions: The effect of industry bias in comparative effectiveness reviews might play a lesser role than in systematic reviews of placebo-controlled trials. [Copyright &y& Elsevier]

Background: Second-generation antidepressants dominate the management of major depressive disorder, dysthymia, and subsyndromal depression. Evidence on the comparative benefits and harms is still accruing. Purpose: To compare the benefits and harms of second-generation antidepressants (bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxine) for the treatment of depressive disorders in adults. Data Sources: MEDLINE, EMBASE, PsychLit, Cochrane Central Register of Controlled Trials, and International Pharmaceutical Abstracts from 1980 to April 2007, limited to English-language articles. Reference lists of pertinent review articles were manually searched and the Center for Drug Evaluation and Research database was explored to identify unpublished research. Study Selection: Abstracts and full-text articles were independently reviewed by 2 persons. Six previous good- or fair-quality systematic reviews or meta-analyses were included, as were 155 good- or fair-quality double-blind, placebo-controlled, or head-to-head randomized, controlled trials of at least 6 weeks' duration. For harms, 35 observational studies with at least 100 participants and follow- up of at least 12 weeks were also included. Data Extraction: Using a standard protocol, investigators abstracted data on study design and quality-related details, funding, settings, patients, and outcomes. Data Synthesis: If data were sufficient, meta-analyses of head-tohead trials were conducted to determine the relative benefit of response to treatment and the weighted mean differences on specific depression rating scales. If sufficient evidence was not available, adjusted indirect comparisons were conducted by using meta-regressions and network meta-analyses. Secondgeneration antidepressants did not substantially differ in efficacy or effectiveness for the treatment of major depressive disorder on the basis of 203 studies; however, the incidence of specific adverse events and the onset of action differed. The evidence is insufficient to draw conclusions about the comparative efficacy, effectiveness, or harms of these agents for the treatment of dysthymia and subsyndromal depression. Limitation: Adjusted indirect comparisons have methodological limitations and cannot conclusively rule out differences in efficacy. Conclusion: Current evidence does not warrant the choice of one second-generation antidepressant over another on the basis of differences in efficacy and effectiveness. Other differences with respect to onset of action and adverse events may be relevant for the choice of a medication. [ABSTRACT FROM AUTHOR]

Objective: This meta-analysis reviewed data on the efficacy and effectiveness of second-generation antidepressants for preventing major depression relapse and recurrence during continuation and maintenance phases of treatment, respectively. Methods: MEDLINIE, EMBASE, and PsycINFO, the Cochrane Library, and International Pharmaceutical Abstracts were searched for the period of January 1980 through April 2007 for reviews, randomized controlled trials, meta-analyses, and observational studies on the topic. Two persons independently reviewed abstracts and full-text articles using a structured data abstraction form to ensure consistency in appraisal and data extraction. Results: Four comparative trials and 23 placebo-controlled trials that addressed relapse or recurrence prevention were included. Results of comparative trials have not demonstrated statistically significant differences between duloxetine and paroxetine, fluoxetine and sertraline, fluvoxamine and sertraline, and trazodone and venlafaxine. Pooled data for the class of second-generation antidepressants compared with placebo suggested a relatively large effect size that persists over time. For preventing both relapse and recurrence, the number of patients needed to treat is five (95% confidence interval of 4 to 6). Differences in the length of open-label treatment before randomization, drug type, and trial duration did not affect pooled estimates of relapse rates. Across all trials, 7% of patients randomly assigned to receive active treatment and 5% of patients randomly assigned to receive a placebo discontinued treatment because of adverse events. Conclusions: This review demonstrates the overall benefits of continuation- and maintenance-phase treatment of major depression with second-generation antidepressants and emphasizes the need for additional studies of comparative differences among drugs. [ABSTRACT FROM AUTHOR]

Background: Reviews have compared the efficacy and tolerability of newer second-generation antidepressants with those of placebo or older treatments, but comparative evidence for use of second-generation antidepressants to treat major depressive disorder has not been evaluated. Purpose: To systematically evaluate comparative data on the efficacy, effectiveness, and tolerability of commonly prescribed second-generation anti depressants (selective seroton in reuptake inhibitors, bupropion, duloxetine, mirtazapine, and venlafaxine) in the treatment of major depressive disorder. Data Sources: MEDLINE, EMBASE, and PsychLit; the Cochrane Library; and the International Pharmaceutical Abstracts were searched from January 1980 through February 2005 for reviews; randomized, controlled trials; meta-analyses; and observational studies. Study Selection: The authors reviewed 46 head-to-head randomized, controlled trials comparing one second-generation antidepressant with another. Twenty-four observational studies and placebo-controlled trials were also included for assessment of safety and tolerability. Data Extraction: Two researchers independently reviewed titles and abstracts. Trained reviewers abstracted data from each study and assigned an initial quality rating. A second reviewer verified the data extraction and quality rating. Data Synthesis: According to fair to good evidence, the second-generation antidepressants that were compared had only minimal differences in efficacy, and 88% of comparative efficacy studies reported no statistically significant difference in any outcome measure at the end of the study. One effectiveness trial rated good and 2 effectiveness trials rated fair reported no statistically significant differences in primary outcome measures for compared drugs. Meta-analyses showed a modest but statistically significant additional treatment effect for sertraline and venlafaxine compared with fluoxetine. About 96% of comparative trials were sponsored by or had at least 1 author affiliated with a pharmaceutical company; the remaining trials did not report funding sources. Adverse event profiles differed among drugs; however, the degree and quality of adverse event assessment varied and only 13% of trials used a standardized scale to assess adverse events. Limitations: Quantitative analyses could not be done for many drug comparisons because the quantity and quality of the evidence were inadequate. Most published evidence was from trials sponsored by pharmaceutical companies, and publication bias may have occurred. Conclusions: Overall, second-generation antidepressants probably do not differ substantially for treatment of major depressive disorder. Choosing the agent that is most appropriate for a given patient is difficult. [ABSTRACT FROM AUTHOR]

The authors discuss implications for private and public insurers of the STAB*D trial (Sequenced Treatment Alternatives to Relieve Depression), which found evidence that for second- and third-line treatment, no second-generation antidepressant was superior to another in terms of effectiveness or of the overall incidence of harmful effects. These findings have permitted payers to construct formulary coverage rules with more confidence and have highlighted the benefits of policies that improve access to care (for example, encouraging primary care treatment of depression) or promote treatment adherence (for example, implementing pay-for-performance initiatives). [ABSTRACT FROM AUTHOR]

The article focuses on the study by A. Cipriani and colleagues which rated second-generation antidepressants sertraline and escitalopram as having the most favorable balance between benefit and harm in patients with major depressive disorder (MDD) published in "The Lancet." The authors are said to formulate their results using a statistical technique called multiple treatment meta-analysis. It cites the authors' use of attrition rates in their study, which is said to be an inadequate measure of treatment tolerability.

A letter to the editor and a reply are presented regarding the efficacy of fluvoxamine in comparison to other antidepressants.

A letter to the editor is presented in response to the article "Comparative Efficacy and Acceptability of 12 New-generation Antidepressants: A Multiple-treatments Meta-analysis," by A. Cipriani, T.A. Furukawa, G. Salanti, et al. published in the February 28, 2009 issue.

Objectives: Pooled-studies publications (PSPs) present statistical analyses of multiple randomized controlled trials without a systematic literature search or critical appraisal. We explored the characteristics of PSPs and their potential impact on a systematic review (SR). Study Design and Setting: We systematically evaluated PSPs excluded from an SR of second-generation antidepressants. We analyzed their basic characteristics, risk of bias, and the effect of new data on review conclusions. Results: We identified 57 PSPs containing a median of five trials (range, 2-11) and 1,233 patients (range, 117 2,919). Ninety-six percent of PSPs were industry funded, and 49% of PSPs contained unpublished data. The median number of citations for PSPs was 29 (range, 0-549). Only 7% planned pooling a priori, and 19% combined trials with identical protocols. Fifty-nine percent of PSPs eligible e for general efficacy provided no new data. For some subgroups and accompanying symptoms (e.g., anxiety, insomnia, melancholia, fatigue, sex, and race), more than 30% of PSPs presented entirely new data or data that could alter the strength of the evidence available in the SR. Conclusion: In this case study, PSPs provided new information on subgroups and secondary outcomes; however, guidance for reviewers and development of a system to assess their susceptibility to bias are required. [ABSTRACT FROM AUTHOR]