Abstract
Background: Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder. Methods: We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291. Findings: We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89–2·41) for amitriptyline and 1·37 (1·16–1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72–0·97) and fluoxetine (0·88, 0·80–0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01–1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19–1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51–0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43–0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30–2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low. Interpretation: All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants. Funding: National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1357-1366 |
| Number of pages | 10 |
| Journal | The Lancet |
| Volume | 391 |
| Issue number | 10128 |
| DOIs | |
| State | Published - Apr 7 2018 |
ASJC Scopus subject areas
- Medicine(all)
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In: The Lancet, Vol. 391, No. 10128, 07.04.2018, p. 1357-1366.
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}
TY - JOUR
T1 - Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder
T2 - a systematic review and network meta-analysis
AU - Cipriani, Andrea
AU - Furukawa, Toshi A.
AU - Salanti, Georgia
AU - Chaimani, Anna
AU - Atkinson, Lauren Z.
AU - Ogawa, Yusuke
AU - Leucht, Stefan
AU - Ruhe, Henricus G.
AU - Turner, Erick H.
AU - Higgins, Julian P.T.
AU - Egger, Matthias
AU - Takeshima, Nozomi
AU - Hayasaka, Yu
AU - Imai, Hissei
AU - Shinohara, Kiyomi
AU - Tajika, Aran
AU - Ioannidis, John P.A.
AU - Geddes, John R.
N1 - Funding Information: This study is based on 522 double-blind studies, which included 116 477 patients randomly assigned to 21 individual first-generation and second-generation antidepressant drugs or placebo. The project extends our previous work that had addressed 12 antidepressants with data for head-to-head comparisons. 9 The present analysis is substantially more comprehensive because it includes 21 active treatments and placebo. The much larger evidence base (about 117 000 vs 26 000 patients), obtained through exhaustive search for published and unpublished information, allowed us to investigate additional important outcomes, such as remission, change in mood symptoms and dropouts due to side-effects, and a number of methodological issues, such as sponsorship, dosing schedule, study precision, and novelty effect. 16 We found that all antidepressants included in the meta-analysis were more efficacious than placebo in adults with major depressive disorder and the summary effect sizes were mostly modest. Some antidepressants, such as escitalopram, mirtazapine, paroxetine, agomelatine, and sertraline had a relatively higher response and lower dropout rate than the other antidepressants. By contrast, reboxetine, trazodone, and fluvoxamine were associated with generally inferior efficacy and acceptability profiles compared with the other antidepressants, making them less favourable options. To make our results as relevant and robust as possible to inform clinical practice, we decided to focus on head-to-head studies and at the same time emphasise the certainty of the retrieved evidence. Our assessment overall found few differences between antidepressants when all data were considered, while there was more diversity in the range of efficacy and dropout patterns seen across the head-to-head comparisons than the meta-analysis of antidepressants versus placebo. The present findings in adults contrast with the efficacy of antidepressants in children and adolescents, for which fluoxetine is probably the only antidepressant that might reduce depressive symptoms. 21 This differential efficacy across age groups might reflect heterogeneous mechanisms and causes of depression, 22 smaller number of studies in young people, or different methodological issues affecting adult and paediatric trials. 23 The effect sizes were also smaller in more recent and larger placebo-controlled trials than in older and smaller ones, which might be an indicator of bias. Estimated differences between drugs were smaller in placebo-controlled trials than in head-to-head studies. There are several potential explanations, as many factors have been associated with higher placebo response rates, such as randomisation ratio and the expectation of receiving an active treatment, the therapeutic setting, or the frequency of study visits. 24 In our dataset, we found that response to the same antidepressant was on average smaller and dropouts more likely to occur in placebo controlled trials than in head-to-head studies. Moreover, for the same drug and the same probability of receiving placebo, larger all-cause dropout rates were associated with a lower response to treatment. The use of the last observation carried forward (LOCF) approach for imputing missing outcome data might have affected the estimates of treatment effect. 25 Depressive symptoms tend to spontaneously improve over time and this phenomenon contributes to the high percentage of placebo responders in antidepressant trials. 26 Patients randomly assigned to the active drug in a double-blind, placebo-controlled trial might leave studies earlier than in head-to-head studies because they might suspect they have been allocated to the placebo group than to the intervention group. Antidepressants usually take full effect only after weeks of treatment; therefore, participants who dropped out earlier tend to have poorer responses than those who remain on treatment, which are carried forward to the end of the trial by the LOCF analysis. The final result can be an underestimate of the true efficacy of the active drug. Another possible explanation could be a bias in conduct, analysis, or reporting of head-to-head trials, driven by commercial interests. 27 In our analyses, funding by industry was not associated with substantial differences in terms of response or dropout rates. However, non-industry funded trials were few and many trials did not report or disclose any funding. We also observed that drugs tended to show a better efficacy profile when they were novel and used as experimental treatments than when they had become old. This novelty effect might arise where a novel agent is perceived to be more effective and better tolerated; alternatively, selective analyses and outcome reporting bias might be more prominent when a treatment is first launched. 16 Our literature search was as comprehensive as possible, including the largest amount of unpublished data to date, which are associated with less favourable effect sizes for antidepressants. 28 Although it is possible that a certain amount of unpublished data could not be retrieved, our comparison-adjusted funnel plots did not suggest that small studies gave different results from larger studies either among placebo-controlled trials or head-to-head comparison trials ( appendix pp 179–81, 225–27 ). The estimates of treatment effect from our study are in line with previous reviews on the same matter, 28 but they are considerably more precise because of our larger quantity of data and resulting statistical power. Our review has some limitations. According to the GRADE framework, the quality of many comparisons was assessed as low or very low for amitriptyline, bupropion, and venlafaxine, whereas it was often rated as moderate for agomelatine, escitalopram, and mirtazapine. We incorporated the certainty of evidence in the main results of our analysis to highlight the most robust findings for further use in clinical judgment. However, many trials did not report adequate information about randomisation and allocation concealment, which restricts the interpretation of these results. To increase the methodological rigour of the contributing evidence, we included only double-blind trials, which were generally very similar in design and conduct. The poor information in terms of risk of bias assessment might be a matter of reporting; however, we presented full details about the risk of bias of all included studies in the appendix (pp 115–32) . We did not do a formal cost-effectiveness analysis. All of the most effective antidepressants are now off patent and available in generic form. Some of the antidepressants are included in the WHO Model List of Essential Medicines, which makes them available worldwide and ready to use also in developing countries. We analysed only average treatment effects and were not able to investigate potentially important clinical and demographical modifiers of treatment response at the individual patient level (eg, age, sex, severity of symptoms, or duration of illness). Patients recruited in randomised trials tend to be highly selected and we also excluded patients with psychotic or treatment-resistant depression, which might limit the applicability of the results to these clinical subgroups, but it was intended as a methodological strength to assure transitivity in the network. We did not cover important clinical issues that might inform treatment decision making in routine clinical practice (eg, specific adverse events, withdrawal symptoms, or combination with non-pharmacological treatments). Additionally, because of the paucity of information reported in the original studies, we were not able to quantify some outcomes, such as global functioning. It should also be noted that some of the adverse effects of antidepressants occur over a prolonged period, meaning that positive results need to be taken with great caution, because the trials in this network meta-analysis were of short duration. The current report summarises evidence of differences between antidepressants when prescribed as an initial treatment. Given the modest effect sizes, non-response to antidepressants will occur. Our information unfortunately cannot guide next-step choices after failure of such a first step (ie, they do not apply to treatment-resistant depression), for which well performed trials are scarce. 29 Using the data made available on the websites of the US Food and Drug Administration and European Medicines Agency, on the international trial registries, and from contacting study authors and pharmaceutical companies, we managed to incorporate in the analysis a considerable amount of unpublished data for some drugs—namely, agomelatine, escitalopram, paroxetine, reboxetine, sertraline, venlafaxine, vilazodone, and vortioxetine—but not for all the antidepressants included in the network meta-analysis. This limitation in the primary trials might affect the validity of the findings for some antidepressants, but the incorporation of both direct and indirect comparisons might have contributed to reduce the potential risk of bias. 30 We did our best to retrieve all unpublished data and contacted study authors for supplemental material, but we are aware that a substantial amount of information is still not available to the public. There are online archives where trials are prospectively registered; however, they collect reliable information only about the most recent studies and we cannot rule out the possibility that some studies are absent or the same study has been counted twice in our analyses. It is not uncommon for the same study to go by different names in different publications, which complicates the process of data synthesis. 31 By making the dataset fully and freely available, we welcome any information that might help clarify any mistakes in our dataset. Notwithstanding these limitations, the findings from this network meta-analysis represent the most comprehensive currently available evidence base to guide the initial choice about pharmacological treatment for acute major depressive disorder in adults. All statements comparing the merits of one antidepressant with another must be tempered by the potential limitations of the methodology, 32 the complexity of specific patient populations, and the uncertainties that might result from choice of dose or treatment setting. We hope that these results will assist in shared decision making between patients, carers, and their clinicians. Contributors ACi, TAF, GS, and JRG conceived and designed the study. ACi, TAF, LZA, SL, HGR, YO, NT, YH, EHT, HI, KS, and AT selected the articles and extracted the data. GS, Ach, JPTH, and ME analysed the data. ACi, TAF, GS, and JRG wrote the first draft of the manuscript. ACh, LZA, YO, SL, HGR, EHT, JPTH, ME, and JPAI interpreted the data and contributed to the writing of the final version of the manuscript. All authors agreed with the results and conclusions of this Article. Declaration of interests ACi is supported by the National Institute for Health Research (NIHR) Oxford Cognitive Health Clinical Research Facility. TAF has received lecture fees from Eli Lilly, Janssen, Meiji, Mitsubishi-Tanabe, Merck Sharp & Dohme, and Pfizer; consultancy fees from Takeda Science Foundation; and research support from Mochida and Mitsubishi-Tanabe. SL has received honoraria for consulting from LB Pharma, Lundbeck, Otsuka, TEVA, Geodon Richter, Recordati, LTS Lohmann, and Boehringer Ingelheim; and for lectures from Janssen, Lilly, Lundbeck, Otsuka, SanofiAventis, and Servier. NT has received lecture fees from Otsuka and Meiji. YH has received lecture fees from Yoshitomi. JRG is an NIHR Senior Investigator. All other authors declare no competing interests. Acknowledgments This study was funded by the National Institute for Health Research (NIHR) Oxford Health Biomedical Research Centre (BRC-1215-20005) and the Japan Society for the Promotion of Science (17K19808). The views expressed are those of the authors and not necessarily those of the UK National Health Service, the NIHR, or the UK Department of Health. Publisher Copyright: © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2018/4/7
Y1 - 2018/4/7
N2 - Background: Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder. Methods: We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291. Findings: We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89–2·41) for amitriptyline and 1·37 (1·16–1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72–0·97) and fluoxetine (0·88, 0·80–0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01–1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19–1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51–0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43–0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30–2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low. Interpretation: All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants. Funding: National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.
AB - Background: Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder. Methods: We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291. Findings: We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89–2·41) for amitriptyline and 1·37 (1·16–1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72–0·97) and fluoxetine (0·88, 0·80–0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01–1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19–1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51–0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43–0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30–2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low. Interpretation: All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants. Funding: National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.
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UR - http://www.scopus.com/inward/citedby.url?scp=85043237371&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(17)32802-7
DO - 10.1016/S0140-6736(17)32802-7
M3 - Article
C2 - 29477251
AN - SCOPUS:85043237371
SN - 0140-6736
VL - 391
SP - 1357
EP - 1366
JO - The Lancet
JF - The Lancet
IS - 10128
ER -