A Network Meta-Analysis Comparing Effects of Various Antidepressant Classes on the Digit Symbol Substitution Test (DSST) as a Measure of Cognitive Dysfunction in Patients with Major Depressive Disorder

A Network Meta-Analysis Comparing Effects of Various Antidepressant Classes on the Digit Symbol... Background: Major depressive disorder is a common condition that often includes cognitive dysfunction. A  systematic literature review of studies and a network meta-analysis were carried out to assess the relative effect of antidepressants on cognitive dysfunction in major depressive disorder. Methods: MEDLINE, Embase, Cochrane, CDSR, and PsychINFO databases; clinical trial registries; and relevant conference abstracts were searched for randomized controlled trials assessing the effects of antidepressants/placebo on cognition. A network meta-analysis comparing antidepressants was conducted using a random effects model. Results: The database search retrieved 11 337 citations, of which 72 randomized controlled trials from 103 publications met the inclusion criteria. The review identified 86 cognitive tests assessing the effect of antidepressants on cognitive functioning. However, the Digit Symbol Substitution Test, which targets multiple domains of cognition and is recognized as being sensitive to change, was the only test that was used across 12 of the included randomized controlled trials and that allowed the construction of a stable network suitable for the network meta-analysis. The interventions assessed included selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and other non-selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors. The network meta-analysis using the Digit Symbol Substitution Test showed that vortioxetine was the only antidepressant that improved cognitive dysfunction on the Digit Symbol Substitution Test vs placebo {standardized mean difference: 0.325 (95% CI = 0.120; 0.529, P = .009}. Compared with other antidepressants, vortioxetine was statistically more efficacious on the Digit Symbol Substitution Test vs escitalopram, nortriptyline, and the selective serotonin reuptake inhibitor and tricyclic antidepressant classes. Conclusions: This study highlighted the large variability in measures used to assess cognitive functioning. The findings on the Digit Symbol Substitution Test indicate differential effects of various antidepressants on improving cognitive function in patients with major depressive disorder. Keywords: major depressive disorder, vortioxetine, cognitive dysfunction, systematic literature review, network meta-analysis Received: January 10, 2017; Revised: July 3, 2017; Accepted: September 27, 2017 © The Author(s) 2017. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any 97 medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/97/4555267 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 98 | International Journal of Neuropsychopharmacology, 2018 Significance Statement Cognitive dysfunction is a common impairment for patients with major depressive disorder (MDD) and leads to debilitating problems such as missed workdays, poor academic performance, and reduced ability to perform day-to-day tasks. Numerous studies have investigated cognitive function in depression in a variety of domains, including attention, processing speed, execu - tive function, and memory. Nevertheless, there is limited evidence on comparative effectiveness of antidepressants on cognitive symptoms, mainly due to the diversity of tools used in clinical trials. This study compared the effects of antidepressants on a commonly used cognitive outcome, the Digit Symbol Substitution Test (DSST), and showed that vortioxetine had the largest improvement in DSST vs all investigated classes of single antidepressants. It was the only antidepressant demonstrating stat - istically significant improvement vs placebo and vs specific antidepressants. The findings support the effect of vortioxetine in improving cognitive function in MDD patients measured by the DSST. Introduction Administration as a target for pharmacological treatments in Background patients with MDD ( Food and Drug Administration, 2016 ). Major depressive disorder (MDD) is one of the most common Many clinical studies of antidepressants have shown psychiatric disorders, affecting more than 350 million people improvements in cognition; however, there are several worldwide (World Health Organization, 2016 ). MDD is character - unanswered questions, including whether certain classes of ized by psychological, physical, and behavioral symptoms that antidepressants are superior to others in improving neur - o can be complex and vary widely between individuals. In general, psychological function. Studies suggest that serotonin nor - patients with MDD experience a prolonged period of low mood epinephrine reuptake inhibitors (SSRIs), including duloxetine often accompanied by low self-esteem, loss of interest in usually and other antidepressants such as vortioxetine, bupropion, and enjoyable activities, feelings of hopelessness, and low energy moclobemide, may improve cognitive function in depression (World Health Organization, 2016 ). MDD exerts a substantial (Baune and Renger, 2014). Vortioxetine, a novel antidepressant burden on the patient, including a negative impact on health- with multimodal activity, has shown evidence of cognitive bene - related quality of life ( Daly et  al., 2010 ; Fournier et  al., 2013 ), fit in animal models ( Wallace et al., 2014 ; Sanchez et al., 2015 ) as impairments in multiple domains of cognitive function, prema - well as in patients with MDD ( Katona et al., 2012 ; McIntyre et al., ture mortality due to a range of physical disorders, and suicide 2014; Mahableshwarkar et al., 2015 ). Clinical effect of vortioxe - in about 4% to 15% of patients ( Seguin et al., 2006 ; Gonda et al., tine on cognitive function is reported in the product characteris - 2007; American Psychiatric Association, 2013 ). As of 2010, the tics in many countries, including in Europe. In addition, a recent World Health Organization has listed MDD as the second lead - meta-analysis by McIntyre et al. included 3 randomized con - ing cause of disability worldwide, and it is expected to become trolled trials (RCTs) and showed that vortioxetine significantly the leading cause of disease burden in high-income countries by improved cognition measured by the Digit Symbol Substitution 2030 (Mathers and Loncar, 2006 ; Ferrari et al., 2013 ). Test (DSST), independent of changes in overall depressive symp - Patients with MDD often experience impairment in cognitive toms (McIntyre et al., 2016 ). function in several domains, including executive functioning, Numerous studies have investigated cognitive function processing speed, concentration/attention, learning, and mem - in depression in a variety of cognitive domains, including ory (Porter et  al., 2007 ; Hammar and Ardal, 2009 ; Baune et  al., attention, processing speed, executive function, and mem - 2010; Beblo et  al., 2011 ; National Academies of Sciences, 2015 ). ory. Nevertheless, there is limited evidence on the compar - a Patients with MDD may experience cognitive impairments tive effectiveness of antidepressants on cognitive symptoms, not only before and during depressive episodes but also after mainly due to the diversity of tools used in clinical trials cr - e remission of mood symptoms (Baune et  al., 2010 ; Papakostas ating heterogeneous outcomes. At least 3 recent reviews were and Culpepper, 2015). A 3-year prospective study of 267 patients conducted to investigate the effects of antidepressants on co - g found that cognitive problems were present 94% of the time nitive dysfunction (Baune and Renger, 2014; Keefe et  al., 2014; during depressive episodes and 44% of the time during remis - Rosenblat et al., 2016 ). These reviews highlighted the fact that sion (Conradi et al., 2011 ). In addition to the burden for patients, antidepressants may reduce cognitive dysfunction in MDD. cognitive dysfunction in mood disorders including depression is However, the variability in the study design and the high level also associated with economic and psychosocial consequences of heterogeneity of cognitive tests are important limitations (Baune et al., 2010 , 2013; Baune and Malhi, 2015). These impair- in assessing the relative effect of antidepressants on cognitive ments may lead to debilitating problems for patients such as dysfunction in MDD. missed workdays, poor academic performance, and a reduced ability to carry out day-to-day tasks ( McIntyre et  al., 2015 ). Objectives This, in turn, can lead to elevated costs due to absenteeism The objective of this study was to assess the comparative effect and reduced productivity, which are the main drivers of the economic burden due to MDD (Marazziti et  al., 2010 ; National of a variety of antidepressants on cognitive dysfunction, as measured by DSST, in patients with MDD through a system - Academies of Sciences, 2015). Cognitive dysfunction is increas - ingly becoming recognized as an important symptom dimen - atic literature review and a network meta-analysis (NMA). The DSST is the most extensively used and validated cognitive test sion of MDD. The Diagnostic and Statistical Manual 5 lists impairment in cognition (i.e., diminished ability to think or con - in neuropsychology (Jaeger and Zaragoza Domingo, 2016 ). The current analysis presents the results of the comparison of v -ari centrate, or indecisiveness) as a diagnostic criterion for MDD (American Psychiatric Association, 2013 ). In addition, cognitive ous classes and single antidepressants vs placebo on improving cognitive dysfunction as assessed on the DSST. dysfunction has recently been identified by the Food and Drug Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/97/4555267 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Baune et al. | 99 Studies that evaluated the effect of the interventions included Methods in Table 1 were eligible for inclusion. A first-pass screening of each citation was conducted based Systematic Literature Review on the abstracts. Citations that did not match the eligibility cri - A systematic literature review (SLR) was carried out to appraise teria and duplicates (due to overlap in the coverage of the data - the clinical evidence currently available, focusing on RCTs for bases) were excluded at the first-pass stage. Full-text copies of interventions treating cognitive dysfunction in adult patients all included references were then assessed, and citations that with MDD. Studies were obtained from a comprehensive search did not match the eligibility criteria were excluded at the sec - of Embase, MEDLINE, MEDLINE In-Process, Cochrane Central ond-pass screening. Register of Controlled Trials (CENTRAL), Cochrane Database During data extraction, publications describing the same for Systematic Reviews (CDSR), and PsychINFO, from database trial were compiled into a single entry to avoid double counting inception date to 13 November 2014. Hand-searching of con - of patients and studies. Data were extracted on methodological ference abstracts and trial registries (American Psychiatric and clinical characteristics of the studies, including sample size, Association, International College of Neuropsychology, European age, gender, race, disease duration, disease severity, interven - College of Neuropsychopharmacology, International College of tions assessed, study duration, and assessment time points. Neuropsychopharmacology, Clinical.trials.gov, and European Both stages of screening and the data extraction were carried Union Clinical Trials Register) was also conducted to retrieve out by 2 independent reviewers, and any discrepancies between clinical studies that are unpublished in journals as full-text arti - reviewers were reconciled by a third independent reviewer. cles or supplement results of previously published studies. Studies were critically appraised using comprehensive To be included in this review, trials had to meet the prede - assessment criteria based on the recommendations in the NICE fined eligibility criteria provided in Table  1. The review focused guidelines (NICE, 2013) according to 7 categories: (1) statistical on evidence from RCTs assessing the impact of antidepressants analyses, (2) outcome selection and reporting, (3) withdrawals, or placebo on cognitive dysfunction in adult patients with MDD, (4) blinding, (5) baseline comparability, (6) allocation conceal - with no restrictions on gender, race, or publication language. ment, and (7) randomization. Table 1. Eligibility Criteria for Trials to Be Included in the SLR Parameter Inclusion/exclusion criteria in current review Patient population • Age: adult patients (≥18 years of age) • Gender: any • Race: any • Disease: major depressive disorder Study design • RCTs (irrespective of blinding status) • Comparative controlled trials (including nonrandomized studies, retrospective and prospective controlled cohort studies) will be included during screening stage to supplement the RCTs in case of limited evidence Intervention Pharmacological interventions • Other antidepressants • SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, o Bupropion sertraline) o Reboxetine • SNRIs (desvenlafaxine, duloxetine, venlafaxine, milnacipran, levomilnacipran) o Viloxazine • TCAs (desipramine, imipramine, clomipramine, nortriptyline, tianeptine, o Trazodone dothiepin, opipramol, trimipramine, lofepramine, dibenzepin, amitriptyline, o Vortioxetine protriptyline, doxepin, melitracen, butriptyline, dimetacrine, quinupramine) o Etoperidone • TeCA (mirtazapine, maprotiline, mianserin, amoxapine) o Nefazodone • MAOI (moclobemide, isocarboxazid, tranylcypromine, phenelzine, toloxatone) o Bifemelane Nonpharmacological interventions o Agomelatine • Cognitive therapy/remediation therapy o Vilazodone • Exercise therapy Alternative therapy • Diet therapy • S-adenosylmethionine • Vitamins • Omega 3 fatty acid • Tryptophan • 5-hydroxytryptophan • Hypericum perforatum Effect on cognition and • Studies evaluating the effect of above listed interventions on cognition in MDD patients were included cognitive impact • Studies that assess the impact of cognitive dysfunction on patient’s daily functioning, work productivity, assessment and quality of life were also of interest in the review Comparator • Any of the above included interventions • Placebo/best supportive care • Any other pharmacological/nonpharmacological therapy Publication timeframe • From database inception till 13 November 2014 Language • English language articles Abbreviations: MAOI, monoamine oxidase inhibitor; RCT, randomized controlled trial; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; TeCA, tetracyclic antidepressant. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/97/4555267 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 100 | International Journal of Neuropsychopharmacology, 2018 dysfunction and the change in cognitive function across a wide Evidence Network Development range of clinical populations. Due to its brief administration A feasibility assessment was carried out to determine possible time and high discriminant (known group) validity, the DSST is approaches for developing an NMA to compare the compar - a a frequently used test that allows the opportunity to benchmark tive effect of antidepressants on cognitive dysfunction. Two clinical effects. DSST performance is one of the most robust pr - e approaches were considered: (1) Assessing studies evaluating dictors of outcomes in patients with severe illness and has been the same cognitive test, irrespective of cognitive domain; and (2) shown to correlate with functional outcomes. assessing studies evaluating the same cognitive domain, irr - e spective of the test. The second approach was not pursued due NMA to the lack of consensus for categorizing cognitive symptoms into cognitive domains. In addition, considering the large variety To simultaneously assess the comparative effects of more of 86 cognitive tests used as endpoints in the reviewed studies, than 2 treatments, an NMA was performed. An NMA synthe - collapsing these into domain-specific groups would introduce sizes direct and indirect comparisons over an entire network a validity bias, since different cognitive tests measure differ - of treatments, allowing for all available evidence to be con - ent cognitive abilities, even within the same cognitive domain. sidered in one analysis. Based on the network development Moreover, because certain individual tests would qualify to be process as outlined above, the outcome variable for the NMA assigned to different cognitive domains, this would introduce was the standardized mean change in the DSST (measured uncertainty when interpreting the results. To overcome several using Hedge’s G) from baseline to end of study. The stand - of these problems and allow for the generation of a stable NMA, ardization was based on the pooled (across treatment arms the first approach evaluating studies with a common cognitive within study) estimate of the SDs. The NMA was carried out test was chosen for the NMA. using a frequentist’s approach, and a 2-way ANOVA model was Across the 72 included RCTs, 86 different cognitive tests were used. As the residual variances between treatment groups are used to assess the effect of antidepressants on cognitive dys - known, it was possible for random effect estimates to be pr - o function in patients with MDD. Most of the tests were used in duced, which account for the between-trial heterogeneity. The only one study. A total of 12 tests were reported in 4 or more model was first used to perform ordinary pairwise meta-anal - studies, with the Mini-Mental State Examination (MMSE) and ysis comparing the antidepressants to placebo based on direct DSST being the most commonly reported outcomes (13 stud - evidence from the clinical studies. Secondly, for the NMA, ies each). Even across studies that evaluated cognitive function 2 networks were developed: one network by drug class and using the same test, there were variations in reporting outputs. another by type of antidepressant. Ranking probabilities were For example, some studies reported the mean score as an end - calculated based on the joint distribution of the estimates of point, while others reported either the percentage of correct relative efficacy. answers or a time estimate. Additionally, some studies reported Consistency was addressed through the principle of node- different and/or multiple domains for the same test, and there splitting by using a network meta-regression model. The pur - was variation in whether the cognitive endpoint was a primary pose of node-splitting is to investigate if the relative effect of or secondary outcome. The MMSE is considered to be a poor 2 treatments based on direct comparisons is comparable with choice to measure cognitive function in MDD, because it broadly the same effect based on indirect comparisons. Statistically, the measures global cognitive function, has no alternate form, and model is an extension of the NMA, which allows for a different has extreme ceiling effects ( Keefe et al., 2014). In addition, the relative effect between the 2 treatments that are being split in MMSE is most commonly used for evaluating cognition in late- head-to-head trials compared with all other trials. life depression due to evidence of its validity for dementia ( Rajji et al., 2009 ). Furthermore, the MMSE did not allow for a compari - Results son of all antidepressant drug classes. Other tests were also not appropriate for the network in our analyses: Stroop, Trail Making SLR Test A (TMT A) and Trail Making Test B (TMT B), and Rey Auditory Figure  1 shows the flow of studies through the systematic Verbal Learning Test (RAVLT) were each reported in only 8 to 9 trials, and their networks were all smaller than the DSST net - review process. Searching of literature databases yielded 11 337 references. Due to the overlap of coverage between the data - work. The networks of these 4 tests decomposed into 2, 4, 3, and 4 subnetworks for Stroop, TMT A and TMT B, and RAVLT, bases, 1676 abstracts were found to be duplicates and were removed. First-stage screening of the citations identified 1425 respectively. Since these networks decomposed into small sub - networks, only a limited comparison of 1 to 3 (depending on the potentially relevant references based on their titles/abstracts. Full-text reports of these citations were obtained for more subnetwork) other antidepressants vs placebo, duloxetine, and vortioxetine was possible. In contrast, for the DSST, it was pos - detailed evaluation, following which 190 references remained. Hand-searching identified 20 additional relevant citations, sible to construct a single “connected” network that allowed for multiple comparisons across various antidepressants as shown resulting in a total of 210 publications prior to extraction. The review focused on RCTs assessing pharmacological in the Results. As a conclusion, the subsequent analyses and results are presented for the NMA using published clinical trials interventions, as RCTs are considered the gold standard of clini - cal evidence and they minimize the risk of confounding factors. that utilized the DSST. The DSST is a “pencil and paper” cognitive test that assesses Of the 210 references screened, 72 RCTs from 103 publications were identified based on prespecified eligibility criteria and several aspects of the cognitive function that are most impaired in patients with MDD, such as components of executive func - included for data extraction. The interventions assessed across the studies included tion, processing speed, attention, and working memory. It is r-ec ognized as being sensitive to change during effective treatment SSRIs (citalopram, escitalopram, fluoxetine, paroxetine, sertr - a line, or fluvoxamine), serotonin and norepinephrine reuptake of MDD (Jaeger and Zaragoza Domingo, 2016 ; McIntyre et  al., 2016). The DSST is sensitive to both the presence of cognitive inhibitors (SNRIs) (duloxetine, venlafaxine, desvenlafaxine, or Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/97/4555267 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Baune et al. | 101 Figure 1. Flow diagram for the identification and selection of studies. Note: 12 studies that assessed Digit Symbol Substitution Test (DSST) were included in the final network of evidence. Abbreviations: ADT, antidepressant therapy; MDD, major depressive disorder; RCT, randomized controlled trial. Vortioxetine (a) (b) Vortioxetine Citalopram Escitalopram Duloxetine MAOI SNRI Phenelzine Desipramine Placebo Placebo Nortriptyline TCA Fluoxetine Sertraline SSRI Figure 2. Network for the ( a) by-class analysis and ( b) by-treatment analysis. Note: The size (area) of the nodes is proportional to the number of patients on treatment. The width of the lines is proportional to the number of patients in trials with direct comparison between the nodes. The numbers on the lines indicate the number of trials with direct comparisons, if it is more than one. Abbreviations: MOAI, monoamine-oxidase inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. levomilnacipran), monoamine oxidase inhibitors (phenelzine DSST As the Single Cognitive Measure for Network or tranylcypromine), tricyclic antidepressants (desipramine, Development amitriptyline, imipramine, trimipramine, or tianeptine), tetr - a Although there was large variation in the cognitive meas - cyclic antidepressants (mianserin or mirtazapine), or non-SSRI/ ures used in the RCTs, the DSST was the only cognitive end - SNRI antidepressants (agomelatine, bupropion, reboxetine, or point from the reviewed studies that could be used as a test vortioxetine). Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/97/4555267 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 102 | International Journal of Neuropsychopharmacology, 2018 of cognitive dysfunction for developing a homogeneous and Standardized Effect Size “stable” network of evidence to compare various antidepr-es SMD 1st 2nd sants (see Methods). One study was excluded in the absence of a common link with the other antidepressants, resulting in 12 Vortioxetine vs placebo 0.25 [0.03;0.48] 153 144 studies (3738 patients) in the final network ( Tignol et al., 1998 ). Katona (2012) 0.25 [0.04;0.46] 175 167 Mahableswarkar (2014) DSST was the primary endpoint in 2 of the trials included in the McIntyre (2014) 0.46 [0.26;0.66] 397 194 network, and these both assessed vortioxetine ( McIntyre et al., Fixed effects meta analysis 0.35 [0.23;0.46] 725 505 2014; Mahableshwarkar et al., 2015 ); all other studies in the net - Random effects meta analysis 0.34 [0.18;0.49] 725 505 work assessed DSST as a secondary outcome. Duloxetine vs placebo The total number of patients in the RCTs where the DSST was 0.07 [−0.16;0.30] Katona (2012) 144 144 0.17 [−0.04;0.38] 187 167 employed as a primary or secondary cognitive endpoint ranged Mahableswarkar (2014) −0.04 [−0.28;0.20] 196 99 Raskin (2007) from 27 to 602, the mean age ranged from 36.6 to 79.6 years, and Robinson (2014) 0.22 [−0.03;0.48] 180 87 the percentage of males ranged from 24% to 58%. The time of Fixed effects meta analysis 0.13 [−0.03;0.28] 707 497 0.13 [−0.03;0.28] DSST assessment in the studies included in the network varied Random effects meta analysis 707 497 from 3 to 24 weeks after baseline assessment. The antidepres - Sertraline vs placebo sants assessed (with analyzable number of patients in brac - k −0.17 [−0.57;0.22] 49 49 Hoffman (2008) ets) were SNRIs (duloxetine [707 patients]), SSRIs (citalopram [84 Citalopram vs placebo patients], escitalopram [54 patients], fluoxetine [127 patients], Culang (2009) −0.04 [−0.33;0.26] 84 90 sertraline [240 patients]), MAOIs (phenelzine [28 patients]), tri - cyclic antidepressants (TCAs) (desipramine [9 patients], nor - Escitalopram vs placebo −0.25 [−0.57;0.06] Dube (2010) 54 122 triptyline [102 patients]), and non-SSRI/SNRIs (vortioxetine [725 patients]). Vortioxetine and duloxetine have the most subjects Phenelzine vs placebo Georgotas (1989) −0.02 [−0.52;0.48] 28 18 in which cognition was assessed by the DSST in clinical trials. The majority (9 of 12) of the studies included a placebo control. Nortriptyline vs placebo The studies included in the DSST network of evidence and their 0.01 [−0.56;0.58] Georgotas (1989) 32 18 characteristics are presented in Supplementary Table S1. Vortioxetine vs duloxetine Critical appraisal of the included studies was conducted 0.18 [−0.04;0.41] 153 Katona (2012) 144 using comprehensive assessment criteria based on the recom - 0.08 [−0.13;0.28] 175 187 Mahableswarkar (2014) Fixed effects meta analysis 0.13 [−0.03;0.28] 328 331 mendations in the NICE guidelines (NICE, 2013). The studies Random effects meta analysis 0.13 [−0.03;0.28] 328 331 were generally of good quality with around 4 of the 7 categories being assessed as low risk on average. The best scoring category Fluoxetine vs sertraline −0.27 [−0.53;−0.01] was the baseline comparability (83% low risk) and the worst Newhouse (2000) 119 117 scoring category was outcome selection and reporting (25% low Sertraline vs nortriptyline risk). The FOCUS trial was the best quality, with all 7 aspects of 0.52 [0.20;0.85] 74 70 Bondareff (2000) the assessment deemed to be low risk McIntyr ( e et al., 2014 ). Fluoxetine vs desipramine However, the overall risk of bias was unclear in the majority of Levkovitz (2002) −0.26 [−1.24;0.72] 8 9 the categories for 5 of the 12 studies. A summary of the qualita - tive assessment is provided in Supplementary Table S2. Phenelzine vs nortriptyline −0.03 [−0.53;0.47] Georgotas (1989) 28 32 As a result, 2 networks for the studies using the DSST were developed: one network by drug class and another by type of antidepressant. The network diagrams in Figure  2 provide a graphical representation of how each intervention is connected −1.0 0.0 0.5 1.0 to the others through direct comparisons. Each line depicts a Favors second comparator Favors first comparator direct comparison between 2 intervention nodes. A  forest plot showing the standardized mean differences for each study Figure  3. Standardized mean differences in Digit Symbol Substitution Test in direct comparisons, based on data reported in each of the (DSST) of antidepressants based on direct evidence from clinical studies included in the network of evidence. Abbreviations: SMD, standardized mean included studies, is shown in Figure 3. difference. NMA the DSST from baseline for vortioxetine vs placebo was 0.325 Figure  4 shows the standardized mean differences on DSST [95% CI = 0.120; 0.529, P = .009]. The differences for duloxetine comparing antidepressant classes as well as individual antide - and sertraline vs placebo were not statistically significant. pressants vs placebo. In the by-class analysis Figur ( e 4a), SSRIs, All other antidepressants (citalopram, desipramine, escit - MAOIs, and TCAs showed a smaller effect on DSST vs placebo, alopram, fluoxetine, nortriptyline, and phenelzine) demon - with TCAs showing a significantly worse effect on DSST than strated a smaller effect on cognitive dysfunction vs placebo placebo. Vortioxetine and SNRIs were the only antidepressant (Figure 4b). classes showing an improvement in DSST vs placebo, and this Table  2 shows the comparative effects between antidepres - difference was statistically significant in the comparison of v- or sants in terms of standardized mean differences in the DSST tioxetine vs placebo. for both the treatment class analysis (upper triangle) and the When comparing individual antidepressants vs placebo, individual treatment analysis (lower triangle). The order of the vortioxetine, duloxetine and sertraline showed an impro-ve treatments in the diagonal is based on the efficacy of the treat - ment in the DSST vs placebo, with vortioxetine being the ment classes as well as the individual antidepressants. The 2 only antidepressant showing a statistically significant dif - most efficacious antidepressants in terms of improvement in ference. The standardized mean difference on the change in the DSST were vortioxetine and duloxetine, but duloxetine was Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/97/4555267 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Baune et al. | 103 of cognitive dysfunction for developing a homogeneous and Standardized effect size, relative to placebo “stable” network of evidence to compare various antidepr-es (a) (b) sants (see Methods). One study was excluded in the absence of 0.5 0.5 a common link with the other antidepressants, resulting in 12 studies (3738 patients) in the final network ( Tignol et al., 1998 ). 0.4 0.4 DSST was the primary endpoint in 2 of the trials included in the ** network, and these both assessed vortioxetine ( McIntyre et al., 0.3 0.3 2014; Mahableshwarkar et al., 2015 ); all other studies in the net - work assessed DSST as a secondary outcome. 0.2 The total number of patients in the RCTs where the DSST was 0.2 employed as a primary or secondary cognitive endpoint ranged from 27 to 602, the mean age ranged from 36.6 to 79.6 years, and 0.1 0.1 the percentage of males ranged from 24% to 58%. The time of CIT FLU ESC PHE NOR SSRI MAOI TCA DSST assessment in the studies included in the network varied DES VOR DUL SER VOR SNRI from 3 to 24 weeks after baseline assessment. The antidepres - sants assessed (with analyzable number of patients in brac - k −0.1 −0.1 ets) were SNRIs (duloxetine [707 patients]), SSRIs (citalopram [84 patients], escitalopram [54 patients], fluoxetine [127 patients], −0.2 −0.2 sertraline [240 patients]), MAOIs (phenelzine [28 patients]), tri - cyclic antidepressants (TCAs) (desipramine [9 patients], nor - −0.3 −0.3 triptyline [102 patients]), and non-SSRI/SNRIs (vortioxetine [725 patients]). Vortioxetine and duloxetine have the most subjects −0.4 −0.4 in which cognition was assessed by the DSST in clinical trials. The majority (9 of 12) of the studies included a placebo control. −0.5 −0.5 The studies included in the DSST network of evidence and their characteristics are presented in Supplementary Table S1. Figure 4. Standardized mean difference vs placebo ( a) by-class analysis and ( b) by-treatment analysis. Abbreviations: CIT, citalopram; DES, desipramine; DUL, dulo - x Critical appraisal of the included studies was conducted etine; ESC, escitalopram; FLU, fluoxetine; MOAI, monoamine-oxidase inhibitor; NOR, nortriptyline; PHE, phenelzine; SER, sertraline; SNRI, serotonin and norepinephrine using comprehensive assessment criteria based on the recom - reuptake inhibitors; SSRI, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants; VOR, vortioxetine P < .05; . * ** P < .01. mendations in the NICE guidelines (NICE, 2013). The studies were generally of good quality with around 4 of the 7 categories not statistically significantly different from placebo. Placebo for pharmacological treatments in patients with MDD and is being assessed as low risk on average. The best scoring category was the third most efficacious, highlighting the fact that many increasingly becoming of clinical importance. was the baseline comparability (83% low risk) and the worst of the antidepressants have less impact on cognitive function In the current review, 72 RCTs assessing cognitive function scoring category was outcome selection and reporting (25% low vs placebo. using 86 different cognitive measures in MDD were identified. risk). The FOCUS trial was the best quality, with all 7 aspects of The analysis showed that vortioxetine was numerically more Of these 72 RCTs and 68 cognitive measures, 12 studies were the assessment deemed to be low risk McIntyr ( e et al., 2014 ). efficacious in terms of change in DSST from baseline than all included in the network of evidence for evaluating the effect However, the overall risk of bias was unclear in the majority of other antidepressants included in the analysis. The difference of antidepressants. A single measure of cognitive function, the the categories for 5 of the 12 studies. A summary of the qualita - in DSST was statistically significant for vortioxetine vs SSRIs DSST, was used for the NMA based on results of the network tive assessment is provided in Supplementary Table S2. and TCAs with standardized mean differences of 0.423 [95% development process. The findings of the NMA showed that vor - As a result, 2 networks for the studies using the DSST were CI = 0.147; 0.698, P = .006] and 0.722 [95% CI = 0.316; 1.129, P = .002], tioxetine, duloxetine, sertraline, and the SNRI class  improved developed: one network by drug class and another by type of respectively. In the by-treatment analysis, vortioxetine was stat - cognitive function measured with the DSST vs placebo, with antidepressant. The network diagrams in Figure  2 provide a istically significantly better than escitalopram and nortriptyline vortioxetine being the only antidepressant or non-SSRI/SNRI graphical representation of how each intervention is connected with standardized mean differences of 0.579 [95% CI = 0.117; showing a statistically significant effect vs placebo. All other to the others through direct comparisons. Each line depicts a 1.041, P = .021] and 0.691 [95% CI = 0.165; 1.217, P = .017], respect- antidepressants or classes of antidepressants included in the direct comparison between 2 intervention nodes. A  forest plot ively. Moreover, based on the by-class ranking analysis, the analysis demonstrated no effect on the DSST. The comparative showing the standardized mean differences for each study probability of vortioxetine having a higher change in DSST from analysis showed that vortioxetine was statistically significantly in direct comparisons, based on data reported in each of the baseline than all other classes of antidepressants (including -pla more efficacious in terms of change in the DSST from baseline included studies, is shown in Figure 3. cebo) is 97%. compared with escitalopram and nortriptyline. Placebo was the Consistency was addressed by node-splitting. Due to the size third most efficacious, further highlighting the fact that many of of the network, the risk of inconsistency was relatively small, the antidepressants have less impact on the DSST than placebo. NMA and only 2 potential loops were identified in each of the by-treat - These findings confirm previous research by showing that Figure  4 shows the standardized mean differences on DSST ment and by-class analyses. Although there were mild incon - some antidepressants improve cognitive function, and it also comparing antidepressant classes as well as individual antide - sistencies in the vortioxetine/SNRI and the placebo/SSRI/TCA highlights that many antidepressants and classes of antide - pressants vs placebo. In the by-class analysis Figur ( e 4a), SSRIs, comparisons, none were considered significant. Heterogeneity pressants may have less impact on cognition than placebo MAOIs, and TCAs showed a smaller effect on DSST vs placebo, was mainly driven by the vortioxetine/placebo comparison. This (Baune and Renger, 2014; Keefe et al., 2014; McIntyre et al., 2016 ; with TCAs showing a significantly worse effect on DSST than was accounted for by using a random effects model for estimat - Rosenblat et al., 2016 ). Vortioxetine showed the largest improv - e placebo. Vortioxetine and SNRIs were the only antidepressant ing both relative mean differences and their CIs in the NMA. ment on the DSST, which is in line with the results of previous classes showing an improvement in DSST vs placebo, and this studies (McIntyre et  al., 2016 ; Rosenblat et  al., 2016 ). In addi- difference was statistically significant in the comparison of v- or tion, the current analysis showed that vortioxetine was the Discussion tioxetine vs placebo. only antidepressant that demonstrated a statistically significant When comparing individual antidepressants vs placebo, Cognitive dysfunction is a well-known impairment associ - improvement on the DSST vs placebo. The European Medicines vortioxetine, duloxetine and sertraline showed an impro-ve ated with MDD and causes a significant additional burden to Agency has also recognized vortioxetine’s improvement on ment in the DSST vs placebo, with vortioxetine being the patients and society. The effects of antidepressants on cogni - the DSST, stating that it has a statistically significant effect vs only antidepressant showing a statistically significant dif - tive function are still not fully understood, but cognitive d - ys placebo according to 2 studies and a meta-analysis ( European ference. The standardized mean difference on the change in function has recently been identified by the FDA as a target Medicines Agency, 2016). Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/97/4555267 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 104 | International Journal of Neuropsychopharmacology, 2018 Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/97/4555267 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Treatment Effect Estimates (standardized mean differences of DSST change from baseline) VOR 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) 0.192 SNRI 0.133 0.230 0.410 0.530 (-0.027; 0.411) DUL (-0.032; 0.298) (-0.041; 0.502) (-0.199; 1.018) (0.126; 0.934) 0.325 0.133 PBO 0.097 0.277 0.397 (0.120; 0.529) (-0.043; 0.308) PBO (-0.129; 0.323) (-0.313; 0.867) (0.022; 0.771) 0.305 0.112 -0.020 SER (-0.168; 0.777) (-0.358; 0.582) (-0.460; 0.420) SSRI 0.362 0.170 0.038 0.058 CIT (-0.079; 0.804) (-0.268; 0.608) (-0.368; 0.443) (-0.540; 0.656) 0.180 0.300 (-0.411; 0.770) (-0.037; 0.636) 0.578 0.386 0.253 0.273 0.215 FLU (-0.018; 1.173) (-0.208; 0.979) (-0.317; 0.823) (-0.089;0.635) (-0.484; 0.914) 0.579 0.387 0.254 0.274 0.216 0.001 ESC (0.117; 1.041) (-0.073; 0.846) (-0.174; 0.682) (-0.340; 0.888) (-0.374; 0.806) (-0.712; 0.714) 0.582 0.390 0.257 0.277 0.219 0.004 0.003 MAOI 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) PHE (-0.437; 0.677) 0.319 0.127 -0.006 0.014 -0.044 -0.259 -0.260 -0.263 TCA (-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) DES 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) NOR Note: This table shows the treatment effect estimates in terms of standardized mean differences with corresponding 95% CIs displayed in parentheses. The lower triangle shows the results for the by-treatment analysis and the upper triangle shows the results for the by-class analysis. The order of the treatments in the diagonal is based first on the efficacy of the antidepressant classes and second on the efficacy of the treatments within the classes. A positive estimate indicates that the treatment/antidepressant class to the left is numerically better than the one to the right and vice versa. Statistically significant differences are shown in bold. Abbreviations: CIT, citalopram; DES, desipramine; DUL, duloxetine; ESC, escitalopram; FLU, fluoxetine; MOAI, monoamine-oxidase inhibitor; NOR, nortriptyline; PBO, placebo; PHE, phenelzine; SER, sertraline; SNRI, serotonin and norepinephrine reuptake inhibitors; SSRI, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants; VOR, vortioxetine. Copyedited by: oup Baune et al. | 105 The magnitude of the cognitive deficit in MDD is typic - 240 patients. Although a lower number of patients treated with ally between 0.2 and 0.7 standardized mean differences below a specific compound does not in itself bias the relative effect what would be normal, depending on disease state and cogni - of that compound, it will decrease the likelihood of finding a tive domain (Rund et al., 2006 ; Lee et al., 2012; Rock et al., 2014 ). significant difference between that compound and any of the For comparison, cognitive dysfunction in disorders such as other compounds, because fewer patients means wider CIs in Alzheimer’s dementia is greater than in MDD and usually up the results of the NMA. It should also be noted that vortioxetine to several SDs greater than what would be considered normal is very clearly significantly better than placebo, due to the r- ela (Buchanan et al., 2011 ). A meta-analysis of 22 studies in patients tively large number of patients in trials with both vortioxetine with MDD showed that patients were impaired on the DSST and placebo. One of the reasons for vortioxetine showing a sig - with a standardized mean difference of 0.55 compared with nificant difference vs other antidepressants (despite the rela - healthy controls. The DSST was shown to be strongly associated tively few patients in the trials of the other antidepressants) is with the level of functioning at work, school, and home. These the generally poor performance of the SSRIs and TCAs. In addi - findings suggest that the DSST provides an effective means to tion, the DSST was only a primary endpoint in 2 of the trials, and detect clinically relevant treatment effects of antidepressants 3 of the studies did not include a placebo control arm. on important components of cognitive function in patients with Across the 72 RCTs identified in our review, 86 differ- MDD (Jaeger and Zaragoza Domingo, 2016 ). ent cognitive tests were employed and hence 2 possible Vortioxetine’s statistically significant improvement on the approaches for the NMA were considered: assessing studies DSST is likely to be due to its unique pharmacological pr - o that used a common cognitive test or a common cognitive file vs other antidepressants. These mechanisms include domain. It was decided that the network of evidence would increased glutamate neurotransmission (via inhibition of be developed using the DSST as a common single cognitive gamma-aminobutyric acid interneurons expressing 5-HT3 test to reduce the amount of variability between studies as heteroreceptors) and neuroplasticity in brain regions such as much as possible. The feasibility of the alternative approach, hippocampus and prefrontal cortex ( Haddjeri et al., 2012 ; Riga et using a common cognitive domain, was investigated but was al., 2013; Sanchez et al., 2015 ; Pehrson et al., 2015 ). For example, not pursued due to the lack of standardization for classifying vortioxetine significantly enhances excitatory synaptic trans - the different symptoms into commonly accepted domains. It mission and neuroplasticity (increased cell proliferation and was also considered whether multiple tests could be included maturation) compared with SSRIs ( Dale et al., 2014 ). In addition, in the network; however, it was not considered prudent to do cognitive improvements with vortioxetine may be due to direct so, because different tests measure different aspects of cogni - and/or indirect effects via serotonergic, noradrenergic, choliner - tive function and may span across various cognitive domains. gic, dopaminergic, and histaminergic systems ( Elmaadawi et al., In addition, the studies that could have been included would 2015; Sanchez et al., 2015 ). Further research is needed to under - all sit as “appendices” to the network, and there would be stand if pharmacological differences translate into differential no change to the estimates of the already included studies. effects on cognition. Further, the additions would each be connected to the net - To the best of our knowledge, the current NMA included the work only through one trial, which yields very wide CIs, and largest network of evidence published to date in assessing the hence it was not deemed reasonable to introduce more than impact of antidepressants on cognitive function in MDD and one test in the NMA in this paper. As a consequence, our significantly extends a recently published meta-analysis that results have to be interpreted as an effect on the DSST only, included only 3 RCTs (McIntyre et  al., 2016 ). Importantly, none and results should not be generalized to other cognitive tests of the previous publications have quantitatively assessed the during interpretation. comparative effects of antidepressant classes, and therefore this An important limitation of the underlying RCTs is the large analysis provides new insights into the effects of the classes as variability of the reported cognitive outcomes. Although there well as the individual antidepressants. The strengths of our ana - is an abundance of studies exploring the effects of antidepr- es lysis include a robust and thorough SLR obtaining high-quality sants on cognition, the heterogeneity of cognitive tests and RCTs for inclusion in the analysis and consideration of heter - o outcomes used limits the analysis that can be performed in a geneity within the NMA by using random effects models. In meta-analysis such as ours. The advantage of selecting the DSST addition, the important issue of consistency between direct and as a single cognitive test for the NMA is that like-for-like com - indirect effects in the network was also addressed. Although the parisons between treatments could be made and that a “stable” SLR was initially carried out in November 2014, an additional network was generated for the DSST; however, the selection of search was carried out in October 2016, which found no new the DSST also means that a smaller number of RCTs was used studies assessing the effects on cognition using the DSST. in the analysis. Further research using other cognitive scales is There are also some limitations of the current analysis. The needed in the future, and recommendations for using a stand - evidence retrieved from the SLR suggests that there is ample ardized cognitive test battery would be highly useful for future clinical data evaluating the effect of antidepressants on co - g clinical research and would help to overcome some of the limi - nitive functioning. However, due to the lack of defined clinical tations of this type of research. In addition, further research into recommendations for the management of cognitive dysfunction the effects within different subpopulations, for example based in patients with MDD, a high variability is observed in report - on age and gender, would be valuable. ing of cognitive outcomes. There are also several methodolo -gi In summary, although some antidepressants have shown cal constraints in the studies with regards to large variability improvements in cognitive function in patients with MDD, the in the outcomes, domains, time points of assessments, report - majority of antidepressants have not shown an effect on co - g ing of outputs, and patient numbers. These variations limit the nition. Comparing the effects of a large group of antidepr -es generalizability of the results and caution the interpretation. In sants across classes on single cognitive measures, the DSST particular, vortioxetine and duloxetine had the most patients indicated that vortioxetine was the only antidepressant that included in the trials in the network (725 and 707, respec - exerted statistically significant effects on the DSST between tively), whereas the other antidepressants had between 9 and baseline and follow-up when compared with both placebo and Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/97/4555267 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 106 | International Journal of Neuropsychopharmacology, 2018 all other antidepressants analyzed. Further research is needed Rush AJ (2010) Health-related quality of life in depression: to overcome the limitations associated with the large amount a STAR*D report. 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A Network Meta-Analysis Comparing Effects of Various Antidepressant Classes on the Digit Symbol Substitution Test (DSST) as a Measure of Cognitive Dysfunction in Patients with Major Depressive Disorder

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Abstract

Background: Major depressive disorder is a common condition that often includes cognitive dysfunction. A  systematic literature review of studies and a network meta-analysis were carried out to assess the relative effect of antidepressants on cognitive dysfunction in major depressive disorder. Methods: MEDLINE, Embase, Cochrane, CDSR, and PsychINFO databases; clinical trial registries; and relevant conference abstracts were searched for randomized controlled trials assessing the effects of antidepressants/placebo on cognition. A network meta-analysis comparing antidepressants was conducted using a random effects model. Results: The database search retrieved 11 337 citations, of which 72 randomized controlled trials from 103 publications met the inclusion criteria. The review identified 86 cognitive tests assessing the effect of antidepressants on cognitive functioning. However, the Digit Symbol Substitution Test, which targets multiple domains of cognition and is recognized as being sensitive to change, was the only test that was used across 12 of the included randomized controlled trials and that allowed the construction of a stable network suitable for the network meta-analysis. The interventions assessed included selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and other non-selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors. The network meta-analysis using the Digit Symbol Substitution Test showed that vortioxetine was the only antidepressant that improved cognitive dysfunction on the Digit Symbol Substitution Test vs placebo {standardized mean difference: 0.325 (95% CI = 0.120; 0.529, P = .009}. Compared with other antidepressants, vortioxetine was statistically more efficacious on the Digit Symbol Substitution Test vs escitalopram, nortriptyline, and the selective serotonin reuptake inhibitor and tricyclic antidepressant classes. Conclusions: This study highlighted the large variability in measures used to assess cognitive functioning. The findings on the Digit Symbol Substitution Test indicate differential effects of various antidepressants on improving cognitive function in patients with major depressive disorder. Keywords: major depressive disorder, vortioxetine, cognitive dysfunction, systematic literature review, network meta-analysis Received: January 10, 2017; Revised: July 3, 2017; Accepted: September 27, 2017 © The Author(s) 2017. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any 97 medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/97/4555267 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 98 | International Journal of Neuropsychopharmacology, 2018 Significance Statement Cognitive dysfunction is a common impairment for patients with major depressive disorder (MDD) and leads to debilitating problems such as missed workdays, poor academic performance, and reduced ability to perform day-to-day tasks. Numerous studies have investigated cognitive function in depression in a variety of domains, including attention, processing speed, execu - tive function, and memory. Nevertheless, there is limited evidence on comparative effectiveness of antidepressants on cognitive symptoms, mainly due to the diversity of tools used in clinical trials. This study compared the effects of antidepressants on a commonly used cognitive outcome, the Digit Symbol Substitution Test (DSST), and showed that vortioxetine had the largest improvement in DSST vs all investigated classes of single antidepressants. It was the only antidepressant demonstrating stat - istically significant improvement vs placebo and vs specific antidepressants. The findings support the effect of vortioxetine in improving cognitive function in MDD patients measured by the DSST. Introduction Administration as a target for pharmacological treatments in Background patients with MDD ( Food and Drug Administration, 2016 ). Major depressive disorder (MDD) is one of the most common Many clinical studies of antidepressants have shown psychiatric disorders, affecting more than 350 million people improvements in cognition; however, there are several worldwide (World Health Organization, 2016 ). MDD is character - unanswered questions, including whether certain classes of ized by psychological, physical, and behavioral symptoms that antidepressants are superior to others in improving neur - o can be complex and vary widely between individuals. In general, psychological function. Studies suggest that serotonin nor - patients with MDD experience a prolonged period of low mood epinephrine reuptake inhibitors (SSRIs), including duloxetine often accompanied by low self-esteem, loss of interest in usually and other antidepressants such as vortioxetine, bupropion, and enjoyable activities, feelings of hopelessness, and low energy moclobemide, may improve cognitive function in depression (World Health Organization, 2016 ). MDD exerts a substantial (Baune and Renger, 2014). Vortioxetine, a novel antidepressant burden on the patient, including a negative impact on health- with multimodal activity, has shown evidence of cognitive bene - related quality of life ( Daly et  al., 2010 ; Fournier et  al., 2013 ), fit in animal models ( Wallace et al., 2014 ; Sanchez et al., 2015 ) as impairments in multiple domains of cognitive function, prema - well as in patients with MDD ( Katona et al., 2012 ; McIntyre et al., ture mortality due to a range of physical disorders, and suicide 2014; Mahableshwarkar et al., 2015 ). Clinical effect of vortioxe - in about 4% to 15% of patients ( Seguin et al., 2006 ; Gonda et al., tine on cognitive function is reported in the product characteris - 2007; American Psychiatric Association, 2013 ). As of 2010, the tics in many countries, including in Europe. In addition, a recent World Health Organization has listed MDD as the second lead - meta-analysis by McIntyre et al. included 3 randomized con - ing cause of disability worldwide, and it is expected to become trolled trials (RCTs) and showed that vortioxetine significantly the leading cause of disease burden in high-income countries by improved cognition measured by the Digit Symbol Substitution 2030 (Mathers and Loncar, 2006 ; Ferrari et al., 2013 ). Test (DSST), independent of changes in overall depressive symp - Patients with MDD often experience impairment in cognitive toms (McIntyre et al., 2016 ). function in several domains, including executive functioning, Numerous studies have investigated cognitive function processing speed, concentration/attention, learning, and mem - in depression in a variety of cognitive domains, including ory (Porter et  al., 2007 ; Hammar and Ardal, 2009 ; Baune et  al., attention, processing speed, executive function, and mem - 2010; Beblo et  al., 2011 ; National Academies of Sciences, 2015 ). ory. Nevertheless, there is limited evidence on the compar - a Patients with MDD may experience cognitive impairments tive effectiveness of antidepressants on cognitive symptoms, not only before and during depressive episodes but also after mainly due to the diversity of tools used in clinical trials cr - e remission of mood symptoms (Baune et  al., 2010 ; Papakostas ating heterogeneous outcomes. At least 3 recent reviews were and Culpepper, 2015). A 3-year prospective study of 267 patients conducted to investigate the effects of antidepressants on co - g found that cognitive problems were present 94% of the time nitive dysfunction (Baune and Renger, 2014; Keefe et  al., 2014; during depressive episodes and 44% of the time during remis - Rosenblat et al., 2016 ). These reviews highlighted the fact that sion (Conradi et al., 2011 ). In addition to the burden for patients, antidepressants may reduce cognitive dysfunction in MDD. cognitive dysfunction in mood disorders including depression is However, the variability in the study design and the high level also associated with economic and psychosocial consequences of heterogeneity of cognitive tests are important limitations (Baune et al., 2010 , 2013; Baune and Malhi, 2015). These impair- in assessing the relative effect of antidepressants on cognitive ments may lead to debilitating problems for patients such as dysfunction in MDD. missed workdays, poor academic performance, and a reduced ability to carry out day-to-day tasks ( McIntyre et  al., 2015 ). Objectives This, in turn, can lead to elevated costs due to absenteeism The objective of this study was to assess the comparative effect and reduced productivity, which are the main drivers of the economic burden due to MDD (Marazziti et  al., 2010 ; National of a variety of antidepressants on cognitive dysfunction, as measured by DSST, in patients with MDD through a system - Academies of Sciences, 2015). Cognitive dysfunction is increas - ingly becoming recognized as an important symptom dimen - atic literature review and a network meta-analysis (NMA). The DSST is the most extensively used and validated cognitive test sion of MDD. The Diagnostic and Statistical Manual 5 lists impairment in cognition (i.e., diminished ability to think or con - in neuropsychology (Jaeger and Zaragoza Domingo, 2016 ). The current analysis presents the results of the comparison of v -ari centrate, or indecisiveness) as a diagnostic criterion for MDD (American Psychiatric Association, 2013 ). In addition, cognitive ous classes and single antidepressants vs placebo on improving cognitive dysfunction as assessed on the DSST. dysfunction has recently been identified by the Food and Drug Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/97/4555267 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Baune et al. | 99 Studies that evaluated the effect of the interventions included Methods in Table 1 were eligible for inclusion. A first-pass screening of each citation was conducted based Systematic Literature Review on the abstracts. Citations that did not match the eligibility cri - A systematic literature review (SLR) was carried out to appraise teria and duplicates (due to overlap in the coverage of the data - the clinical evidence currently available, focusing on RCTs for bases) were excluded at the first-pass stage. Full-text copies of interventions treating cognitive dysfunction in adult patients all included references were then assessed, and citations that with MDD. Studies were obtained from a comprehensive search did not match the eligibility criteria were excluded at the sec - of Embase, MEDLINE, MEDLINE In-Process, Cochrane Central ond-pass screening. Register of Controlled Trials (CENTRAL), Cochrane Database During data extraction, publications describing the same for Systematic Reviews (CDSR), and PsychINFO, from database trial were compiled into a single entry to avoid double counting inception date to 13 November 2014. Hand-searching of con - of patients and studies. Data were extracted on methodological ference abstracts and trial registries (American Psychiatric and clinical characteristics of the studies, including sample size, Association, International College of Neuropsychology, European age, gender, race, disease duration, disease severity, interven - College of Neuropsychopharmacology, International College of tions assessed, study duration, and assessment time points. Neuropsychopharmacology, Clinical.trials.gov, and European Both stages of screening and the data extraction were carried Union Clinical Trials Register) was also conducted to retrieve out by 2 independent reviewers, and any discrepancies between clinical studies that are unpublished in journals as full-text arti - reviewers were reconciled by a third independent reviewer. cles or supplement results of previously published studies. Studies were critically appraised using comprehensive To be included in this review, trials had to meet the prede - assessment criteria based on the recommendations in the NICE fined eligibility criteria provided in Table  1. The review focused guidelines (NICE, 2013) according to 7 categories: (1) statistical on evidence from RCTs assessing the impact of antidepressants analyses, (2) outcome selection and reporting, (3) withdrawals, or placebo on cognitive dysfunction in adult patients with MDD, (4) blinding, (5) baseline comparability, (6) allocation conceal - with no restrictions on gender, race, or publication language. ment, and (7) randomization. Table 1. Eligibility Criteria for Trials to Be Included in the SLR Parameter Inclusion/exclusion criteria in current review Patient population • Age: adult patients (≥18 years of age) • Gender: any • Race: any • Disease: major depressive disorder Study design • RCTs (irrespective of blinding status) • Comparative controlled trials (including nonrandomized studies, retrospective and prospective controlled cohort studies) will be included during screening stage to supplement the RCTs in case of limited evidence Intervention Pharmacological interventions • Other antidepressants • SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, o Bupropion sertraline) o Reboxetine • SNRIs (desvenlafaxine, duloxetine, venlafaxine, milnacipran, levomilnacipran) o Viloxazine • TCAs (desipramine, imipramine, clomipramine, nortriptyline, tianeptine, o Trazodone dothiepin, opipramol, trimipramine, lofepramine, dibenzepin, amitriptyline, o Vortioxetine protriptyline, doxepin, melitracen, butriptyline, dimetacrine, quinupramine) o Etoperidone • TeCA (mirtazapine, maprotiline, mianserin, amoxapine) o Nefazodone • MAOI (moclobemide, isocarboxazid, tranylcypromine, phenelzine, toloxatone) o Bifemelane Nonpharmacological interventions o Agomelatine • Cognitive therapy/remediation therapy o Vilazodone • Exercise therapy Alternative therapy • Diet therapy • S-adenosylmethionine • Vitamins • Omega 3 fatty acid • Tryptophan • 5-hydroxytryptophan • Hypericum perforatum Effect on cognition and • Studies evaluating the effect of above listed interventions on cognition in MDD patients were included cognitive impact • Studies that assess the impact of cognitive dysfunction on patient’s daily functioning, work productivity, assessment and quality of life were also of interest in the review Comparator • Any of the above included interventions • Placebo/best supportive care • Any other pharmacological/nonpharmacological therapy Publication timeframe • From database inception till 13 November 2014 Language • English language articles Abbreviations: MAOI, monoamine oxidase inhibitor; RCT, randomized controlled trial; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; TeCA, tetracyclic antidepressant. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/97/4555267 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 100 | International Journal of Neuropsychopharmacology, 2018 dysfunction and the change in cognitive function across a wide Evidence Network Development range of clinical populations. Due to its brief administration A feasibility assessment was carried out to determine possible time and high discriminant (known group) validity, the DSST is approaches for developing an NMA to compare the compar - a a frequently used test that allows the opportunity to benchmark tive effect of antidepressants on cognitive dysfunction. Two clinical effects. DSST performance is one of the most robust pr - e approaches were considered: (1) Assessing studies evaluating dictors of outcomes in patients with severe illness and has been the same cognitive test, irrespective of cognitive domain; and (2) shown to correlate with functional outcomes. assessing studies evaluating the same cognitive domain, irr - e spective of the test. The second approach was not pursued due NMA to the lack of consensus for categorizing cognitive symptoms into cognitive domains. In addition, considering the large variety To simultaneously assess the comparative effects of more of 86 cognitive tests used as endpoints in the reviewed studies, than 2 treatments, an NMA was performed. An NMA synthe - collapsing these into domain-specific groups would introduce sizes direct and indirect comparisons over an entire network a validity bias, since different cognitive tests measure differ - of treatments, allowing for all available evidence to be con - ent cognitive abilities, even within the same cognitive domain. sidered in one analysis. Based on the network development Moreover, because certain individual tests would qualify to be process as outlined above, the outcome variable for the NMA assigned to different cognitive domains, this would introduce was the standardized mean change in the DSST (measured uncertainty when interpreting the results. To overcome several using Hedge’s G) from baseline to end of study. The stand - of these problems and allow for the generation of a stable NMA, ardization was based on the pooled (across treatment arms the first approach evaluating studies with a common cognitive within study) estimate of the SDs. The NMA was carried out test was chosen for the NMA. using a frequentist’s approach, and a 2-way ANOVA model was Across the 72 included RCTs, 86 different cognitive tests were used. As the residual variances between treatment groups are used to assess the effect of antidepressants on cognitive dys - known, it was possible for random effect estimates to be pr - o function in patients with MDD. Most of the tests were used in duced, which account for the between-trial heterogeneity. The only one study. A total of 12 tests were reported in 4 or more model was first used to perform ordinary pairwise meta-anal - studies, with the Mini-Mental State Examination (MMSE) and ysis comparing the antidepressants to placebo based on direct DSST being the most commonly reported outcomes (13 stud - evidence from the clinical studies. Secondly, for the NMA, ies each). Even across studies that evaluated cognitive function 2 networks were developed: one network by drug class and using the same test, there were variations in reporting outputs. another by type of antidepressant. Ranking probabilities were For example, some studies reported the mean score as an end - calculated based on the joint distribution of the estimates of point, while others reported either the percentage of correct relative efficacy. answers or a time estimate. Additionally, some studies reported Consistency was addressed through the principle of node- different and/or multiple domains for the same test, and there splitting by using a network meta-regression model. The pur - was variation in whether the cognitive endpoint was a primary pose of node-splitting is to investigate if the relative effect of or secondary outcome. The MMSE is considered to be a poor 2 treatments based on direct comparisons is comparable with choice to measure cognitive function in MDD, because it broadly the same effect based on indirect comparisons. Statistically, the measures global cognitive function, has no alternate form, and model is an extension of the NMA, which allows for a different has extreme ceiling effects ( Keefe et al., 2014). In addition, the relative effect between the 2 treatments that are being split in MMSE is most commonly used for evaluating cognition in late- head-to-head trials compared with all other trials. life depression due to evidence of its validity for dementia ( Rajji et al., 2009 ). Furthermore, the MMSE did not allow for a compari - Results son of all antidepressant drug classes. Other tests were also not appropriate for the network in our analyses: Stroop, Trail Making SLR Test A (TMT A) and Trail Making Test B (TMT B), and Rey Auditory Figure  1 shows the flow of studies through the systematic Verbal Learning Test (RAVLT) were each reported in only 8 to 9 trials, and their networks were all smaller than the DSST net - review process. Searching of literature databases yielded 11 337 references. Due to the overlap of coverage between the data - work. The networks of these 4 tests decomposed into 2, 4, 3, and 4 subnetworks for Stroop, TMT A and TMT B, and RAVLT, bases, 1676 abstracts were found to be duplicates and were removed. First-stage screening of the citations identified 1425 respectively. Since these networks decomposed into small sub - networks, only a limited comparison of 1 to 3 (depending on the potentially relevant references based on their titles/abstracts. Full-text reports of these citations were obtained for more subnetwork) other antidepressants vs placebo, duloxetine, and vortioxetine was possible. In contrast, for the DSST, it was pos - detailed evaluation, following which 190 references remained. Hand-searching identified 20 additional relevant citations, sible to construct a single “connected” network that allowed for multiple comparisons across various antidepressants as shown resulting in a total of 210 publications prior to extraction. The review focused on RCTs assessing pharmacological in the Results. As a conclusion, the subsequent analyses and results are presented for the NMA using published clinical trials interventions, as RCTs are considered the gold standard of clini - cal evidence and they minimize the risk of confounding factors. that utilized the DSST. The DSST is a “pencil and paper” cognitive test that assesses Of the 210 references screened, 72 RCTs from 103 publications were identified based on prespecified eligibility criteria and several aspects of the cognitive function that are most impaired in patients with MDD, such as components of executive func - included for data extraction. The interventions assessed across the studies included tion, processing speed, attention, and working memory. It is r-ec ognized as being sensitive to change during effective treatment SSRIs (citalopram, escitalopram, fluoxetine, paroxetine, sertr - a line, or fluvoxamine), serotonin and norepinephrine reuptake of MDD (Jaeger and Zaragoza Domingo, 2016 ; McIntyre et  al., 2016). The DSST is sensitive to both the presence of cognitive inhibitors (SNRIs) (duloxetine, venlafaxine, desvenlafaxine, or Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/97/4555267 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Baune et al. | 101 Figure 1. Flow diagram for the identification and selection of studies. Note: 12 studies that assessed Digit Symbol Substitution Test (DSST) were included in the final network of evidence. Abbreviations: ADT, antidepressant therapy; MDD, major depressive disorder; RCT, randomized controlled trial. Vortioxetine (a) (b) Vortioxetine Citalopram Escitalopram Duloxetine MAOI SNRI Phenelzine Desipramine Placebo Placebo Nortriptyline TCA Fluoxetine Sertraline SSRI Figure 2. Network for the ( a) by-class analysis and ( b) by-treatment analysis. Note: The size (area) of the nodes is proportional to the number of patients on treatment. The width of the lines is proportional to the number of patients in trials with direct comparison between the nodes. The numbers on the lines indicate the number of trials with direct comparisons, if it is more than one. Abbreviations: MOAI, monoamine-oxidase inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. levomilnacipran), monoamine oxidase inhibitors (phenelzine DSST As the Single Cognitive Measure for Network or tranylcypromine), tricyclic antidepressants (desipramine, Development amitriptyline, imipramine, trimipramine, or tianeptine), tetr - a Although there was large variation in the cognitive meas - cyclic antidepressants (mianserin or mirtazapine), or non-SSRI/ ures used in the RCTs, the DSST was the only cognitive end - SNRI antidepressants (agomelatine, bupropion, reboxetine, or point from the reviewed studies that could be used as a test vortioxetine). Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/97/4555267 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 102 | International Journal of Neuropsychopharmacology, 2018 of cognitive dysfunction for developing a homogeneous and Standardized Effect Size “stable” network of evidence to compare various antidepr-es SMD 1st 2nd sants (see Methods). One study was excluded in the absence of a common link with the other antidepressants, resulting in 12 Vortioxetine vs placebo 0.25 [0.03;0.48] 153 144 studies (3738 patients) in the final network ( Tignol et al., 1998 ). Katona (2012) 0.25 [0.04;0.46] 175 167 Mahableswarkar (2014) DSST was the primary endpoint in 2 of the trials included in the McIntyre (2014) 0.46 [0.26;0.66] 397 194 network, and these both assessed vortioxetine ( McIntyre et al., Fixed effects meta analysis 0.35 [0.23;0.46] 725 505 2014; Mahableshwarkar et al., 2015 ); all other studies in the net - Random effects meta analysis 0.34 [0.18;0.49] 725 505 work assessed DSST as a secondary outcome. Duloxetine vs placebo The total number of patients in the RCTs where the DSST was 0.07 [−0.16;0.30] Katona (2012) 144 144 0.17 [−0.04;0.38] 187 167 employed as a primary or secondary cognitive endpoint ranged Mahableswarkar (2014) −0.04 [−0.28;0.20] 196 99 Raskin (2007) from 27 to 602, the mean age ranged from 36.6 to 79.6 years, and Robinson (2014) 0.22 [−0.03;0.48] 180 87 the percentage of males ranged from 24% to 58%. The time of Fixed effects meta analysis 0.13 [−0.03;0.28] 707 497 0.13 [−0.03;0.28] DSST assessment in the studies included in the network varied Random effects meta analysis 707 497 from 3 to 24 weeks after baseline assessment. The antidepres - Sertraline vs placebo sants assessed (with analyzable number of patients in brac - k −0.17 [−0.57;0.22] 49 49 Hoffman (2008) ets) were SNRIs (duloxetine [707 patients]), SSRIs (citalopram [84 Citalopram vs placebo patients], escitalopram [54 patients], fluoxetine [127 patients], Culang (2009) −0.04 [−0.33;0.26] 84 90 sertraline [240 patients]), MAOIs (phenelzine [28 patients]), tri - cyclic antidepressants (TCAs) (desipramine [9 patients], nor - Escitalopram vs placebo −0.25 [−0.57;0.06] Dube (2010) 54 122 triptyline [102 patients]), and non-SSRI/SNRIs (vortioxetine [725 patients]). Vortioxetine and duloxetine have the most subjects Phenelzine vs placebo Georgotas (1989) −0.02 [−0.52;0.48] 28 18 in which cognition was assessed by the DSST in clinical trials. The majority (9 of 12) of the studies included a placebo control. Nortriptyline vs placebo The studies included in the DSST network of evidence and their 0.01 [−0.56;0.58] Georgotas (1989) 32 18 characteristics are presented in Supplementary Table S1. Vortioxetine vs duloxetine Critical appraisal of the included studies was conducted 0.18 [−0.04;0.41] 153 Katona (2012) 144 using comprehensive assessment criteria based on the recom - 0.08 [−0.13;0.28] 175 187 Mahableswarkar (2014) Fixed effects meta analysis 0.13 [−0.03;0.28] 328 331 mendations in the NICE guidelines (NICE, 2013). The studies Random effects meta analysis 0.13 [−0.03;0.28] 328 331 were generally of good quality with around 4 of the 7 categories being assessed as low risk on average. The best scoring category Fluoxetine vs sertraline −0.27 [−0.53;−0.01] was the baseline comparability (83% low risk) and the worst Newhouse (2000) 119 117 scoring category was outcome selection and reporting (25% low Sertraline vs nortriptyline risk). The FOCUS trial was the best quality, with all 7 aspects of 0.52 [0.20;0.85] 74 70 Bondareff (2000) the assessment deemed to be low risk McIntyr ( e et al., 2014 ). Fluoxetine vs desipramine However, the overall risk of bias was unclear in the majority of Levkovitz (2002) −0.26 [−1.24;0.72] 8 9 the categories for 5 of the 12 studies. A summary of the qualita - tive assessment is provided in Supplementary Table S2. Phenelzine vs nortriptyline −0.03 [−0.53;0.47] Georgotas (1989) 28 32 As a result, 2 networks for the studies using the DSST were developed: one network by drug class and another by type of antidepressant. The network diagrams in Figure  2 provide a graphical representation of how each intervention is connected −1.0 0.0 0.5 1.0 to the others through direct comparisons. Each line depicts a Favors second comparator Favors first comparator direct comparison between 2 intervention nodes. A  forest plot showing the standardized mean differences for each study Figure  3. Standardized mean differences in Digit Symbol Substitution Test in direct comparisons, based on data reported in each of the (DSST) of antidepressants based on direct evidence from clinical studies included in the network of evidence. Abbreviations: SMD, standardized mean included studies, is shown in Figure 3. difference. NMA the DSST from baseline for vortioxetine vs placebo was 0.325 Figure  4 shows the standardized mean differences on DSST [95% CI = 0.120; 0.529, P = .009]. The differences for duloxetine comparing antidepressant classes as well as individual antide - and sertraline vs placebo were not statistically significant. pressants vs placebo. In the by-class analysis Figur ( e 4a), SSRIs, All other antidepressants (citalopram, desipramine, escit - MAOIs, and TCAs showed a smaller effect on DSST vs placebo, alopram, fluoxetine, nortriptyline, and phenelzine) demon - with TCAs showing a significantly worse effect on DSST than strated a smaller effect on cognitive dysfunction vs placebo placebo. Vortioxetine and SNRIs were the only antidepressant (Figure 4b). classes showing an improvement in DSST vs placebo, and this Table  2 shows the comparative effects between antidepres - difference was statistically significant in the comparison of v- or sants in terms of standardized mean differences in the DSST tioxetine vs placebo. for both the treatment class analysis (upper triangle) and the When comparing individual antidepressants vs placebo, individual treatment analysis (lower triangle). The order of the vortioxetine, duloxetine and sertraline showed an impro-ve treatments in the diagonal is based on the efficacy of the treat - ment in the DSST vs placebo, with vortioxetine being the ment classes as well as the individual antidepressants. The 2 only antidepressant showing a statistically significant dif - most efficacious antidepressants in terms of improvement in ference. The standardized mean difference on the change in the DSST were vortioxetine and duloxetine, but duloxetine was Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/97/4555267 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Baune et al. | 103 of cognitive dysfunction for developing a homogeneous and Standardized effect size, relative to placebo “stable” network of evidence to compare various antidepr-es (a) (b) sants (see Methods). One study was excluded in the absence of 0.5 0.5 a common link with the other antidepressants, resulting in 12 studies (3738 patients) in the final network ( Tignol et al., 1998 ). 0.4 0.4 DSST was the primary endpoint in 2 of the trials included in the ** network, and these both assessed vortioxetine ( McIntyre et al., 0.3 0.3 2014; Mahableshwarkar et al., 2015 ); all other studies in the net - work assessed DSST as a secondary outcome. 0.2 The total number of patients in the RCTs where the DSST was 0.2 employed as a primary or secondary cognitive endpoint ranged from 27 to 602, the mean age ranged from 36.6 to 79.6 years, and 0.1 0.1 the percentage of males ranged from 24% to 58%. The time of CIT FLU ESC PHE NOR SSRI MAOI TCA DSST assessment in the studies included in the network varied DES VOR DUL SER VOR SNRI from 3 to 24 weeks after baseline assessment. The antidepres - sants assessed (with analyzable number of patients in brac - k −0.1 −0.1 ets) were SNRIs (duloxetine [707 patients]), SSRIs (citalopram [84 patients], escitalopram [54 patients], fluoxetine [127 patients], −0.2 −0.2 sertraline [240 patients]), MAOIs (phenelzine [28 patients]), tri - cyclic antidepressants (TCAs) (desipramine [9 patients], nor - −0.3 −0.3 triptyline [102 patients]), and non-SSRI/SNRIs (vortioxetine [725 patients]). Vortioxetine and duloxetine have the most subjects −0.4 −0.4 in which cognition was assessed by the DSST in clinical trials. The majority (9 of 12) of the studies included a placebo control. −0.5 −0.5 The studies included in the DSST network of evidence and their characteristics are presented in Supplementary Table S1. Figure 4. Standardized mean difference vs placebo ( a) by-class analysis and ( b) by-treatment analysis. Abbreviations: CIT, citalopram; DES, desipramine; DUL, dulo - x Critical appraisal of the included studies was conducted etine; ESC, escitalopram; FLU, fluoxetine; MOAI, monoamine-oxidase inhibitor; NOR, nortriptyline; PHE, phenelzine; SER, sertraline; SNRI, serotonin and norepinephrine using comprehensive assessment criteria based on the recom - reuptake inhibitors; SSRI, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants; VOR, vortioxetine P < .05; . * ** P < .01. mendations in the NICE guidelines (NICE, 2013). The studies were generally of good quality with around 4 of the 7 categories not statistically significantly different from placebo. Placebo for pharmacological treatments in patients with MDD and is being assessed as low risk on average. The best scoring category was the third most efficacious, highlighting the fact that many increasingly becoming of clinical importance. was the baseline comparability (83% low risk) and the worst of the antidepressants have less impact on cognitive function In the current review, 72 RCTs assessing cognitive function scoring category was outcome selection and reporting (25% low vs placebo. using 86 different cognitive measures in MDD were identified. risk). The FOCUS trial was the best quality, with all 7 aspects of The analysis showed that vortioxetine was numerically more Of these 72 RCTs and 68 cognitive measures, 12 studies were the assessment deemed to be low risk McIntyr ( e et al., 2014 ). efficacious in terms of change in DSST from baseline than all included in the network of evidence for evaluating the effect However, the overall risk of bias was unclear in the majority of other antidepressants included in the analysis. The difference of antidepressants. A single measure of cognitive function, the the categories for 5 of the 12 studies. A summary of the qualita - in DSST was statistically significant for vortioxetine vs SSRIs DSST, was used for the NMA based on results of the network tive assessment is provided in Supplementary Table S2. and TCAs with standardized mean differences of 0.423 [95% development process. The findings of the NMA showed that vor - As a result, 2 networks for the studies using the DSST were CI = 0.147; 0.698, P = .006] and 0.722 [95% CI = 0.316; 1.129, P = .002], tioxetine, duloxetine, sertraline, and the SNRI class  improved developed: one network by drug class and another by type of respectively. In the by-treatment analysis, vortioxetine was stat - cognitive function measured with the DSST vs placebo, with antidepressant. The network diagrams in Figure  2 provide a istically significantly better than escitalopram and nortriptyline vortioxetine being the only antidepressant or non-SSRI/SNRI graphical representation of how each intervention is connected with standardized mean differences of 0.579 [95% CI = 0.117; showing a statistically significant effect vs placebo. All other to the others through direct comparisons. Each line depicts a 1.041, P = .021] and 0.691 [95% CI = 0.165; 1.217, P = .017], respect- antidepressants or classes of antidepressants included in the direct comparison between 2 intervention nodes. A  forest plot ively. Moreover, based on the by-class ranking analysis, the analysis demonstrated no effect on the DSST. The comparative showing the standardized mean differences for each study probability of vortioxetine having a higher change in DSST from analysis showed that vortioxetine was statistically significantly in direct comparisons, based on data reported in each of the baseline than all other classes of antidepressants (including -pla more efficacious in terms of change in the DSST from baseline included studies, is shown in Figure 3. cebo) is 97%. compared with escitalopram and nortriptyline. Placebo was the Consistency was addressed by node-splitting. Due to the size third most efficacious, further highlighting the fact that many of of the network, the risk of inconsistency was relatively small, the antidepressants have less impact on the DSST than placebo. NMA and only 2 potential loops were identified in each of the by-treat - These findings confirm previous research by showing that Figure  4 shows the standardized mean differences on DSST ment and by-class analyses. Although there were mild incon - some antidepressants improve cognitive function, and it also comparing antidepressant classes as well as individual antide - sistencies in the vortioxetine/SNRI and the placebo/SSRI/TCA highlights that many antidepressants and classes of antide - pressants vs placebo. In the by-class analysis Figur ( e 4a), SSRIs, comparisons, none were considered significant. Heterogeneity pressants may have less impact on cognition than placebo MAOIs, and TCAs showed a smaller effect on DSST vs placebo, was mainly driven by the vortioxetine/placebo comparison. This (Baune and Renger, 2014; Keefe et al., 2014; McIntyre et al., 2016 ; with TCAs showing a significantly worse effect on DSST than was accounted for by using a random effects model for estimat - Rosenblat et al., 2016 ). Vortioxetine showed the largest improv - e placebo. Vortioxetine and SNRIs were the only antidepressant ing both relative mean differences and their CIs in the NMA. ment on the DSST, which is in line with the results of previous classes showing an improvement in DSST vs placebo, and this studies (McIntyre et  al., 2016 ; Rosenblat et  al., 2016 ). In addi- difference was statistically significant in the comparison of v- or tion, the current analysis showed that vortioxetine was the Discussion tioxetine vs placebo. only antidepressant that demonstrated a statistically significant When comparing individual antidepressants vs placebo, Cognitive dysfunction is a well-known impairment associ - improvement on the DSST vs placebo. The European Medicines vortioxetine, duloxetine and sertraline showed an impro-ve ated with MDD and causes a significant additional burden to Agency has also recognized vortioxetine’s improvement on ment in the DSST vs placebo, with vortioxetine being the patients and society. The effects of antidepressants on cogni - the DSST, stating that it has a statistically significant effect vs only antidepressant showing a statistically significant dif - tive function are still not fully understood, but cognitive d - ys placebo according to 2 studies and a meta-analysis ( European ference. The standardized mean difference on the change in function has recently been identified by the FDA as a target Medicines Agency, 2016). Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/97/4555267 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 104 | International Journal of Neuropsychopharmacology, 2018 Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/97/4555267 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Treatment Effect Estimates (standardized mean differences of DSST change from baseline) VOR 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) 0.192 SNRI 0.133 0.230 0.410 0.530 (-0.027; 0.411) DUL (-0.032; 0.298) (-0.041; 0.502) (-0.199; 1.018) (0.126; 0.934) 0.325 0.133 PBO 0.097 0.277 0.397 (0.120; 0.529) (-0.043; 0.308) PBO (-0.129; 0.323) (-0.313; 0.867) (0.022; 0.771) 0.305 0.112 -0.020 SER (-0.168; 0.777) (-0.358; 0.582) (-0.460; 0.420) SSRI 0.362 0.170 0.038 0.058 CIT (-0.079; 0.804) (-0.268; 0.608) (-0.368; 0.443) (-0.540; 0.656) 0.180 0.300 (-0.411; 0.770) (-0.037; 0.636) 0.578 0.386 0.253 0.273 0.215 FLU (-0.018; 1.173) (-0.208; 0.979) (-0.317; 0.823) (-0.089;0.635) (-0.484; 0.914) 0.579 0.387 0.254 0.274 0.216 0.001 ESC (0.117; 1.041) (-0.073; 0.846) (-0.174; 0.682) (-0.340; 0.888) (-0.374; 0.806) (-0.712; 0.714) 0.582 0.390 0.257 0.277 0.219 0.004 0.003 MAOI 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) PHE (-0.437; 0.677) 0.319 0.127 -0.006 0.014 -0.044 -0.259 -0.260 -0.263 TCA (-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) DES 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) NOR Note: This table shows the treatment effect estimates in terms of standardized mean differences with corresponding 95% CIs displayed in parentheses. The lower triangle shows the results for the by-treatment analysis and the upper triangle shows the results for the by-class analysis. The order of the treatments in the diagonal is based first on the efficacy of the antidepressant classes and second on the efficacy of the treatments within the classes. A positive estimate indicates that the treatment/antidepressant class to the left is numerically better than the one to the right and vice versa. Statistically significant differences are shown in bold. Abbreviations: CIT, citalopram; DES, desipramine; DUL, duloxetine; ESC, escitalopram; FLU, fluoxetine; MOAI, monoamine-oxidase inhibitor; NOR, nortriptyline; PBO, placebo; PHE, phenelzine; SER, sertraline; SNRI, serotonin and norepinephrine reuptake inhibitors; SSRI, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants; VOR, vortioxetine. Copyedited by: oup Baune et al. | 105 The magnitude of the cognitive deficit in MDD is typic - 240 patients. Although a lower number of patients treated with ally between 0.2 and 0.7 standardized mean differences below a specific compound does not in itself bias the relative effect what would be normal, depending on disease state and cogni - of that compound, it will decrease the likelihood of finding a tive domain (Rund et al., 2006 ; Lee et al., 2012; Rock et al., 2014 ). significant difference between that compound and any of the For comparison, cognitive dysfunction in disorders such as other compounds, because fewer patients means wider CIs in Alzheimer’s dementia is greater than in MDD and usually up the results of the NMA. It should also be noted that vortioxetine to several SDs greater than what would be considered normal is very clearly significantly better than placebo, due to the r- ela (Buchanan et al., 2011 ). A meta-analysis of 22 studies in patients tively large number of patients in trials with both vortioxetine with MDD showed that patients were impaired on the DSST and placebo. One of the reasons for vortioxetine showing a sig - with a standardized mean difference of 0.55 compared with nificant difference vs other antidepressants (despite the rela - healthy controls. The DSST was shown to be strongly associated tively few patients in the trials of the other antidepressants) is with the level of functioning at work, school, and home. These the generally poor performance of the SSRIs and TCAs. In addi - findings suggest that the DSST provides an effective means to tion, the DSST was only a primary endpoint in 2 of the trials, and detect clinically relevant treatment effects of antidepressants 3 of the studies did not include a placebo control arm. on important components of cognitive function in patients with Across the 72 RCTs identified in our review, 86 differ- MDD (Jaeger and Zaragoza Domingo, 2016 ). ent cognitive tests were employed and hence 2 possible Vortioxetine’s statistically significant improvement on the approaches for the NMA were considered: assessing studies DSST is likely to be due to its unique pharmacological pr - o that used a common cognitive test or a common cognitive file vs other antidepressants. These mechanisms include domain. It was decided that the network of evidence would increased glutamate neurotransmission (via inhibition of be developed using the DSST as a common single cognitive gamma-aminobutyric acid interneurons expressing 5-HT3 test to reduce the amount of variability between studies as heteroreceptors) and neuroplasticity in brain regions such as much as possible. The feasibility of the alternative approach, hippocampus and prefrontal cortex ( Haddjeri et al., 2012 ; Riga et using a common cognitive domain, was investigated but was al., 2013; Sanchez et al., 2015 ; Pehrson et al., 2015 ). For example, not pursued due to the lack of standardization for classifying vortioxetine significantly enhances excitatory synaptic trans - the different symptoms into commonly accepted domains. It mission and neuroplasticity (increased cell proliferation and was also considered whether multiple tests could be included maturation) compared with SSRIs ( Dale et al., 2014 ). In addition, in the network; however, it was not considered prudent to do cognitive improvements with vortioxetine may be due to direct so, because different tests measure different aspects of cogni - and/or indirect effects via serotonergic, noradrenergic, choliner - tive function and may span across various cognitive domains. gic, dopaminergic, and histaminergic systems ( Elmaadawi et al., In addition, the studies that could have been included would 2015; Sanchez et al., 2015 ). Further research is needed to under - all sit as “appendices” to the network, and there would be stand if pharmacological differences translate into differential no change to the estimates of the already included studies. effects on cognition. Further, the additions would each be connected to the net - To the best of our knowledge, the current NMA included the work only through one trial, which yields very wide CIs, and largest network of evidence published to date in assessing the hence it was not deemed reasonable to introduce more than impact of antidepressants on cognitive function in MDD and one test in the NMA in this paper. As a consequence, our significantly extends a recently published meta-analysis that results have to be interpreted as an effect on the DSST only, included only 3 RCTs (McIntyre et  al., 2016 ). Importantly, none and results should not be generalized to other cognitive tests of the previous publications have quantitatively assessed the during interpretation. comparative effects of antidepressant classes, and therefore this An important limitation of the underlying RCTs is the large analysis provides new insights into the effects of the classes as variability of the reported cognitive outcomes. Although there well as the individual antidepressants. The strengths of our ana - is an abundance of studies exploring the effects of antidepr- es lysis include a robust and thorough SLR obtaining high-quality sants on cognition, the heterogeneity of cognitive tests and RCTs for inclusion in the analysis and consideration of heter - o outcomes used limits the analysis that can be performed in a geneity within the NMA by using random effects models. In meta-analysis such as ours. The advantage of selecting the DSST addition, the important issue of consistency between direct and as a single cognitive test for the NMA is that like-for-like com - indirect effects in the network was also addressed. Although the parisons between treatments could be made and that a “stable” SLR was initially carried out in November 2014, an additional network was generated for the DSST; however, the selection of search was carried out in October 2016, which found no new the DSST also means that a smaller number of RCTs was used studies assessing the effects on cognition using the DSST. in the analysis. Further research using other cognitive scales is There are also some limitations of the current analysis. The needed in the future, and recommendations for using a stand - evidence retrieved from the SLR suggests that there is ample ardized cognitive test battery would be highly useful for future clinical data evaluating the effect of antidepressants on co - g clinical research and would help to overcome some of the limi - nitive functioning. However, due to the lack of defined clinical tations of this type of research. In addition, further research into recommendations for the management of cognitive dysfunction the effects within different subpopulations, for example based in patients with MDD, a high variability is observed in report - on age and gender, would be valuable. ing of cognitive outcomes. There are also several methodolo -gi In summary, although some antidepressants have shown cal constraints in the studies with regards to large variability improvements in cognitive function in patients with MDD, the in the outcomes, domains, time points of assessments, report - majority of antidepressants have not shown an effect on co - g ing of outputs, and patient numbers. These variations limit the nition. Comparing the effects of a large group of antidepr -es generalizability of the results and caution the interpretation. In sants across classes on single cognitive measures, the DSST particular, vortioxetine and duloxetine had the most patients indicated that vortioxetine was the only antidepressant that included in the trials in the network (725 and 707, respec - exerted statistically significant effects on the DSST between tively), whereas the other antidepressants had between 9 and baseline and follow-up when compared with both placebo and Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/97/4555267 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 106 | International Journal of Neuropsychopharmacology, 2018 all other antidepressants analyzed. Further research is needed Rush AJ (2010) Health-related quality of life in depression: to overcome the limitations associated with the large amount a STAR*D report. Ann Clin Psychiatry 22:43–55. of heterogeneity of cognitive measures in MDD, and future Elmaadawi A, Singh N, Reddy J (2015) Prescriber’s guide to using analyses would benefit from a standardized cognitive test bat - 3 new antidepressants: vilazodone, levomilnacipran, vortio - x tery in MDD. etine. Current Psychiatry 14:28–29, 32–26. European Medicines Agency (2016) Brintellix summary of prod - uct characteristics. Funding Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G, This work was supported by H.  Lundbeck A/S and Takeda Murray CJ, Vos T, Whiteford HA (2013) Burden of depres - sive disorders by country, sex, age, and year: findings Pharmaceutical Company, Ltd. from the global burden of dizease study 2010. PLoS Med 10:e1001547. Acknowledgments Food and Drug Administration (2016) Psychopharmacologic Drugs Advisory Committee: (PDAC) Meeting. 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