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Expert Opinion on Pharmacotherapy

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Vortioxetine: a New Treatment for MajorDepressive Disorder

K. Ryan Connolly & Michael E. Thase

To cite this article: K. Ryan Connolly & Michael E. Thase (2016) Vortioxetine: a New Treatmentfor Major Depressive Disorder, Expert Opinion on Pharmacotherapy, 17:3, 421-431, DOI:10.1517/14656566.2016.1133588

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DRUG EVALUATION

Vortioxetine: a New Treatment for Major Depressive DisorderK. Ryan Connollya,b and Michael E. Thasea,b

aPhiladelphia Veterans Affairs Medical Center, Philadelphia, PA, 19104, USA; bDepartment of Psychiatry, University of Pennsylvania,Philadelphia, PA 19104, USA

ABSTRACTIntroduction: Vortioxetine is a structurally novel medication that has recently been approvedfor treatment of major depressive disorder (MDD). This medication is a serotonin reuptakeinhibitor that also has a number of other potentially relevant effects on serotoninergic recep-tors, which may differentiate the drug’s effects from those of current first-line antidepressants,such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptakeinhibitors (SNRIs).Areas Covered: This article will review the basic clinical pharmacology of vortioxetine, summar-ize the major clinical trials that were performed prior to approval by the US Food and DrugAdministration (FDA), discuss relevant post-marketing studies of this drug, and offer expertcommentary on the significance of this new agent in clinical practice. Pre-approval studies wereidentified as all randomized, placebo-controlled studies of vortioxetine listed on clinicaltrials.gov. Other referenced studies were identified via a MEDLINE database literature search inAugust 2015 using the key search terms, vortioxetine and Lu AA21004, combined with addi-tional terms that included pharmacological profile, pharmacokinetics, drug interactions, adverseeffects, side effects, safety, major depression, and major depressive disorder. We identifiedrelevant systematic reviews, meta-analyses, randomized trials and preclinical studies ofimportance.Expert Opinion: Results of placebo-controlled trials suggest efficacy and an overall safety profilecomparable to existing first-line antidepressants. The most common side effects are nausea,vomiting and constipation. Results of several studies indicate that vortioxetine may have ther-apeutic effects on cognition (e.g., memory and executive functioning) that exceed that ofstandard antidepressants. Disadvantages include cost and the current paucity of long-termefficacy data from large clinical trials. The authors suggest that vortioxetine is currently a goodsecond-line antidepressant option and shows promise, pending additional long-term data, tobecome a first-line antidepressant option.

ARTICLE HISTORYReceived 1 September 2015Accepted 15 December 2015Published online 12 February2016

KEYWORDSVortioxetine; majordepressive disorder (MDD);antidepressants; selectiveserotonin reuptake inhibitors(SSRIs); serotoninnorepinephrine reuptakeinhibitors (SNRIs);multimodal serotoninmodulator

1. Introduction

Major depressive disorder (MDD) is a common psychia-tric disorder that affects up to 16.2% of individuals overthe course of their lives.[1] A wide range of effectiveantidepressants already exists and, given the consider-able societal burden that is caused by MDD, promptrecognition and vigorous treatment of depression isconsidered a public health priority.[2] Following theserendipitous discovery of the therapeutic effects ofthe medications that comprise the first generation ofantidepressants (i.e. tricyclic antidepressants [TCAs] andmonoamine oxidase inhibitors [MAOIs]), concertedefforts over the past 40 years have led to the introduc-tion of safer, better tolerated, and easier-to-prescribeantidepressants, most notably selective serotonin reup-take inhibitors (SSRIs) and serotonin norepinephrine

reuptake inhibitors (SNRIs). Nevertheless, at least 50%of patients who begin therapy with newer-generationmedications either fail to respond or discontinue ther-apy because of intolerable side effects, so there remainsan ongoing need for antidepressants that are eithermore effective or better tolerated than existing stan-dards.[3,4] As part of the effort to address this unmetneed, several novel drugs have recently been intro-duced, including the subject of this review, the multi-modal serotoninergic drug vortioxetine (see Box 1).

2. Market review

Although the dramatic growth in the use of antidepres-sants in the last 30 years has leveled off in theUS, untreated depression remains a significant problemthroughout theworld and inmost settings antidepressant

CONTACT Michael E. Thase thase@mail.med.upenn.edu

EXPERT OPINION ON PHARMACOTHERAPY, 2016VOL. 17, NO. 3, 421–431http://dx.doi.org/10.1517/14656566.2016.1133588

© 2016 Taylor & Francis

medications remain a cornerstone of therapeutics.[5]Indeed, despite pessimistic forecasts about the limitedcommercial viability of new antidepressants in the currentclimate, nearly US$7 billion are spent on antidepressantmedications each year.[5] With the SSRIs securelyentrenched as the favorite antidepressants for first-lineuse throughout most of the industrialized world, it isnevertheless interesting that the major shift in the use ofantidepressants since the mid-1990s has involved greateruse of other types of newer-generation antidepressants,including SNRIs (venlafaxine, duloxetine, milnacipran,desvenlafaxine, and levomilnacipran), mirtazapine, andbupropion. This particular trend underscores the realitythat, despite the great utility of SSRIs, there is a consider-able need for alternate therapies, specifically medicationsthat work through mechanisms other than selective inhi-bition of neuronal uptake of serotonin.

Beyond the existing first-line therapies – SSRIs, SNRIs,bupropion, and mirtazapine – several other recentlyintroduced medications might be considered competi-tors of vortioxetine in a crowded marketplace. Thesemedications include extended-release (XR) trazodone,vilazodone, and levomilnacipran.

2.1. Extended-release trazodone

First introduced in the early 1980s, trazodone isarguably both the first drug that could be called amultimodal serotonin modulator and the first mem-ber of a so-called second generation of antidepres-sants. Most of trazodone’s effects on depression andanxiety are thought to derive from antagonism atserotonin 5HT2A receptors, though partial agonismat serotonin 5HT1A receptors may also be clinicallysignificant.[6,7] However, the original formulation oftrazodone was judged to be no easier to use thanTCAs and, probably, less effective.[8] After the intro-duction of SSRIs and mirtazapine, trazodone wasseldom used in doses adequate to treat depression.Rather, because low doses of trazodone can pro-mote sleep (presumably through antagonism at his-tamine H1 and adrenergic α1 receptors) withoutconcerns about abuse liability, this drug continuesto be widely prescribed ‘off label’ in 25–100 mgdoses as a hypnotic.[9]

An XR formulation of trazodone was developed inthe hope of encouraging a re-consideration of thismedication’s utility as an antidepressant by addressingsome of the side effect concerns that hindered use ofhigher doses, particularly lightheadedness and seda-tion.[8] Two placebo-controlled studies of this formula-tion have documented the tolerability and efficacy ofonce-daily dosing.[10,11] Nevertheless, to date, the clin-ical use of the extended-release formulation of trazo-done in the US has been quite limited.

2.2. Vilazodone

Vilazodone is, like trazodone, a drug with multimodalserotoninergic activity. In this case, vilazodone is a par-tial agonist of the serotonin 5-HT1A receptor, in additionto being a potent serotonin reuptake inhibitor.[12]Approved by the US FDA in 2011, the efficacy of vila-zodone was demonstrated in a pair of double-blind,placebo-controlled, randomized clinical trials (RCTs).[13,14] As these trials did not include an active com-parator, no assessments of relative efficacy were possi-ble. Nevertheless, the efficacy of vilazodone can beestimated from drug versus placebo differences, whichappear to be comparable to other, recently developedantidepressants. For example, the number needed totreat (NNT) for response versus placebo in the pooledsample from the pivotal trials was eight. The NNT valuefor remission was only 14, which may reflect the factthat vilazodone must be slowly titrated upward to thetherapeutic dose (i.e. from 10 mg to 20 mg to 40 mg)during the first 3 weeks of therapy and, as a result, a

Box 1. Drug Summary

Drug name (generic) VortioxetinePhase (for indication underdiscussion)

Launched

Indication (specific to discussion) Major Depressive DisorderPharmacology description/mechanism of action

5 Hydroxytryptamine 1Areceptor agonist5 Hydroxytryptamine 7 receptorantagonist5 Hydroxytryptamine 1Breceptor agonist5 Hydroxytryptamine uptakeinhibitor5 Hydroxytryptamine 1Dreceptor antagonist5 Hydroxytryptamine 3 receptorantagonist

Route of administration OralChemical structure

Pivotal trial(s) [27,31,32,35–37]

422 K. R. CONNOLLY AND M. E. THASE

somewhat longer course of therapy may be needed fora response to evolve into a remission.

One of the more interesting aspects of the clinicalpharmacology of vilazodone is that the serotonin par-tial agonism would be expected to convey greatertherapeutic effects for anxiety symptoms, as well aspossibly protective effects against sexual side effectsmediated by serotonin reuptake inhibition.[12] Apooled analysis of the impact of vilazodone therapyon the symptoms of anxiety associated with MDDdemonstrated that the drug’s effect on anxiety symp-toms was comparable to its effect on core depressivesymptoms.[15] Of course, head-to-head trials are neces-sary to confirm that this effect differs from that of SSRIsor SNRIs. The RCTs of vilazodone have used structuredscales to collect information on sexual adverse effectsand found the rates of these effects to be only margin-ally greater than placebo.[13,14,16] However, thesedata were not judged to be sufficient by the FDA topermit the manufacturer to market this product ashaving a ‘low risk of sexual dysfunction.’ A secondgroup of studies that may provide necessary additionalevidence pertaining to anxiolytic properties and sexualside effects is nearing completion.

2.3. Levomilnacipran

Levomilnacipran is the more potent stereoisomer ofthe racemic compound milnacipran, a drug that hasbeen approved for antidepressant therapy in severalregions of the world for more than a decade. AmongSNRIs, in vitro studies suggest that milnacipran andlevomilnacipran might be the most noradrenergicallyactive members of this drug class, because these drugshave greater potency for inhibition of norepinephrinethan serotonin.[17] Although the manufacturer of mil-nacipran did not pursue an indication for treatment ofdepression in the US, a second US-based company didthe requisite research to obtain an indication for treat-ment of fibromyalgia and, in turn, levomilnacipran wasapproved by the FDA for treatment of MDD in late2013. The summary basis of approval for levomilnaci-pran consisted of five placebo-controlled RCTs.Although not all of the individual studies are yetpublished, Montgomery and colleagues recently pub-lished a meta-analysis of the five placebo-controlledRCTs, summarizing the efficacy of this drug in doses of40–120 mg/day.[18] This analysis found that levomil-nacipran XR versus placebo resulted in greaterimprovement in Montgomery–Åsberg DepressionRating Scale (MADRS) score (−15.8 versus −12.9; LSmean difference, −2.9; P < .001), higher responserates (44.7% versus 34.5%; P < .001), and higher

remission rates (27.7% versus 21.5%; P < .05) in theoverall population.

3. Introduction to vortioxetine

Vortioxetine, previously called Lu AA21004, was devel-oped as a partnership between H. Lundbeck A/S andTakeda Global Research & Development Center, Inc.

3.1. Chemistry

Vortioxetine is chemically identified as 1-(2-((2,4-dimethyl-phenylthio)phenyl)piperazine; the compoundbelongs to the arylpiperazine class.[19] Along with tra-zodone, nefazodone, vilazodone, and buspirone, vor-tioxetine shares a piperazine group as part of itsstructure; this family of compounds shows significanteffects on multiple serotonin receptors.

3.2. Pharmacodynamics

Although classified by the FDA as an SSRI, vortioxetinehas a number of effects on serotoninergic neurotrans-mission and, as such, can be described as a ‘multimodalserotonin modulator’ (see Table 1). In addition to block-ade of the serotonin transporter (SERT), the compoundhas affinity for 5-HT1A, 5-HT1B, 5-HT3, and 5-HT7 recep-tors. In concert, these effects increase extracellular ser-otonin, acetylcholine, norepinephrine, and histamine inanimal models.[19]

Table 1. Summary of effects of vortioxetine on serotoninergictargets.Target Action at Target Potential Effect

SERT (serotonintransporter)

Antagonist, (Ki* 1.6 nM,increases synapticserotonin, SSRI-like action)

Antidepressant &anxiolytic

5-HT1A Near-full agonist (Ki 15 nM,unclear in vivo effect,agonism at postsynapticreceptors would lead toserotonin-like effect, partialantagonism at inhibitoryautoreceptors mayenhance serotonin release)

Antidepressant &anxiolytic. May also speedsymptomatic response.May reduce risk of sexualside effects

5-HT1B Partial agonist (Ki 33 nM) Modulates release ofmonoamines,acetylcholine, glutamateand GABA; uncertainclinical impact

5-HT3 Antagonist, (Ki 3.7 nM) Antiemetic, possibleantidepressant/anxiolyticeffects, possible effectson memory and learning

5-HT7 Antagonist, (Ki 19 nM) Possible effects onmemory and learning

*Ki = inhibitory constant. Adapted from information published inArenberg et. al, 2011 [20], Bang-Andersen et. al, 2011 [21], andSanchez et al., 2014.[19] GABA: gamma-aminobutyric acid.

EXPERT OPINION ON PHARMACOTHERAPY 423

3.3. Pharmacokinetics and metabolism

Vortioxetine is metabolized in the liver into four majormetabolites via cytochromes 2D6, 2C19, 3A4, 2C9, and2B6, as well as alcohol and aldehyde dehydrogenases;2D6 seems to catalyze the rate-limiting step overall.[19]The compound does not appear to significantly induceor inhibit cytochrome oxidase enzymes. Vortioxetine is75% bioavailable orally, is extensively protein-bound,and has an elimination half-life (t1/2) of 60 hours.[19,22] Thus, when it is necessary to discontinue ther-apy, it will take several weeks to fully wash out theeffects of the drug, which warrants caution whenswitching to an MAOI. On the positive side, a drugwith this pharmacokinetic profile is unlikely to be asso-ciated with problematic discontinuation symptoms.Cytochrome-related drug interactions are likely to beunusual given the multiple metabolic pathwaysinvolved in the metabolism of vortioxetine, thoughbupropion may significantly increase vortioxetinelevels, while rifampicin may lower these levels signifi-cantly. [22] Coadministration with other strong cyto-chrome 2d6 inhibitors (e.g. fluoxetine, paroxetine, andquinidine) or inducers (carbamazepine and phenytoin)should also prompt consideration of dose modification.When treating patients known to be poor 2D6 metabo-lizers, dose reduction is advised. [From manufacturer’sprescribing information]

3.4. Special populations

Vortioxetine is approved in the US only for use in adultpatients and has not been investigated in child andadolescent populations. As vortioxetine is currentlylisted as category ‘C’ in pregnancy and as its transmis-sion into the breast milk of nursing mothers is not yetcharacterized, caution is advisable when consideringthis medication for women who are or who plan tobecome pregnant. No dosage adjustment is necessaryfor elderly patients or those with renal impairment ormild to moderate hepatic impairment. [From manufac-turer’s prescribing information]

3.5. Preclinical studies

In animal in vivo microdialysis studies, vortioxetine hasbeen shown to increase extracellular serotonin in keydepression-related areas, such as the hippocampus andmedial prefrontal cortex (mPFC), to a greater degreethan SSRIs.[23,24] Vortioxetine also increases the extra-cellular concentration of norepinephrine, dopamine,acetylcholine, and histamine (HA) in rat prefrontal cor-tical areas, presumably though modulation of serotonin

receptors.[23,24] In addition to these effects, vortioxe-tine has also demonstrated significantly greater effectson synaptic plasticity, long-term potentiation, and glu-tamatergic signaling than escitalopram in animal stu-dies, suggesting a potential for a specific effect oncognitive functioning.[25,26]

4. Vortioxetine premarketing clinical trials

Eleven premarketing clinical trials submitted to the FDAwere considered for this review of the efficacy of vor-tioxetine: all nine short-term efficacy trials and one 6-month relapse prevention trial submitted to the FDAand one Phase 2 study conducted in the EU wereidentified. Phase 1 trials have largely not reported orpublished results, or were focused on pharmacokineticproperties (NCT01299805, and assay of serotonin andmetabolites in plasma and CSF, and, NCT01607125,NCT02112903, NCT01676571, and NCT02072278,which have been completed but have not postedresults).

4.1. Phase 2

The first study of vortioxetine in MDD was conducted inthe EU and included venlafaxine XR at 225 mg/day asan active comparator.[27] In this 6-week, four-arm, par-allel-group RCT, 429 moderate-to-severely depressedoutpatients were randomly assigned to receive one oftwo doses of vortioxetine (5 or 10 mg/day), venlafaxineXR, or placebo. Both doses of vortioxetine were foundto be significantly superior to placebo, as was the com-parator. Attrition due to adverse events was compar-able in the placebo (4%) and 5 mg vortioxetine (3%)groups. About twice as many patients dropped outbecause of side effects in the 10 mg vortioxetinegroup (7%), which in turn had a drop-out rate ofabout half that observed in the venlafaxine 225 mggroup (14%). The results of this study were sufficientlypositive for the manufacturer to pursue Phase 3 studiesand suggested that the 5 mg/day dose of vortioxetinemight offer comparable efficacy as an SNRI with bettertolerability.

4.2. Phase 3 studies and FDA review

In addition to the Phase 2 study described above, nineother, short-term, placebo-controlled RCTs were sub-mitted for regulatory review, along with one 6-monthlong relapse-prevention trial. The FDA review of thisbody of work is nicely summarized by Zhang and col-leagues.[28] All of these studies enrolled adult outpati-ents with MDD (DSM-IV-TR criteria); one study focused

424 K. R. CONNOLLY AND M. E. THASE

specifically on patients aged 65 and older. All studiesrequired that patients were medically stable and werenot taking concomitant medications that might com-plicate study treatment. For most studies, the MADRSwas the primary dependent measure. The studies dif-fered in the minimum or threshold level of symptomseverity required for eligibility, with minimum requiredpretreatment MADRS scores ranging from ≥22 to ≥30to be eligible for randomization. Thus, the portfolioincludes depressed outpatients ranging from milderto more severe depressive states. The study of olderpatients also required that patients have a Mini-MentalState Examination score of at least 24 to excludepatients with more advanced levels of cognitiveimpairment and all patients with a clinical diagnosisof dementia. The studies evaluated vortioxetine indoses ranging from 1 to 20 mg/day. In addition tothe Phase 2 study that included venlafaxine XR as anactive control, five studies employed duloxetine as theactive comparator.

Looking across the regulatory submission portfolio(see Zhang et al., 2015 [28]), it is apparent that thestudies were conducted in two waves. In the first

wave, the maximum dose of vortioxetine studied was10 mg/day. Although in aggregate these studiesshowed that the 5 and 10 mg/day doses were effective,neither of the studies conducted in the US demon-strated efficacy. Therefore, a second wave of studieswas undertaken, focusing on the safety and efficacy ofhigher doses of vortioxetine (15 and 20 mg). In thesecond wave of studies, the efficacy of the 20 mg/daydose of vortioxetine was established in the US. Acrossboth waves, 6 of the 10 RCTs met the FDA’s a priorireview criteria for novel antidepressants; specifically,they were judged to be positive on the basis of astatistically significant effect for at least one dose ofvortioxetine as compared to placebo (see Table 2).Among the four studies that did not find significanttreatment effects, the FDA concluded that one studywas considered to be a failed study because the activecomparator (duloxetine 60 mg per day) also did notstatistically separate from placebo. As the current suc-cess rate for psychiatric medications in Phase 3 RCTshovers around 50%, the FDA concluded that the pre-ponderance of the evidence supported the efficacy ofvortioxetine 20 mg/day.[28,38]

Table 2. Characteristics of the 10 acute-phase RCTs in adults with MDD completed before review by the FDA.Studynumber NCT identifier Location

Studylength Dosage mg/day (n*)

Key inclusioncriteria Main result (primary outcome) Reference

11492A NCT00839423 Non-US 6 weeks VOR 5 (108) VOR 10(100) VEN 225 (113)PBO (105)

MADRS ≥ 30MDE ≥ 3 monthsand <12 months

Significant reduction in MADRS vs.placebo of 5.9 (5 mg), and 5.7 (10 mg)

Alvarez et al., 2012[27]

11984A NCT00635219 Non-US 8 weeks VOR 2.5 (155) VOR 5(157) VOR 10 (151)DUL 60 (155) PBO(148)

MADRS ≥ 26MDE ≥ 3 months

‘Failed’ study. Neither duloxetine norvortioxetine demonstrated a significantreduction in MADRS vs. placebo

Baldwin et al.,2012 [29]

305 NCT00735709 Non-US 8 weeks VOR 1 (140) VOR 5(140) VOR 10 (139)PBO (140)

MADRS ≥ 26MDE ≥ 3 months

Significant reduction in HDRS-24 vs.placebo of 3.52 (1 mg), 4.12 (5 mg) and4.93 (10 mg)

Henigsberg et al.,2012 [30]

12541A NCT00811252 US andnon-US

8 weeks VOR 5 (156) DUL 60(151) PBO (145)

Aged ≥65 yearsMADRS ≥ 26MDE ≥ 4 weeks,recurrent

Significant reduction in HDRS-24 vs.placebo of 3.3

Katona et al., 2012[31]

303 NCT00672958 US 6 weeks VOR 5 (299) PBO(298)

MADRS ≥ 30MDE ≥ 3 months

No significant difference was foundbetween vortioxetine and placebo inreduction of HDRS-24

Jain et al., 2013 [32]

304 NCT00672620 US 8 weeks VOR 2.5 (149) VOR 5(153) DUL 60 (150)PBO (151)

MADRS ≥ 22MDE ≥ 3 months

No significant difference was foundbetween vortioxetine and placebo inreduction of HDRS-24

Mahableshwarkaret al., 2013 [33]

13267A NCT01140906 Non-US 8 weeks VOR 15 (151) VOR 20(151) DUL 60 (147)PBO (158)

MADRS ≥ 26 CGI-S ≥ 4 MDE > 3months, recurrent

Significant reduction in MADRS vs.placebo of 5.5 (15 mg) and 7.1 (20 mg)

Boulenger et al.,2014 [34]

316 NCT01163266 US 8 weeks VOR 10 (155) VOR 20(150) PBO (157)

MADRS ≥ 26 CGI-S ≥ 4 MDE ≥ 3months, recurrent

Significant reduction in MADRS vs.placebo of 3.64 (20 mg), no significantdifference seen with 10 mg vs. placebo

Jacobsen et al.,2015 [35]

315 NCT01153009 US 8 weeks VOR 15 (147) VOR 20(154) DUL 60 (150)PBO (159)

MADRS ≥ 26 CGI-S ≥ 4 MDE ≥ 3months, recurrent

Significant reduction in MADRS vs.placebo of 4.07 (20 mg), no significantdifference seen with 15 mg vs. placebo

Mahableshwarkaret al., 2015 [36]

317 NCT01179516 US 8 weeks VOR 10 (154) VOR 15(151) PBO (160)

MADRS ≥ 26 CGI-S ≥ 4 MDE ≥ 3months, recurrent

No significant difference was foundbetween vortioxetine and placebo inreduction of MADRS

Mahableshwarkaret al., 2015b [37]

*n represents all randomized participants who took at least one dose of study drug. CGI-S: Clinical Global Impression-Severity of Illness; DUL: duloxetine;MADRS: Montgomery–Åsberg Depression Rating Scale; MDE: major depressive episode; PBO: placebo; VEN: venlafaxine; VOR: vortioxetine; HDRS: HamiltonDepression Rating Scale.

Adapted from FDA CDER 2013 [#].

EXPERT OPINION ON PHARMACOTHERAPY 425

The results of the single longer-term, relapse-preven-tion study also were consistent with the FDA’s appraisalof efficacy.[39] In this trial, a total of 693 depressedoutpatients were treated for up to 12 weeks with5–10 mg of vortioxetine, of which 396 responded andwere then blindly randomized to continuation treat-ment or placebo. Across the 24 weeks of double-blindpreventive therapy, the subjects who stayed on activevortioxetine had a significantly lower relapse rate (13%)than those who were switched to placebo (26%). Theobserved magnitude of reduction of risk is comparableto what has been observed in other studies of newer-generation antidepressants using similar designs.[40,41]However, because this study used doses of vortioxetinethat are below the current recommended dose in theUS, the FDA requested that the manufacturer performan additional longer-term study to document the safetyand efficacy of the 20 mg/day dose for recurrenceprevention.

4.2.1. Dose–response relationshipCareful inspection of the registration studies withoutconsideration of the countries in which they were con-ducted would support the conclusion that vortioxetineis effective across a range of doses (5–20 mg/day)(seeTable 2). Visual inspection of mean drug versus placebodifferences likewise suggests that the therapeuticeffects of vortioxetine are dose-dependent, althoughthe FDA concluded that there was only sufficient evi-dence to conclude that the 20 mg/day dose was effec-tive in the US. The FDA recognized that the 5 mg/daydose performed better in the studies conducted outsidethe US, but did not speculate on the reason. However,the FDA reviewers did note that, with respect to signaldetection and assay sensitivity, duloxetine 60 mg/dayalso had a smaller effect size in the US studies than inthe studies conducted outside of the US.[28]

4.2.2. Efficacy in late-life depressionOne 8-week, placebo-controlled RCT evaluated the effi-cacy of the 5 mg dose of vortioxetine in adults aged 65and older (mean age: 70.6 years).[31] The studyincluded duloxetine (60 mg/day) as an active compara-tor and employed a standardized cognitive assessment

battery in addition to symptomatic outcomes. At8 weeks, both active medications were significantlymore effective than the placebo; remission rates (final24-item Hamilton Depression Rating Scale score ≤7)were 19.3%, 29.2%, and 34.7% for placebo, vortioxetineand duloxetine, respectively. Withdrawals due toadverse events were as follows: placebo, 3%; vortioxe-tine, 6%; and duloxetine, 10%.

With respect to effects on cognition, subjects’ cogni-tion was evaluated with the Rey Auditory VerbalLearning Test (RAVLT) and the Digit SymbolSubstitution Test (DSST). Path analysis was performedto differentiate between direct effects of the drug andindirect effects due to symptomatic improvement. Bothduloxetine and vortioxetine showed significantlygreater improvements than placebo on the RAVLT,with effect sizes of about 0.3 for the active therapies.Vortioxetine, but not duloxetine, also showed a signifi-cant improvement on the DSST.

4.3. Safety and tolerability of vortioxetine

A total of 2616 depressed adult patients took at leastone dose of vortioxetine 5–20 mg/day in the short-term placebo-controlled trials of MDD that werereviewed by the FDA.[28] In this pooled data set, theattrition rates due to side effects in the active vortiox-etine arms were as follows: 5 mg/day = 5%, 10 mg/day = 6%, 15 mg/day = 8%, and 20 mg/day = 8%, ascompared to 4% in the placebo groups. The mostcommon adverse event that led to attrition was nau-sea, which was the reason that about 1% of patientstreated with vortioxetine prematurely discontinuedtherapy. Using the FDA convention to consider anadverse event to be common if has an incidence ofat least 5% and occurs with an incidence that is atleast twice that of placebo, vortioxetine therapy isassociated with only three common side effects: nau-sea, vomiting, and constipation (see Table 3). All threeof these side effects occurred at lower rates in thegroups treated with 5–10 mg/day than in the groupstreated with 15–20 mg/day doses. Moreover, in thestudies that included duloxetine as the active com-parator, the incidence of nausea, vomiting, and con-

Table 3. Side effects reported by at least 5% of subjects taking vortioxetine and at an incidence of atleast twice that of placebo in short-term RCTs reviewed by the FDA.

Side effectPlacebon = 1621

Vortioxetine

Duloxetinen = 753

5 mgn = 1013

10 mgn = 699

15 mgn = 449

20 mgn = 455

Nausea 9% 21% 26% 32% 32% 36%Vomiting 1% 3% 5% 7% 6% 4%Constipation 3% 4% 5% 6% 6% 10%

Adapted from: Zhang et al., 2015 [28].

426 K. R. CONNOLLY AND M. E. THASE

stipation was lower in the groups treated with5–10 mg/day than documented in the patients receiv-ing 60 mg/day of duloxetine (see Table 3). By contrast,the incidence of nausea and vomiting in the groupsthat received 15–20 mg/day vortioxetine was compar-able to that observed in the duloxetine arms.

The manufacturer of vortioxetine was optimistic thatthe receptor profile of this drug would lower the risk oftreatment-emergent sexual side effects. Several of thePhase 3 studies included prospective assessment of sex-ual function with standardized scales, and there didappear to be a low incidence of orgasmic dysfunctionin men and women treated with lower doses of vortiox-etine (i.e. 5–10 mg/day). However, as this potentialadvantage was not clearly evident in patients receiving20 mg/day of vortioxetine, the FDA concluded that thedrug did not have a definite advantage compared toexisting standards.[28] Since then a randomized, doubleblind trial of vortioxetine versus escitalopram found thatvortioxetine was associated with significantly higherscores on the Changes in Sexual FunctioningQuestionnaire, Short Form (CSFQ-14; vortioxetine 8.8vs. escitalopram 6.6 P = 0.013), suggesting a lower pro-pensity for sexual side effects.[42]

Short-term efficacy studies found no significant changesin laboratory parameters, vital signs, or weight.[28]

The tolerability profile during longer courses of therapyis documented by a number of long-term extension trials.The first report, which describes the results of a 52-weekopen-label extension protocol for patients who com-pleted shorter-term double-blind RCTs, enrolled 535patients who had obtained an adequate response tovortioxetine 2.5–10 mg/day.[43] A total of 61.3% (n =328) of the patients completed the study; 83% of thecompleters were in remission, as defined by a finalMADRS score of 10 or less, at the end of 1 year of pre-ventive therapy. The most common side effects observedduring longer-term treatment were nausea, headache,and nasopharyngitis, which occurred in more than 10%of patients. Six patients (2%) reported various complaintsof sexual dysfunction as new side effects during ongoingtherapy. This appears to be a very low incidence of sexualside effects, although in the absence of both a placebocontrol condition and a systematic assessment, it is diffi-cult to calibrate the significance of these side effects.There were no clinically significant safety findings withrespect to mean changes of vital signs, weight, ECG para-meters, or clinical laboratory values.

In a second study, 834 outpatients with MDD whocompleted therapy in one of two double-blind RCTswere offered up to 52 weeks of ongoing therapy withflexibly adjusted (2.5–10 mg/day) vortioxetine therapy.[44] Across the year of extended vortioxetine therapy,

the authors reported that no new safety signals wereidentified. Across all doses, the most common sideeffects were: nausea (15.2%), headache (12.4%), naso-pharyngitis (9.8%), diarrhea (7.2%), and dizziness (6.8%).Again, there were few reports of new-onset sexualdysfunction. Neither weight gain nor changes in labora-tory values, vital signs, or ECGs were noteworthy.

A third large trial, NCT01152996 enrolled 1075 sub-jects who completed a number of Phase 3 short-termtrials [35–37] for a 52-week extension. Adverse eventsseen inmore than 5% of the population included nausea,vomiting, diarrhea, constipation, upper respiratory infec-tion, headache, weight gain, and insomnia. Withdrawaldue to adverse events was 10.9%, and 29 serious adverseevents were recorded. Serious adverse events weremainly single instances and likely unrelated to thestudy medication, though four subjects experienced dis-orders of the gallbladder and three attempted suicide.

NCT01323478, an open-label extension study of oneof the Phase 3 efficacy trials, [34] followed up 71 trialcompleters for an additional 52 weeks, and found onlyone serious adverse event (cholelithiasis) and a 9.9%rate of withdrawal due to adverse events of any kind.Adverse effects were again most commonly nausea,headache, dizziness, and nasopharyngitis.

NCT00761306, another open-label extension study ofone of the Phase 3 efficacy trials, [27] followed up 74trial completers for an additional 52 weeks, and foundonly one serious adverse event (thyroiditis) and a 6.8%rate of withdrawal due to adverse events of any kind.Adverse effects were again most commonly nausea,headache, dizziness, and nasopharyngitis; 18.6% of sub-jects also experienced weight gain.

5. Post-marketing studies of vortioxetine

5.1. Impact of cognitive function

The possibility that the receptor-mediated effects ofvortioxetine may exert beneficial effects on cognitionover and above those attributable to its antidepressantactivity was suggested by both preclinical studies [45–47] and the findings of Katona and colleagues [31] intheir RCT of older, depressed patients. If such effectscould be confirmed prospectively in depressed patients,it would represent an important point of differentiationin clinical pharmacology vis-à-vis the SSRIs or SNRIs. Asecond study of the impact of vortioxetine therapy oncognition in depressed patients therefore was under-taken. [48] In this RCT of adults aged 18–65 years andsuffering from MDD, patients were randomized to8 weeks of double-blind treatment with placebo oreither 10 or 20 mg/day of vortioxetine. The primary

EXPERT OPINION ON PHARMACOTHERAPY 427

outcome measure was improvement in a compositescore derived from the DSST and RAVLT scores. Pathanalysis was also conducted to ascertain if improve-ment in cognition was attributable to reductions indepressive symptoms. Results indicated that bothdoses of vortioxetine were significantly better than pla-cebo on the composite cognition score. Both doses ofvortioxetine also resulted in a statistically significantimprovement in depressive symptoms, and the pathanalysis indicated that the beneficial effect on cognitionwas not simply an epiphenomenon of symptomaticimprovement.

5.2. Relative efficacy

None of the Phase 2 or Phase 3 studies reviewed by theFDA found significant effects favoring vortioxetine overthe standard comparators, venlafaxine (1 study) andduloxetine (5 studies). Direct [49] and indirect [50] com-parisons of efficacy confirm this conclusion.

5.3. Switching from other therapies

Like other newer antidepressants, vortioxetine is mostcommonly positioned as a second- or third-line ther-apy for patients who have not responded to or whohad tolerability problems with an SSRI or SNRI. Todate, only one study has evaluated vortioxetine ther-apy in this clinical context.[49] In this trial, 495 out-patients with MDD who had not responded to acourse of SSRI/SNRI therapy in the current episodewere switched to vortioxetine (10–20 mg/day) or ago-melatine (25–50 mg/day) (1:1, blinded) for 12 weeks.Although not available in the US, agomelatine is oneof the newer alternatives to SSRI/SNRI therapy inEurope and, as such, is a relevant comparator to vor-tioxetine. The first aim of the study was to test non-inferiority (i.e. the efficacy of vortioxetine was notinferior to that of agomelatine with a narrow, pre-defined range). Secondarily, conventional tests ofsuperiority and tolerability also were performed. Theprimary analysis confirmed that vortioxetine (n = 252)was not inferior to agomelatine (n = 241). Moreover,the advantage in symptom improvement in the vor-tioxetine group (2.2 MADRS points) was statisticallysignificantly greater than the improvement observedin the agomelatine group.

5.4. Other post-marketing studies

A Phase 2/3 randomized placebo-controlled trial com-pleted in Asia, Europe, and Oceania, NCT01255787,found no significant difference in MADRS total score

versus placebo for doses of 5, 10, or 20 mg of vortiox-etine in major depression (n = 600). NCT01355081, aPhase 3 randomized placebo-controlled trial completedin Japan, also failed to find a significant reduction inMADRS vs. placebo (n = 366).

6. Conclusion

Vortioxetine is a structurally and mechanistically novelantidepressant with a safety and efficacy profile thatappears to be comparable to that of duloxetine.Classified by the FDA as an SSRI, the novelty of thisdrug is found in its therapeutic activities derived frommultimodal activity at serotonin receptors. Specifically,this agent may have important clinical advantages byvirtue of its cognition-enhancing effects. The drug alsomay have a lower incidence of sexual adverse effects, atleast at lower therapeutic doses. If post-marketing dataand clinical experience confirm such advantages, thenvortioxetine will represent a valuable albeit incrementalnew option for patients.

7. Expert commentary

Although truly novel (i.e. non-monoaminergic)approaches to the pharmacotherapy of depression con-tinue to be a major goal of antidepressant development,there is some cause for hope that vortioxetine, which is amonoaminergic drug with a novel array of effects on pre-and postsynaptic receptors, may offer a clinical profilethat differentiates it from both the current first-linetherapies and other newer antidepressants.

Launched throughout the US and Europe in late2013 and early 2014, the efficacy of this drug wasevident in an unusually extensive Phase 3 researchprogram. As vortioxetine was compared a number oftimes to SNRIs, it was also established that this drug hasan efficacy profile that is comparable to other effectivetreatments of MDD.

With respect to tolerability, early studies suggestedthat vortioxetine therapy at lower doses, especially5 mg/day, may be associated with a lower overall sideeffect burden than the SNRIs. A lower incidence oftreatment-emergent sexual side effects looked particu-larly promising. However, as the efficacy of the 5 mg/day dose could not be established in the US, it wasnecessary to develop the efficacy profile of higherdoses, and ultimately only the 20 mg/day dose wasconsistently established as efficacious in the US.Although further studies are needed with direct head-to-head comparisons, at this time there, is no evidencethat vortioxetine at 20 mg/day has a more favorableside effect profile than SNRIs.

428 K. R. CONNOLLY AND M. E. THASE

A second and potentially unique clinical feature ofvortioxetine pertains to its effects on memory andexecutive function. Recognition of such effects wasnot serendipitous: based on the pharmacology of thisdrug, preclinical studies were undertaken early onthat suggested favorable effects on cognition.Although it can be said that all antidepressantshave some beneficial effects on cognition when effec-tive, two studies have now found that the effects ofvortioxetine on memory and executive functionappear to be largely independent of the magnitudeof the antidepressant effect. If confirmed and parti-cularly if shown in comparison to first-line antidepres-sants, it is conceivable that vortioxetine will becomethe preferred treatment for depression in later life orperhaps even for depressive episodes associated withsignificant complaints of cognitive dysfunction. Astudy of vortioxetine therapy in older, depressedpatients with mild cognitive impairment is nowgreatly needed.

As with any drug that has been marketed for lessthan 1 year, more extensive post-marketing data arenot yet available. The therapeutic landscape is litteredwith discarded claims of superiority for many recentlyintroduced antidepressants. For this reason, we arecautiously optimistic regarding the potential of vor-tioxetine, rather than being as enthusiastic as we

would be, were it a truly revolutionary treatmentoption. It also must be noted that long-term efficacydata is still lacking and so any sound appraisal ofthe longer-term use of this agent must await moredata.

Declaration of interest

M E Thase has been an advisory/ consultant for Alkermes,Allergan, AstraZeneca, Bristol-Myers Squibb Company,Cerecor, Inc., Eli Lilly & Co., Forest Laboratories, GersonLehrman Group, Fabre-Kramer Pharmaceuticals, Inc.,GlaxoSmithKline, Guidepoint Global, H. Lundbeck A/S,MedAvante, Inc., Merck and Co. Inc. (formerly ScheringPlough and Organon), Moksha8, Naurex, Inc., Neuronetics,Inc., Novartis, Ortho-McNeil Pharmaceuticals (Johnson &Johnson; Janssen), Otsuka, Pamlab, L.L.C. (Nestle) Pfizer (for-merly Wyeth Ayerst Pharmaceuticals), Shire US Inc.,Sunovion Pharmaceuticals, Inc., Trius Therapeutical, Inc.and Takeda. He has received grant support from Agencyfor Healthcare Research and Quality, Alkermes, AssureRx,Avanir, Forest Pharmaceuticals, Janssen, National Instituteof Mental Health and Otsuka Pharmaceuticals. M E Thasehas equity holdings in MedAvante, Inc. and receives royal-ties from American Psychiatric Foundation, GuilfordPublications, Herald House and W.W. Norton & Company,Inc. The authors have no other relevant affiliations or finan-cial involvement with any organization or entity with afinancial interest in or financial conflict with the subjectmatter or materials discussed in the manuscript apartfrom those disclosed.

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