Original version: 17 April, 2018
Revised: 16 Jan, 2019

Dose-response relationship of new generation antidepressants: Protocol for asystematic review and dose-response meta-analysis

REVIEW QUESTION

What is the dose-response relationship for selective serotonin reuptake inhibitors (SSRIs),
serotonin noradrenaline reuptake inhibitors (SNRIs) and other second-generation
antidepressants?

METHODSThis study is a derivative study from the systematic review and network meta-analysis of all
second-generation and selected first-generation antidepressants licensed for the acute phasetreatment of major depression in USA, Europe or Japan (Furukawa, Salanti et al. 2016, Cipriani,Furukawa et al. 2018).

Data sources
We will include fixed-dose double-blind, randomized controlled trials (RCTs) comparing
antidepressants among themselves or with placebo as oral monotherapy for the acute phasetreatment of adults (aged 18 years or older) of both sexes, with a primary diagnosis of major
depressive disorder according to standard operationalized diagnostic criteria (Feighner Criteria,
Research Diagnostic Criteria, DSM-III, DSM-III-R, DSM-IV, DSM-5, ICD-10). Trials ofantidepressants for depressive patients with a serious concomitant physical illness will be
excluded.
We have searched Cochrane Central Register of Controlled Trials, CINAHL, EMBASE, LILACS,MEDLINE, MEDLINE In-Process, PsycINFO, AMED, the UK National Research Register, andPSYNDEX from the date of their inception to Jan 8, 2016. We have scrutinized reference lists ofall relevant papers. We have searched files of the national drug licensing agencies in six countries(USA, UK, Netherlands, Sweden, Japan and Australia), the European Medicines Agency andseveral trial registries for published, unpublished and ongoing RCTs. We contacted allpharmaceutical companies marketing second-generation antidepressants and asked forsupplemental unpublished information about their pre-marketing and post-marketing trials. We
contacted the National Institute for Health and Care Excellence (NICE, UK), the Institut fü r
Qualitä t und Wirtschaftlichkeit im Gesundheitswesen (IQWiG, Germany), and any other relevantorganizations and individuals for any additional information not already identified. We usedbroad search terms for depression (depress* or dysthymi* or adjustment disorder* or mooddisorder* or affective disorder or affective symptoms) in conjunction with generic and commercialnames of all antidepressants under review. We imposed no language restriction.
Selection criteria for the study
This study focuses on second-generation antidepressants, as dose-response relationships may
be different for different classes of antidepressants (Adli, Baethge et al. 2005). The
antidepressants of interest in this study will include those most often prescribed in UK: namely,SSRIs (citalopram, escitalopram, fluoxetine, paroxetine, sertraline), venlafaxine, and mirtazapin.
In order to examine dose-response relationships we will include all trials from the larger dataset

above that compared two or more different fixed doses (including placebo, which is 0 mg) of theabove antidepressants within a trial. We will include arms within, below or above the dose
ranges licensed by drug approval agencies.

Data extraction and risk of bias assessment
Two independent reviewers have extracted data and assessed the risk of bias of the included
studies. In case of disagreement, a third member of the review team was consulted and madethe final decision. (Furukawa, Salanti et al. 2016)

Primary outcomes
The primary outcomes of interest in this study are the following benefit as well as harmoutcomes at the time point as close to 8 weeks (range 4-12 weeks) as possible in each included
study.
1 Response, defined as 50% or greater reduction on an observer-rated scale for depression
2 Dropouts for adverse effects
3 Dropouts for any reasons, interpreted as an overall index of treatment acceptability
We will abide by the intention-to-treat principle by taking the number of randomized patientsas the denominator for all outcomes. Those who had been randomized but not accounted for in
the original study will be assumed to have dropped out for some reason other than adverse
effects and without responding.

Statistical analyses
Multivariate dose-response meta-analysis
We will apply the multivariate dose-response meta-analysis(Crippa and Orsini 2016), using thedosres package in R (Crippa and Orsini 2016). Given the clinical and methodologicalheterogeneities likely present in the included studies, we will use the random effects model. Thismodel has recently been applied to estimate dose-response relationships in meta-analyses(Crippa, Discacciati et al. 2014, Di Giuseppe, Crippa et al. 2014, Larsson, Crippa et al. 2015, Smith,Crippa et al. 2016, Vinceti, Filippini et al. 2016, Aneni, Crippa et al. 2017, Crippa, Larsson et al.
2018).

Stages of data synthesis
On the one hand, different drugs and different classes of antidepressants may have different
dose-response relationships. On the other, extant RCTs are likely too few to allow precise
estimation of dose-response for any single drug. This study therefore takes the following
stepwise approach to data synthesis while paying due attention to heterogeneity among theincluded studies.
1 Dose-response analysis for single drugs
2 Dose-response analysis for all SSRIs after dose conversion, as they share a key therapeuticmechanism
There are several methods to define and calculate dose equivalence (Patel, Arista et al. 2013).
We will use the most recent and comprehensive review of dose equivalence of antidepressants(Hayasaka, Purgato et al. 2015), which used the method that was originally used to calculatedose equivalence of antipsychotics by assuming the optimum doses found in double-blind
flexible-dose trials of various antipsychotics to be equivalent (Davis 1974). Previous studies on
dose-response of antidepressants used similar but different conversion algorithms (Bollini,Pampallona et al. 1999, Baker and Woods 2003, Jakubovski, Varigonda et al. 2016). Where no
empirical data for dose conversion were available, we will assume the Daily Defined Dose (DDD),
the average maintenance dose per day calculated from the dosage recommendations in eachdrug’s product information according to WHO (WHO Collaborative Centre for Drug Statistics
Methodology 2006), to be equivalent. We will test the robustness of our primary dose conversion,using Hayasaka et al (Hayasaka, Purgato et al. 2015) supplemented by DDD (WHO Collaborative

Centre for Drug Statistics Methodology 2006), in a sensitivity analysis.

Sensitivity analyses
In order to ascertain the robustness of the primary analyses, we will conduct the following
sensitivity analyses.
1 To test the influence of the dose conversion algorithms
1.1 Using the algorithm by Jakubovski et al (Jakubovski, Varigonda et al. 2016),
supplemented by DDD (WHO Collaborative Centre for Drug Statistics Methodology2006)
1.2 Using the conversion based on average doses actually prescribed for major
depression (Olfson and Marcus 2009)
2 To test the stability of the shape of the spline curves
2.1 Setting knots for spline curves at different doses: We will examine the goodness-offit statistics of different models (Discacciati, Crippa et al. 2017).

CHANGES IMPLEMENTED ON JAN 2019

We have decided to focus on the antidepressants most commonly prescribed in UK, and havetherefore removed mention of the other drugs.

References
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eTable 1. Dose equivalence according to previous studies.
AntidepressantBolliniBaker

Jakubovski

Hayasaka

DDDbupropion---

174.3

300

agomelatine
citalopram

desvenlafaxineduloxetine

escitalopram
fluoxetine

fluvoxamine
milnacipran

mirtazapine
paroxetine
reboxetine
sertraline

venlafaxine
vilazodone

vortioxetine

-

30-

20

100
100-

20-

83

100-

-

20-

30-

100-

-

33.3-

16.7
20

100-

20-

120-

26.6-

9

20

71.7
-

25.5
17

5.7

49.3
74.7
-

25

Current
study
26.6

20

20

50
60
10
20

100
100
30
20
8

50

100
10
10

174.3
50
60
9

20

71.7
100

25.5
17

5.7

49.3
74.7
1010