cadth rapid response report: summary with …

Service Line: Rapid Response Service

Version: 1.0

Publication Date: October 25, 2017

Report Length: 15 Pages

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

SUMMARY WITH CRITICAL APPRAISAL Desv enlaf axine v ersus Venlaf axine f or the Treatment of Adult Patients with Major Depressiv e Disorder 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: 1922-8147 (online)

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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 MDD4 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?


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 meta-

analysis 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, 2017.

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 Adult patients requiring treatment for Major Depressive Disorder

Intervention Desvenlafaxine (e.g., Pristiq)

Comparator Venlafaxine (e.g., Effexor)

Outcomes Q1: Comparative clinical effectiveness, clinical benefit and harm Q2: Cost-effectiveness

Study Designs Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized 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

2012.

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 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 2008,7

2011,13

and 2014.6 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


Outcomes

The outcomes considered in the SRs were response rate (≥ 50% reduction in HAM-D17 or

HAM-D21 scores);6,7

remission rate (HAM-D17 ≤ 7);6,7

change in HAM-D17 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 one6 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 SRs6,7,13

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.


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, -0.12 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.13

2. 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 studies6,7,13

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


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 SRs6,7,13

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.


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. 2016 Mar 1;164(5):350-9.

2. 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. 2016 Sep [cited 2017 Oct 23];61(9):510-

23. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994789

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. 2007 Nov;68(11):1663-72.

4. 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.

2016 [cited 2017 Oct 23];12:2755-64. Available from:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087821

5. Kornstein SG, McIntyre RS, Thase ME, Boucher M. Desvenlafaxine for the treatment of

major depressive disorder. Expert Opin Pharmacother. 2014 Jul;15(10):1449-63.

6. Laoutidis ZG, Kioulos KT. Desvenlafaxine for the acute treatment of depression: a

systematic review and meta-analysis. Pharmacopsychiatry. 2015 Sep;48(6):187-99.

7. 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. 2012 Sep;17(3):131-41.

8. Colvard MD. Key differences between Venlafaxine XR and Desvenlafaxine: An analysis of pharmacokinetic and clinical data. Mental Health Clinician. [Internet]. 2014 [cited 2017 Oct 23];4(1):35-9. Available from:

http://mhc.cpnp.org/doi/full/10.9740/mhc.n186977?code=cpnp-site

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. 2007 Nov;22(6):338-47.

10. CADTH Canadian Drug Expert Committee (CDEC) final recommendation: Desvenlafaxine (Pristiq - Wyeth Canada) [Internet]. Ottawa: CADTH; 2009 Sep 6 [cited 2017 Oct 23]. Available from:

https://www.cadth.ca/media/cdr/complete/cdr_complete_Pristiq_September-25-2009.pdf

11. 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. 2016 Sep [cited 2017 Oct 23];61(9):540-

60. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994790

12. 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]. 2007 [cited 2017 Oct 23];7:10. Available from:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810543/pdf/1471-2288-7-10.pdf

13. 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. 2012 Jun;29(6):495-505.

14. Gartlehner G, Moore CG. Direct versus indirect comparisons: a summary of the evidence. International Journal of Technology Assessment in Health Care [Internet]. 2008 [cited 2017 Oct 23];24(2):170-7. Available from:

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/CA5C46615EB22CC0174DC451E9F9189B/S0266462308080240a.pdf/direct-versus-indirect-comparisons-a-summary-of-the-evidence.pdf



http://mhc.cpnp.org/doi/full/10.9740/mhc.n186977?code=cpnp-site




http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810543/pdf/1471-2288-7-10.pdf





Appendix 1: Selection of Included Studies

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

307 citations identified from electronic

literature search and screened


Appendix 2: Characteristics of Included Publications

Table A1: Characteristics of Included Systematic Reviews and Meta-Analyses

Author, Publication

Year, Country

Types and

Numbers of Primary Studies

Included

Population Characteristics

Intervention(s) Comparator(s) Clinical

Outcomes

Laoutidis and Kioulos 2015

6

Germany and Greece

15 studies in total 2 primary studies relevant to the present review: RCT, n = 2

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

Desvenlafaxine, 200 to 400 mg Duration: 8 weeks

Placebo or other antidepressant agent (venlafaxine, 75 to 150 mg)

Efficacy: response (≥ 50% reduction on HAM-D17) and remission (HAM-D17 ≤ 7) rates Tolerability: discontinuation rate and discontinuation due to adverse events

Coleman et al. 2012

7

Australia

27 studies in total 27 primary studies relevant to the present review: RCT, n = 27

Adult outpatients with HAM-D17 or HAM-D21 ≥ 20

Desvenlafaxine, 50 to 200 mg/day Duration: 8 weeks

Venlafaxine, 75 to 225 mg/day (compared indirectly using placebo as the common comparator)

Mean change in HAM-D17 from baseline, remission (HAM-D17 ≤ 7), response (decrease of ≥ 50% in HAM-D17 and HAM-D21 scores in desvenlafaxine and venlafaxine studies, respectively) adverse events

Thaler et al. 2012

13

Austria and USA

19 studies in total No primary studies relevant to the present review were included

Adult outpatients with MDD and information on anxiety, insomnia, or pain

Second-generation antidepressants (including desvenlafaxine and venlafaxine) Duration: ≥ 6 weeks

Any other second-generation antidepressant

Anxiety, insomnia, pain

CGI-S = Clinical Global Impression-Severity; HAM-D17 or HAM-D21 = Hamilton Rating Scale for Depression; MDD = major depressive disorder; RCT

= randomized controlled trial.


Appendix 3: Critical Appraisal of Included Publications

Table A2: Strengths and Limitations of Systematic Reviews and Meta-Analyses using AMSTAR12

Strengths Limitations


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 I2 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

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

Coleman et al. 20127

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)

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)


Thaler et al. 201213

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

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)


Table A2: Strengths and Limitations of Systematic Reviews and Meta-Analyses using AMSTAR12

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 I2 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)


GRADE = Grading of Recommendations Assessment, Development and Evaluation.


Appendix 4: Main Study Findings and Author’s Conclusions

Table A3: Summary of Findings of Included Systematic Reviews and Meta-Analyses

Main Study Findings Author’s Conclusion


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 = 0.219

Remission rate: Risk Ratio = 0.87; 95% CI, 0.65 to 1.16, P = 0.341

“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

Coleman et al. 20127

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, -1.17 to 0.65

Response rate: Relative Risk = 0.97; 95% CI, 0.85 to 1.10, P = 0.63; RD = -0.02; 95% CI, -0.07 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, -0.09 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, -0.05 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, -0.08 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, -0.12 to -0.01, P = 0.02).

“The results of this indirect Bayesian analysis, adjusted for baseline HAM-D score, indicate that desvenlafaxine is non-inferior 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

Thaler et al. 201213

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).

“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.


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. 2016 Apr;

9(2):87-96.

Comparator: Venlafaxine in combination with duloxetine.

cadth rapid response report: summary with …

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