Efficacy of vortioxetine versus other on cognitive dysfunction in patients with major depressive disorder Bernhard T Baune1, Mélanie Brignone2, Klaus Groes Larsen3 1School of Medicine, University of Adelaide, Australia; 2Lundbeck SAS, Issy-les-Moulineaux, France; 3 P.2.f.027 H. A/S, Valby, Denmark

Standardized effect size, relative to BACKGROUND NMA Figure 4: Standardised effect size relative to placebo by A) AD therapeutic classes and B) individual ADs • Patients with major depressive disorder (MDD) often exhibit Networks of evidence 0.5

impairment in cognitive function, including executive function, • The DSST was used across 13 of the included RCTs, allowing for A 0.4 1 a network of evidence to be generated comparing vortioxetine with ** processing speed, concentration/attention, learning and memory 0.3 • Cognitive dysfunction has been identified as a target of other antidepressants. One study6 was excluded in the absence of a 0.2 pharmacological treatments in patients with MDD2 common link with the other antidepressants included in the network • Nevertheless, only few reviews describe the effect of antidepressants • DSST is a recognised measure of cognitive dysfunction as it assesses 0.1 SSRI MAOI TCA (ADs) on cognitive dysfunction in MDD, focusing mostly on several of the cognitive domains that are the most impaired in MDD 0 ffect size ffect Vortioxetine SNRI 3-5 E comparisons versus placebo patients (executive function, processing speed and attention) and is −0.1 2 recognised as being sensitive to change if treatment is effective −0.2 Aims • The number of patients in the included studies ranged from 27 to −0.3 Standardized effect size, relative to placebo • To conduct a systematic literature review and network meta-analyses 602, and the time of DSST assessment varied from 4 weeks to 24 (NMA) to assess the relative effect of different antidepressants on weeks with the majority of studies reporting DSST data at 8 weeks −0.40.5 cognitive dysfunction in MDD patients (n=8) −0.50.4 B * • Two networks were developed: one network by drug class and another METHODS 0.3 by individual (Figure 2) 0.2 Systematic literature review • Meta-analysis of the effect of antidepressants on DSST based on • MEDLINE®, Embase®, Cochrane, CDSR, PsychINFO® data- 0.1 direct evidence from clinical studies included in the DSST network is CIT FLU ESC PHE NOR bases, registries, and relevant conference abstracts were 0 VOR DUL SER DES

shown in Figure 3 size ffect E searched from database inception date to 13 November 2014 −0.1 • The review focused on evidence from randomised controlled trials Figure 2: Network for the A) by AD class analysis and B) by treatment −0.2 (RCTs) assessing pharmacological interventions and placebo in analysis adult patients with MDD, with no restrictions on gender or race, or A Vortioxetine −0.3 publication language −0.4 *p<0.05; **p<0.01 −0.5 • Included studies underwent a two-stage screening and data Abbreviations: VOR=vortioxetine, DUL=, SER=, CIT=, FLU=, ESC=, extraction process conducted by two independent reviewers, with PHE=, DES=, NOR=. 2 MAOI discrepancies reconciled by a third independent reviewer 3 Relative effect of ADs on DSST SNRI • Studies were critically appraised using a comprehensive assessment • Vortioxetine was also either numerically or statistically more criteria based on the recommendations in the NICE guidelines efficacious than other included AD classes or individual therapies 4 • A feasibility assessment was carried out for determining the (Table 1) approach to assess the relative effect of antidepressants on cognitive • This difference was statistically significant versus SSRIs and TCAs Placebo B dysfunction in MDD (standardised effect size: 0.423 [95% CI=0.147; 0.698] and 0.722 3 [95% CI=0.316; 1.129], respectively) Network meta-analysis (NMA) Vortioxetine Citalopram • The relative treatment effects were estimated through the evaluation of 2 • When comparisons were made between individual antidepressants, TCA the standardised effect size in an NMA taking inter-trial heterogeneity vortioxetine was numerically better than all included antidepressants into account Escitalopram with statistically significant differences versus escitalopram and SSRI Duloxetine 2 • The statistical model was a two-way ANOVA with random effects and nortriptyline (standardised effect size on change from baseline 3 known residual variances varying between treatment groups within compared with vortioxetine: 0.579 [95% CI=0.117; 1.041] and 0.691 [95% CI=0.165; 1.217], respectively) studies 4 Phenelzine • Potential inconsistency was addressed through the concept of node- Table 1: Treatment effect estimates

splitting, i.e. comparing if evidence from direct comparisons are VOR Desipramine Placebo 0.193 0.325 0.423 0.602 0.722 VOR (-0.013; 0.398) (0.135; 0.516) (0.147; 0.698) (-0.008; 1.213) (0.316; 1.129) consistent with evidence from indirect comparisons

0.192 SNRI 0.133 0.230 0.410 0.530 (-0.027; 0.411) (-0.032; 0.298) (-0.041; 0.502) (-0.199; 1.018) (0.126; 0.934) DUL RESULTS

0.325 0.133 PBO 0.097 0.277 0.397 Nortriptyline (0.120; 0.529) (-0.043; 0.308) (-0.129; 0.323) (-0.313; 0.867) (0.022; 0.771) Systematic literature review PBO

0.305 0.112 -0.020 • The database search retrieved 11,337 citations of which 72 RCTs Fluoxetine (-0.168; 0.777) (-0.358; 0.582) (-0.460; 0.420) SER from 103 publications met the inclusion criteria (Figure 1) Sertraline 0.362 0.170 0.038 0.058 SSRI (-0.079; 0.804) (-0.268; 0.608) (-0.368; 0.443) (-0.540; 0.656) • The interventions assessed included ADs of the following therapeutic CIT Note: The size (area) of the nodes is proportional to the number of patients receiving the treatment. The width of lines are 0.180 0.300 (-0.411; 0.770) (-0.037; 0.636) proportional to the number of patients in trials with direct comparison between the nodes. The numbers on the lines indicate how 0.578 0.386 0.253 0.273 0.215 classes: selective inhibitors (SSRIs), serotonin- (-0.018; 1.173) (-0.208; 0.979) (-0.317; 0.823) (-0.089;0.635) (-0.484; 0.914) many trials with direct comparisons, if there are more than one. FLU

0.579 0.387 0.254 0.274 0.216 0.001 norepinephrine reuptake inhibitors (SNRIs) and other non-SSRI/ (0.117; 1.041) (-0.073; 0.846) (-0.174; 0.682) (-0.340; 0.888) (-0.374; 0.806) (-0.712; 0.714) ESC

SNRI antidepressants such as monoamine oxidase inhibitors, MAOI Figure 3: Meta-analysis of the effect of antidepressants on DSST based 0.582 0.390 0.257 0.277 0.219 0.004 0.003 0.120 (-0.103; 1.267) (-0.293; 1.072) (-0.405; 0.919) (-0.395; 0.950) (-0.557; 0.996) (-0.760; 0.768) (-0.786; 0.792) (-0.437; 0.677) antidepressants (TCAs), and tetracyclic antidepressants. on direct evidence from clinical studies included in the network of PHE

0.319 0.127 -0.006 0.014 -0.044 -0.259 -0.260 -0.263 • Amongst the included studies there was a high rate of variability in evidence (-0.984; 1.621) (-1.175; 1.428) (-1.297; 1.285) (-1.199; 1.228) (-1.397; 1.309) (-1.417; 0.900) (-1.620; 1.100) (-1.650; 1.125) TCA DES trial design and methods, with few studies completed to a high quality Standardized Effect Size 0.691 0.499 0.367 0.387 0.329 0.114 0.112 0.109 0.372 (0.165; 1.217) (-0.025; 1.023) (-0.130; 0.863) (-0.008; 0.781) (-0.313; 0.970) (-0.422; 0.649) (-0.544; 0.768) (-0.501; 0.720) (-0.904; 1.648) level SMD 1st 2nd NOR • The review identified 86 cognitive scales used to assess Vortioxetine vs placebo Treatment effect estimates in terms of Standardsed effect size with corresponding 95% confidence intervals based on a network antidepressants effect on cognitive functioning, most of which were Katona (2012) 7 0.25 [0.03;0.48] 153 144 meta analysis by treatment (lower triangle) and by AD class (upper triangle). The order of the treatments in the diagonal is based first Mahableswarkar (2014)8 0.25 [0.04;0.46] 175 167 on the relative efficacy of the AD classes and second on the relative efficacy of the treatments within the classes. A positive estimate 9 used in only one study McIntyre (2014) 0.46 [0.26;0.66] 397 194 indicates that the treatment/AD class to left is numerically better than the one to the right and vice versa. Statistically significant differences in the relative effect estimates are highlighted. Abbreviations: VOR=vortioxetine, DUL=duloxetine, PBO=placebo, Fixed effects meta analysis 0.35 [0.23;0.46] 725 505 • A total of 12 scales were reported in four or more studies, with the Mini SER=sertraline, CIT=citalopram, FLU=fluoxetine, ESC=escitalopram, PHE=phenelzine, DES=desipramine, NOR=nortriptyline. Random effects meta analysis 0.34 [0.18;0.49] 725 505 Mental State Examination (MMSE) and Digit Symbol Substitution Test Duloxetine vs placebo 7 Ranking (DSST) being the most commonly reported outcomes in 13 studies Katona (2012) 0.07 [−0.16;0.30] 144 144 8 Mahableswarkar (2014) 0.17 [−0.04;0.38] 187 167 • Based on the NMA by class, the probability of vortioxetine being each Raskin (2007) 10 −0.04 [−0.28;0.20] 196 99 Robinson (2014) 11 0.22 [−0.03;0.48] 180 87 better than all other classes of ADs and placebo is 97% Figure 1: Flow diagram for identification and selection of studies Fixed effects meta analysis 0.13 [−0.03;0.28] 607 497 Random effects meta analysis 0.13 [−0.03;0.28] 607 497 Consistency analysis n Records identified through Duplicates removed i o database searching Sertraline vs placebo

a n17 12 • Consistency was addressed by node-splitting. There were mild i n11337 −0.17 [−0.57;0.22] 49 49

i f Hoffman (2008) n

e inconsistencies regarding the vortioxetine/SNRI comparison and d I Citalopram vs placebo eords eluded a firs sage sreening n722 Culang (2009)13 −0.04 [−0.33;0.26] 84 90 the placebo/SSRI/TCA comparisons, although none were significant Records screened eords aegoried ased on seuenial sud design g n1 aroah 71 (p=0.085 and p=0.132, respectively) i n - n • Case control studies: 168 Escitalopram vs placebo

e 14 Cross-sectional studies: 66 −0.25 [−0.57;0.06] 54 122 r e Dube (2010) • Single arm studies: 455 • Heterogeneity was mainly found in the comparison between S • Analysis of hospital records/databases: 25 Phenelzine vs placebo vortioxetine and placebo, and was accounted for by the random 15 eords eluded a seond sage sreening n117 Georgotas (1989) −0.02 [−0.52;0.48] 28 18 eords aegoried ased on seuenial sud design

Full-text articles assessed effects in the NMA model aroah 32

i l for eligibility • Case-control studies: 9

i Nortriptyline vs placebo n12 - 15 • Cross sectional studies: 3 Georgotas (1989) 0.01 [−0.56;0.58] 32 18 l i g • Single arm studies: 20 • Analysis of hospital records/databases:0 CONCLUSIONS Articles added through PDFs not available due to copyright issues: 16 Vortioxetine vs duloxetine • hand-searching n20 Katona (2012)7 0.18 [−0.04;0.41] 153 144 Ariles no eraed due o fous on CTs ealuaing 8 0.08 [−0.13;0.28] haraologial heraies n107 Mahableswarkar (2014) 175 187 • A comprehensive overview of studies assessing the • Non-RCTs: 27 0.13 [−0.03;0.28] Studies included in the review Fixed effects meta analysis 328 331 n n210 uliaions • Studies with uncertainty of MDD: 28 0.13 [−0.03;0.28] i o Random effects meta analysis 328 331 relative effect of antidepressants on cognitive dysfunction s • Studies with uncertainty of type of ADT: 8

l u • Studies evaluating pharmacological vs. non-pharmacological: 4 n I • Studies evaluating non-pharmacological vs. non- Fluoxetine vs sertraline in MDD found a high degree of variability in the reporting pharmacological/placebo/Observation : 40 Studies extracted Newhouse (2000)16 −0.27 [−0.53;−0.01] 119 117 n72 fro 103 uliaions, of cognitive outcomes in RCTs ealuaing haraologial s. haraologial or laeo Sertraline vs nortriptyline Bondareff (2000) 17 0.52 [0.20;0.85] 74 70 • Focusing on DSST, which was used across 12 of the studies Fluoxetine vs desipramine included in the network, NMA showed vortioxetine to be the REFERENCES Levkovitz (2002)18 −0.26 [−1.24;0.72] 8 9 1. National Academies of Sciences EaM. Enabling discovery, development, and translation of treatments for cognitive dysfunction in depression. Workshop summary. Washington, DC: only antidepressant demonstrating statistically significant National Academies Press (US). 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