CADTH RAPID RESPONSE REPORT: SUMMARY WITH CRITICAL APPRAISAL

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1 CADTH RAPID RESPONSE REPORT: SUMMARY WITH CRITICAL APPRAISAL Desvenlafaxine versus Venlafaxine for the Treatment of Adult Patients with Major Depressive Disorder: A Review of the Comparative Clinical and Cost-Effectiveness Service Line: Rapid Response Service Version: 1.0 Publication Date: October 25, 2017 Report Length: 15 Pages

2 Authors: Veronica Poitras, Sarah Visintini Cite As: Desv enlaf axine v ersus Venlaf axine for the Treatment of Adult Patients with Major Depressiv e Disorder: A Rev iew of the Comparativ e Clinical and Cost-Ef f ectiveness. Ottawa: CADTH; 2017 Oct. (CADTH rapid response report: summary with critical appraisal). Acknowledgments: ISSN: (online) Disclaimer: The inf ormation in this document is intended to help Canadian health care decision-makers, health care prof essionals, health sy stems leaders, and policy -makers make well-inf ormed decisions and thereby improv e the quality of health care serv ices. While patients and others may access this document, the document is made av ailable f or inf ormational purposes only and no representations or warranties are made with respect to its f itness f or any particular purpose. The inf ormation in this document should not be used as a substitute f or prof essional medical adv ice or as a substitute f or the application of clinical judgment in respect of the care of a particular patient or other prof essional judgment in any decision-making process. The Canadian Agency f or Drugs and Technologies in Health (CADTH) does not endorse any inf ormation, drugs, therapies, treatments, products, processes, or serv ic es. While care has been taken to ensure that the inf ormation prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was f irst published by CADTH, CADTH does not make any guarantees to that ef f ect. CADTH does not guarantee and is not responsible f or the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The v iews and opinions of third parties published in this document do not necessarily state or ref lect those of CADTH. CADTH is not responsible f or any errors, omissions, injury, loss, or damage arising f rom or relating to the use (or misuse) of any inf ormation, statements, or conclusions contained in or implied by the contents of this document or any of the source materials. This document may contain links to third-party websites. CADTH does not hav e control ov er the content of such sites. Use of third-party sites is gov erned by the third-party website owners own terms and conditions set out f or such sites. CADTH does not make any guarantee with respect to any inf ormation contained on such third-party sites and CADTH is not responsible f or any injury, loss, or damage suf f ered as a result of using such third-party sites. CADTH has no responsibility f or the collection, use, and disclosure of personal inf ormation by third-party sites. Subject to the af orementioned limitations, the v iews expressed herein are those of CADTH and do not necessarily represent the v iews of Canada s f ederal, prov incial, or territorial gov ernments or any third party supplier of inf ormation. This document is prepared and intended f or use in the context of the Canadian health care sy stem. The use of this document outside of Canada is done so at the user s own risk. This disclaimer and any questions or matters of any nature arising f rom or relating to the content or use (or misuse) of this document will be gov erned by and interpreted in accordance with the laws of the Prov ince of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusiv e jurisdiction of the courts of the Prov ince of Ontario, Canada. The copy right and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document f or non-commercial purposes only, prov ided it is not modif ied when reproduced and appropriate credit is giv en to CADTH and its licensors. About CADTH: CADTH is an independent, not-f or-prof it organization responsible f or prov iding Canada s health care decision-makers with objectiv e ev idence to help make inf ormed decisions about the optimal use of drugs, medical dev ices, diagnostics, and procedures in our health care sy stem. SUMMARY WITH CRITICAL APPRAISAL Desv enlaf axine v ersus Venlaf axine f or the Treatment of Adult Patients with Major Depressiv e Disorder 2

3 Context and Policy Issues Major Depressive Disorder (MDD) is a chronic, disabling disorder characterized by depressed mood or diminished interest or pleasure in activities of daily living, along with changes in weight, appetite and/or sleep, fatigue or loss of energy, feelings of worthlessness or inappropriate guilt, inability to concentrate, or recurrent thoughts of death or suicide that last at least two weeks and that affect normal functioning. 1,2 In Canada, the annual prevalence of MDD is 4.7% and the lifetime prevalence is 11.3%. 2 MDD is the second leading cause of disability worldwide, with considerable economic impact due to treatment costs and lost productivity. 2 MDD is thus associated with substantial personal, societal, and economic burden. 3 Serotonin-norepinephrine reuptake inhibitors (SNRIs) are a first-line pharmacotherapy option in the treatment of MDD 4 that function by inhibiting the neuronal reuptake of serotonin and norepinephrine, two neurotransmitters that play an important role in mood. 5 Venlafaxine was the first-available SNRI and is considered to be one of the most effective antidepressants. 6 Desvenlafaxine is the primary metabolite of venlafaxine, 5 and administering desvenlafaxine directly has some theoretical advantages. For example, venlafaxine, like most antidepressants, is metabolized by the cytochrome P450 enzymatic pathway; this pathway exhibits marked genetic polymorphism and inter-individual variability in activity, which could lead to sub-therapeutic drug concentrations in those who have rapid P450 pathway metabolism. 7 In contrast, desvenlafaxine is metabolized independently of this pathway (and is cleared primarily via the kidney), which may result in more stable plasma concentrations and fewer drug-drug interactions. 7-9 In addition, the binding affinity for serotonin and norepinephrine reuptake pumps is higher for desvenlafaxine than venlafaxine, which theoretically could translate to greater efficacy. 5,8 The clinical effectiveness of active metabolites should not be assumed however, 6 and in 2009 a CADTH report of the Common Drug Review recommended not to list desvenlafaxine, because at that time there were no randomized controlled trials directly comparing desvenlafaxine and venlafaxine, and desvenlafaxine was more expensive at recommended doses. 10 Both venlafaxine and desvenlafaxine are used in the treatment of MDD in Canada, 11 however, and an updated examination of the comparative clinical effectiveness and cost-effectiveness is warranted. The purpose of this report is to examine the clinical effectiveness and cost-effectiveness of desvenlafaxine compared to venlafaxine for the treatment of adults patients with MDD. Research Questions 1. What is the comparative clinical effectiveness of desvenlafaxine versus venlafaxine for the treatment of adult patients with Major Depressive Disorder? 2. What is the comparative cost-effectiveness of desvenlafaxine versus venlafaxine for the treatment of adult patients with Major Depressive Disorder? SUMMARY WITH CRITICAL APPRAISAL Desv enlaf axine v ersus Venlaf axine f or the Treatment of Adult Patients with Major Depressiv e Disorder 3

4 Key Findings Limited evidence from three systematic reviews suggested there was no significant difference in the clinical effectiveness of desvenlafaxine versus venlafaxine for the treatment of adult patients with Major Depressive Disorder. However, the totality of the evidence across the reviews comprised only two head-to-head trials and an indirect metaanalysis based on comparisons with placebo; therefore, results should be interpreted with caution. No evidence regarding the comparative cost-effectiveness of desvenlafaxine versus venlafaxine for the treatment of adult patients with Major Depressive Disorder was identified. Methods Literature Search Methods A limited literature search was conducted on key resources including PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD), Embase, Medline, Canadian and major international health technology agencies, as well as a focused Internet search. No methodological filters were employed. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2012 and September 22, Selection Criteria and Methods One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1. Table 1: Selection Criteria Population Intervention Comparator Outcomes Study Designs Adult patients requiring treatment for Major Depressive Disorder Desvenlafaxine (e.g., Pristiq) Venlafaxine (e.g., Effexor) Q1: Comparative clinical effectiveness, clinical benefit and harm Q2: Cost-effectiveness Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, nonrandomized studies, economic evaluations Exclusion Criteria Articles were excluded if they did not meet the selection criteria outlined in Table 1, or if they were not published in English, were duplicate publications, or were published prior to Critical Appraisal of Individual Studies The included systematic reviews were critically appraised using the AMSTAR tool. 12 Summary scores were not calculated for the included studies; rather, a review of the strengths and limitations of each included study were described. SUMMARY WITH CRITICAL APPRAISAL Desv enlaf axine v ersus Venlaf axine f or the Treatment of Adult Patients with Major Depressiv e Disorder 4

5 Summary of Evidence Quantity of Research Available A total of 307 citations were identified in the literature search. Following screening of titles and abstracts, 299 citations were excluded and eight potentially relevant reports from the electronic search were retrieved for full-text review. No potentially relevant publications were retrieved from the grey literature search. Of these potentially relevant articles, five publications were excluded for various reasons, while three publications met the inclusion criteria and were included in this report. Appendix 1 describes the PRISMA flowchart of the study selection. Additional references of potential interest are provided in Appendix 5. Summary of Study Characteristics Additional details regarding the characteristics of included publications are provided in Appendix 2. Study Design Three systematic reviews (SRs) with the objective of comparing the clinical effectiveness of desvenlafaxine versus venlafaxine for the treatment of adult patients with major depressive disorder (MDD) were identified. 6,7,13 The reviews included literature searches up to 2008, , 13 and One SR included indirect comparisons between desvenlafaxine and venlafaxine, using placebo as the common comparator, and included 27 randomized controlled trials (RCTs). 7 The other two SRs included zero, 13 and two 6 relevant RCTs with head-to-head comparisons of desvenlafaxine and venlafaxine. All SRs pooled results across studies using meta-analyses where appropriate. 6,7,13 No relevant economic studies were identified. Country of Origin The SRs were led by authors based in Australia, 7 Austria, 13 Germany, 6 Greece, 6 and the United States. 13 In two SRs, the countries in which the RCTs were conducted were not reported, 6,13 and in the third it was reported that the majority of included studies were conducted in the United States or in Europe. 7 Patient Population The population of interest in one SR was not explicitly specified, but all included studies involved outpatients with depression. 6 The other two SRs included adult outpatients with scores of 20 on the Hamilton Rating Scale for Depression (HAM-D; 17- or 21-item version), 7 or adult outpatients with MDD and information on anxiety, insomnia or pain. 13 Interventions and Comparators In one SR, eight weeks of treatment with desvenlafaxine (50 to 200 mg) was indirectly compared to eight weeks of treatment with venlafaxine (75 to 225 mg) using placebo as a common comparator. 7 In the second SR, eight weeks of treatment with desvenlafaxine (200 to 400 mg) was compared to eight weeks of treatment with venlafaxine (75 to 150 mg). 6 In the third SR, the interventions of interest included at least six weeks of treatment with 13 different second-generation antidepressants compared to one another. 13 As such, one eligible comparison was treatment with desvenlafaxine versus venlafaxine; however, no studies relevant to the present review were captured. 13 SUMMARY WITH CRITICAL APPRAISAL Desv enlaf axine v ersus Venlaf axine f or the Treatment of Adult Patients with Major Depressiv e Disorder 5

6 Outcomes The outcomes considered in the SRs were response rate ( 50% reduction in HAM-D 17 or HAM-D 21 scores); 6,7 remission rate (HAM-D 17 7); 6,7 change in HAM-D 17 from baseline; 7 anxiety, insomnia, and pain; 13 tolerability (discontinuation rate and discontinuation rate due to adverse events); 6 and adverse events. 7 Summary of Critical Appraisal Additional details regarding the strengths and limitations of included publications are provided in Appendix 3. Systematic Reviews Strengths common to all three SRs included the use of comprehensive literature searches, provision of a list and some key characteristics of included studies, and use of appropriate methods to combine the findings of studies. 6,7,13 However, grey literature sources were formally searched in only one SR, 13 and only one SR provided a list of excluded studies. 6 Study selection and data extraction were performed in duplicate by two independent reviewers in two SRs, 6,13 but the methods for screening and data extraction were not specified, and a flow diagram for selection of included studies was not provided, in the third SR. 7 Consideration of the scientific quality of evidence varied across the SRs. Quality was assessed in one SR at the individual study level using the Cochrane Collaboration s Risk of Bias tool. 6 In another SR, quality was assessed using criteria based on those developed by the US Preventive Services Task Force and National Health Service Centre for Reviews and Dissemination for individual studies, and using the Grading of Recommendations Assessment, Development and Evaluation for the overall body of evidence for each outcome. 13 The third SR did not include a formal assessment or documentation of scientific quality and did not adequately consider the strengths and limitations of the included studies in formulating conclusions. 7 The likelihood of publication bias was only assessed in one 6 of the three SRs. None of the SRs made reference to a protocol or ethics approval to indicate that the research question and inclusion criteria were established a priori, and none reported potential conflicts of interest for the included studies. 6,7,13 The review authors declared no conflicts of interest in one SR, 6 but authors of the other two SRs reported receipt of funding or employment from pharmaceutical companies. 7,13 Summary of Findings Rapid Response reports are organized so that the evidence for each research question is presented separately. 1. What is the comparative clinical effectiveness of desvenlafaxine versus venlafaxine for the treatment of adult patients with Major Depressive Disorder? Three SRs 6,7,13 were identified regarding the comparative clinical effectiveness of desvenlafaxine versus venlafaxine for the treatment of adult patients with MDD. In general, the evidence showed no significant differences in the clinical effectiveness of desvenlafaxine versus venlafaxine. SUMMARY WITH CRITICAL APPRAISAL Desv enlaf axine v ersus Venlaf axine f or the Treatment of Adult Patients with Major Depressiv e Disorder 6

7 In the first SR, pooled results from two trials demonstrated no difference in response rate (risk ratio = 0.91; 95% CI, 0.78 to 1.06, P = 0.219) or remission rate (risk ratio = 0.87; 95% CI, 0.65 to 1.16, P = 0.341) between patients treated with desvenlafaxine versus venlafaxine for eight weeks. 6 The second SR included a total of 27 trials and performed indirect comparisons between desvenlafaxine and venlafaxine, using placebo as the com mon comparator. 7 To assess non-inferiority, a minimum clinically-important difference of 1.5 points on the HAM-D17 scale was applied, although how this threshold was established was not reported. 7 It was found that desvenlafaxine was non-inferior to venlafaxine with respect to mean change in depressive symptoms. 7 Additionally, indirect comparisons indicated that remission and response rates and adverse events were not different between desvenlafaxine and venlafaxine. 7 The authors reported that desvenlafaxine may have better tolerability than venlafaxine because the risk difference for nausea was significantly lower (risk difference = -0.07; 95% CI, to -0.01, P = 0.02), however when the data were expressed as a relative risk there was no significant difference between treatment groups (relative risk = 0.97; 95% CI, 0.77 to 1.22, P = 0.80). 7 In the third SR, no head-to-head trials comparing the effects of desvenlafaxine with venlafaxine on the outcomes of anxiety, pain, or insomnia were identified What is the comparative cost-effectiveness of desvenlafaxine versus venlafaxine for the treatment of adult patients with Major Depressive Disorder? No relevant evidence comparing the cost-effectiveness of desvenlafaxine versus venlafaxine for the treatment of adult patients with MDD was identified; therefore, no summary can be provided. Limitations The primary limitation of this review is the paucity of evidence. Across the three included SRs, 6,7,13 only two trials were identified that conducted head-to-head comparisons of the clinical effectiveness of desvenlafaxine and venlafaxine. Although findings from 27 studies were pooled via indirect comparisons using placebo as the common comparator in one SR and meta-analysis, 7 head-to-head studies are required to confirm results. 7,14 Similarly, no evidence was identified regarding the comparative cost-effectiveness of desvenlafaxine versus venlafaxine for the treatment of adult patients with MDD; this is a research gap that remains to be addressed. Additional limitations of this review are related to limited study populations and generalizability of findings. All studies 6,7,13 included outpatients with MDD, and the results may not be generalizable to other populations, such as patients with treatment-resistant depression. Moreover, there was substantial variability in the antidepressant dosages in the included trials; 6,7 the dosages of desvenlafaxine and venlafaxine ranged from 50 to 400 mg/day and 75 to 225 mg/day across the included studies respectively, and whether this may have diluted between-treatment differences is unknown. However, it was reported in one SR that there were no differences in the efficacy and tolerability of different dosages of desvenlafaxine (ranging from 50 to 400 mg/day) compared to placebo, suggesting that these dosage differences may be inconsequential. 6 SUMMARY WITH CRITICAL APPRAISAL Desv enlaf axine v ersus Venlaf axine f or the Treatment of Adult Patients with Major Depressiv e Disorder 7

8 Conclusions and Implications for Decision or Policy Making This report identified evidence on the comparative clinical effectiveness of desvenlafaxine versus venlafaxine for the treatment of adult patients with MDD. No evidence was identified for the cost-effectiveness of desvenlafaxine versus venlafaxine for the treatment of adult patients with MDD. In general, results from three SRs 6,7,13 identified no significant differences in the clinical effectiveness of desvenlafaxine versus venlafaxine for the treatment of adult patients with MDD. Evidence was limited however; one SR included only two head-to-head trials that directly compared the clinical effectiveness of desvenlafaxine and venlafaxine, 6 a second SR included indirect comparisons using placebo as a common comparator, 7 and the third identified no relevant studies (that included information on anxiety, insomnia, and pain outcomes specifically). 13 All studies in this report included adult outpatients with MDD, and generalizability of findings to other populations, such as those with treatment-resistant depression, may be limited. Additional RCTs that directly compare the clinical effectiveness of desvenlafaxine and venlafaxine are necessary to more definitely establish the comparative clinical effectiveness for the treatment of adult patients with MDD. SUMMARY WITH CRITICAL APPRAISAL Desv enlaf axine v ersus Venlaf axine f or the Treatment of Adult Patients with Major Depressiv e Disorder 8

9 References 1. Qaseem A, Barry MJ, Kansagara D, Clinical Guidelines Committee of the American College of Physicians. Nonpharmacologic versus pharmacologic treatment of adult patients with major depressive disorder: a clinical practice guideline from the American College of Physicians. Ann Intern Med Mar 1;164(5): Lam RW, McIntosh D, Wang J, Enns MW, Kolivakis T, Michalak EE, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 1. Disease Burden and Principles of Care. [Internet]. Can J Psychiatry Sep [cited 2017 Oct 23];61(9): Available from: 3. Liebowitz MR, Yeung PP, Entsuah R. A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in adult outpatients with major depressive disorder. J Clin Psychiatry Nov;68(11): Solem CT, Shelbaya A, Wan Y, Deshpande CG, Alvir J, Pappadopulos E. Analysis of treatment patterns and persistence on branded and generic medications in major depressive disorder using retrospective claims data. [Internet]. Neuropsychiatr Dis Treat [cited 2017 Oct 23];12: Available from: 5. Kornstein SG, McIntyre RS, Thase ME, Boucher M. Desvenlafaxine for the treatment of major depressive disorder. Expert Opin Pharmacother Jul;15(10): Laoutidis ZG, Kioulos KT. Desvenlafaxine for the acute treatment of depression: a systematic review and meta-analysis. Pharmacopsychiatry Sep;48(6): Coleman KA, Xavier VY, Palmer TL, Meaney JV, Radalj LM, Canny LM. An indirect comparison of the efficacy and safety of desvenlafaxine and venlafaxine using placebo as the common comparator. CNS Spectr Sep;17(3): Colvard MD. Key differences between Venlafaxine XR and Desvenlafaxine: An analysis of pharmacokinetic and clinical data. Mental Health Clinician. [Internet] [cited 2017 Oct 23];4(1):35-9. Available from: 9. Septien-Velez L, Pitrosky B, Padmanabhan SK, Germain JM, Tourian KA. A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in the treatment of major depressive disorder. Int Clin Psychopharmacol Nov;22(6): CADTH Canadian Drug Expert Committee (CDEC) final recommendation: Desvenlafaxine (Pristiq - Wyeth Canada) [Internet]. Ottawa: CADTH; 2009 Sep 6 [cited 2017 Oct 23]. Available from: Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. [Internet]. Pharmacological Treatments. Can J Psychiatry Sep [cited 2017 Oct 23];61(9): Available from: Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet] [cited 2017 Oct 23];7:10. Available from: Thaler KJ, Morgan LC, Van NM, Gaynes BN, Hansen RA, Lux LJ, et al. Comparative effectiveness of second-generation antidepressants for accompanying anxiety, insomnia, and pain in depressed patients: a systematic review. Depress Anxiety Jun;29(6): Gartlehner G, Moore CG. Direct versus indirect comparisons: a summary of the evidence. International Journal of Technology Assessment in Health Care [Internet] [cited 2017 Oct 23];24(2): Available from: a.pdf/direct-versus-indirect-comparisons-a-summary-of-the-evidence.pdf SUMMARY WITH CRITICAL APPRAISAL Desv enlaf axine v ersus Venlaf axine f or the Treatment of Adult Patients with Major Depressiv e Disorder 9

10 Appendix 1: Selection of Included Studies 307 citations identified from electronic literature search and screened 299 citations excluded 8 potentially relevant articles retrieved for scrutiny (full text, if available) 0 potentially relevant reports retrieved from other sources (grey literature, hand search) 8 potentially relevant reports 5 reports excluded: -irrelevant population (1) -irrelevant comparator (3) -other (non-systematic review) (1) 3 reports included in review SUMMARY WITH CRITICAL APPRAISAL Desv enlaf axine v ersus Venlaf axine f or the Treatment of Adult Patients with Major Depressiv e Disorder 10

11 Appendix 2: Characteristics of Included Publications Table A1: Characteristics of Included Systematic Reviews and Meta-Analyses Author, Publication Year, Country Laoutidis and Kioulos Germany and Greece Coleman et al Australia Thaler et al Austria and USA Types and Numbers of Primary Studies Included 15 studies in total 2 primary studies relevant to the present review: RCT, n = 2 27 studies in total 27 primary studies relevant to the present review: RCT, n = studies in total No primary studies relevant to the present review were included Population Characteristics Not specified overall For the studies relevant to the present review: outpatients with HAM-D17 22, 1 st item 2, CGI-S 4, score in Raskin Depression Scale > score in Covi Anxiety Scale Adult outpatients with HAM-D17 or HAM-D21 20 Adult outpatients with MDD and information on anxiety, insomnia, or pain Intervention(s) Desvenlafaxine, 200 to 400 mg Duration: 8 weeks Desvenlafaxine, 50 to 200 mg/day Duration: 8 weeks Second-generation antidepressants (including desvenlafaxine and venlafaxine) Duration: 6 weeks Comparator(s) Placebo or other antidepressant agent (venlafaxine, 75 to 150 mg) Venlafaxine, 75 to 225 mg/day (compared indirectly using placebo as the common comparator) Any other secondgeneration antidepressant Clinical Outcomes Efficacy: response ( 50% reduction on HAM- D17) and remission (HAM-D17 7) rates Tolerability: discontinuation rate and discontinuation due to adverse events Mean change in HAM-D17 from baseline, remission (HAM-D17 7), response (decrease of 50% in HAM-D17 and HAM-D 21 scores in desvenlafaxine and venlafaxine studies, respectively) adverse events Anxiety, insomnia, pain CGI-S = Clinical Global Impression-Severity; HAM-D 17 or HAM-D 21 = Hamilton Rating Scale for Depression; MDD = major depressive disorder; RCT = randomized controlled trial. SUMMARY WITH CRITICAL APPRAISAL Desv enlaf axine v ersus Venlaf axine f or the Treatment of Adult Patients with Major Depressiv e Disorder 11

12 Appendix 3: Critical Appraisal of Included Publications Table A2: Strengths and Limitations of Systematic Reviews and Meta-Analyses using AMSTAR 12 Strengths Limitations Laoutidis and Kioulos Comprehensive literature search performed, including database and trial registry searching, and searching of reference lists of reviews and related articles Study selection and data extraction performed by two independent reviewers, with a third reviewer resolving conflicts Lists of included and excluded studies provided Some characteristics of included studies provided (e.g., sample size where reported in primary studies, trial duration and treatment dose) Risk of bias for individual studies assessed using the Cochrane Collaboration s Risk of Bias tool Statistical heterogeneity assessed using I 2 statistic when clinically appropriate to combine studies and random-effects meta-analyses used appropriately Likelihood of publication bias assessed using a funnel plot and Egger s regression method Review authors declared no conflict of interest Comprehensive literature search performed, including database and trial registry searching List of included studies, and their key characteristics, provided Appropriate methods used to combine the findings of studies (Bayesian indirect analysis) Comprehensive literature search performed, including database searching, trial registry searching, grey literature sources, manufacturer dossiers with citations for relevant trials, and searching of reference lists of relevant review articles and letters to the editor Study selection and data extraction performed by two independent reviewers, with a third reviewer resolving conflicts Coleman et al Thaler et al No reference to a protocol or ethics approval to indicate that the research question and inclusion criteria were established a priori No formal grey literature search conducted Some characteristics of included studies not provided (e.g., patient age) Overall risk of bias in included studies was rated as moderate, and this was not adequately considered in the analysis and conclusions of the review Potential conflict of interest not reported for the included studies No reference to a protocol or ethics approval to indicate that the research question and inclusion criteria were established a priori No formal grey literature search conducted Flow diagram for selection of included studies not included List of excluded studies not provided Methods for study selection and data extraction not provided Scientific quality of included studies not assessed or considered in formulating conclusions Likelihood of publication bias not assessed Five of six authors declared conflicts of interest (former or current direct or indirect employees of a pharmaceutical company) Potential conflict of interest not reported for the included studies No reference to a protocol or ethics approval to indicate that the research question and inclusion criteria were established a priori; review was conducted as part of a larger comparative effectiveness review that also did not refer to a protocol or ethics approval List of excluded studies not provided Some characteristics of included studies not provided (e.g., patient age, depression severity) SUMMARY WITH CRITICAL APPRAISAL Desv enlaf axine v ersus Venlaf axine f or the Treatment of Adult Patients with Major Depressiv e Disorder 12

13 Table A2: Strengths and Limitations of Systematic Reviews and Meta-Analyses using AMSTAR 12 Strengths Limitations List of included studies provided Some characteristics of included studies provided (e.g., sample size, trial duration and treatment dose) Scientific quality assessed using criteria based on those by the US Preventive Services Task Force and National Health Service Centre for Reviews and Dissemination for individual studies, and GRADE for the overall body of evidence for each outcome Scientific quality used appropriately in formulating conclusions Statistical heterogeneity assessed using I 2 statistic when clinically appropriate to combine studies and random-effects meta-analyses used appropriately Publication bias not assessed, however this limitation was due to the low number of included studies Two contributing authors declared conflicts of interest (receipt of funding from pharmaceutical companies) Potential conflict of interest not reported for the included studies GRADE = Grading of Recommendations Assessment, Development and Evaluation. SUMMARY WITH CRITICAL APPRAISAL Desv enlaf axine v ersus Venlaf axine f or the Treatment of Adult Patients with Major Depressiv e Disorder 13

14 Appendix 4: Main Study Findings and Author s Conclusions Table A3: Summary of Findings of Included Systematic Reviews and Meta-Analyses Main Study Findings The following were not significantly different between patients treated with desvenlafaxine and venlafaxine in two trials (n = NR): Response rate: Risk Ratio = 0.91; 95% CI, 0.78 to 1.06, P = Remission rate: Risk Ratio = 0.87; 95% CI, 0.65 to 1.16, P = The following were not significantly different between patients treated with desvenlafaxine and venlafaxine, compared using Bayesian indirect comparisons against placebo (adjusted for baseline HAM-D): Mean change in HAM-D: WMD = -0.27; 95% CI, to 0.65 Response rate: Relative Risk = 0.97; 95% CI, 0.85 to 1.10, P = 0.63; RD = -0.02; 95% CI, to 0.03, P = 0.43 Remission rate: Relative Risk = 0.94; 95% CI, 0.78 to 1.12, P = 0.48; RD = -0.04; 95% CI, to 0.01, P = 0.12 Adverse event rate: Relative Risk = 1.01; 95% CI, 0.96 to 1.06, P = 0.70; RD = -0.01, 95% CI, to 0.03, P = 0.59 Rate of discontinuation due to adverse events: Relative Risk = 0.86; 95% CI, 0.58 to 1.29, P = 0.48; RD = -0.04, 95% CI, to 0.00, P = 0.06 There was no significant difference in nausea between patients treated with desvenlafaxine versus venlafaxine using relative risk (Relative Risk = 0.97; 95% CI, 0.77 to 1.22, P = 0.80) however using RD those treated with desvenlafaxine had significantly less nausea (RD = -0.07; 95% CI, to -0.01, P = 0.02). No head-to-head trials comparing desvenlafaxine with venlafaxine were identified. Note: This SR identified head-to-head trials comparing other antidepressants (e.g., fluoxetine versus venlafaxine). Laoutidis and Kioulos Coleman et al Thaler et al Author s Conclusion Based on the current literature we cannot support the view that desvenlafaxine should be used as a standard antidepressant agent; more evidence on its efficacy needs to be provided. p. 194 The results of this indirect Bayesian analysis, adjusted for baseline HAM-D score, indicate that desvenlafaxine is noninferior to venlafaxine in terms of efficacy at Australian approved doses [50 to 200 mg/day and 75 to 225 mg/day for desvenlafaxine and venlafaxine, respectively] for the treatment of major depression. p. 139 The results of the analysis also suggest that desvenlafaxine has a tolerability advantage over venlafaxine in terms of less nausea; however, both the safety and efficacy results require confirmation via adequately powered head-to-head studies. p. 139 Unfortunately, our review shows that the current head-to-head evidence cannot be considered adequate to draw many conclusions about the superiority of any one agent for anxiety, insomnia, or pain. We recommend that practicing clinicians base their choices about the appropriate antidepressant for their individual patients on other factors such as differential tolerability and side effect profiles until stronger evidence regarding effectiveness for accompanying symptoms exists. p. 502 CI = confidence interval; HAM-D = Hamilton Rating Scale for Depression (17- or 21-item version); NR = not reported; RD = risk difference; SR = systematic review; WMD = w eighted mean difference. SUMMARY WITH CRITICAL APPRAISAL Desv enlaf axine v ersus Venlaf axine f or the Treatment of Adult Patients with Major Depressiv e Disorder 14

15 Appendix 5: Additional References of Potential Interest Economic Evaluation Alternative Comparator Rejas GJ, Blanca TM, Gascon BJ, Armada PB. Economic evaluation of desvenlafaxine in the treatment of major depressive disorder in Spain. Rev Psiquiatr Salud Ment Apr; 9(2): Comparator: Venlafaxine in combination with duloxetine. SUMMARY WITH CRITICAL APPRAISAL Desv enlaf axine v ersus Venlaf axine f or the Treatment of Adult Patients with Major Depressiv e Disorder 15