`
`REVIEW ARTICLE
`
`A Review of Vilazodone, Serotonin,
`and Major Depressive Disorder
`Kerri A. Pierz, PhD, and Michael E. Thase, MD
`
`This work maynot be copied,distributed,
`displayed, published, reproduced,
`transmitted, modified, posted, sold,
`licensed, or used for commercial purposes.
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`to the publisher's Terms & Conditions.
`
`ABSTRACT
`
`Objective: To review the mechanism ofselective
`serotonin reuptake inhibitor (SSRI)—mediated
`serotonergic neurotransmission,focusing on
`serotonin 1A (5-HT;,4) autoreceptors, which are
`proposed to beinvolvedin delaying therapeutic
`efficacy. Vilazodone was specifically designed to
`function both as an SSRI and a partial agonist at
`5-HT,q receptors. This combined mechanism is
`proposed to decrease time to efficacy, minimize
`sexual side effects, and provide concomitant
`anxiolytic properties.
`
`Data Sources: A PubMedsearch ofall English-
`language articles from January 1990 to January 2013
`was conducted using the search terms depression
`and 5-HT,,, depression and buspirone, depression and
`pindolol, and vilazodone.
`Study Selection: We found 47 articles and
`abstracts that were selected for inclusion on the
`basis of information about the pharmacologyof
`5-HT,4 receptors andtheclinical data on pindolol,
`buspirone, and vilazodonein depression.
`Data Extraction: This review summarizes current
`literature involving antidepressantactivity, the role
`of 5-HT;, autoreceptors, andclinical trials involving
`serotonin reuptakeinhibition in conjunction with
`5-HT,, agonists and partial agonists, with a focus on
`vilazodone.
`
`Results: Vilazodone has demonstratedefficacy in 2
`large, randomized, double-blind, placebo-controlled
`trials in major depressive disorder. Results suggest
`that vilazodone hasa low incidenceof sexualside
`effects andis effective in patients with high levels
`of anxiety. A pooled analysis shows evidence of
`significant symptom reduction after only 1 weekof
`therapy.
`Conclusions:If future studies corroboratetheclinical
`benefits attriputed to its mechanism ofaction,
`vilazodone may show potential advantagesin terms
`of onsetof action, sexual side effects, and anxiolytic
`activity in patients with major depressive disorder.
`Prim Care Companion CNS Disord
`2014; 16(1):doi:10.4088/PCC. 13r01554
`© Copyright 2014 Physicians Postgraduate Press, Inc.
`
`
`Submitted: July 10, 2013; accepted October1, 2013.
`Published online: January 9, 2014.
`Corresponding author: Kerri A. Pierz, PhD, c/o John Edwards,
`185 Hudson St, Plaza 5 28th Floor, Jersey City, NJ07311
`(kerripierz@gmail.com).
`
`ajor depressive disorder (MDD)is a debilitating condition with
`lifetime prevalence in the United States of 19.2%.’ The World
`Health Organization ranks MDDastheleadingcauseof disease burden
`in high- and middle-incomecountries” and the second-leading cause of
`years lived with disability worldwide.’ Data from the 1995-1996 National
`Ambulatory Medical Care Survey demonstrated that 8% ofall primary
`care office visits were depression related,* and the role of primary care
`in treating MDDis increasing due to changes in health care coverage,
`improved depression screening tools, and the developmentof newer-
`generation antidepressants with improved safety profiles.*-° Since a
`growingshare of the responsibility for MDD diagnosis and treatment
`falls on primary care physicians, an understanding of the history,
`neurobiological mechanisms, and pharmacologic treatment of MDD may
`enhancepatient care.
`In the 1950s, the discovery of the therapeutic effects of medications
`nowclassified as tricyclic antidepressants (TCAs) and monoamineoxidase
`inhibitors (MAOIs) led to more widespread treatment of depression.’
`Althoughthe antidepressant actions of the TCAs and MAOIsarelikely
`to be initiated by different mechanisms, they ultimately have a similar
`effect of increasing neurotransmitter availability in the synaptic cleft.
`The TCAsinhibit reuptake of certain neurotransmitters, particularly
`norepinephrine and,for some TCAs, serotonin. The MAOIs,in contrast,
`inhibit the metabolism of serotonin, dopamine, and norepinephrine.’
`One majorlimiting factor in the use of these 2 drug classesis their side
`effect profiles. For example, the TCAs can produce adverse cholinergic
`| and adrenergic effects, and, in excessive doses or overdoses, can cause
`seizures and potentially lethal arrhythmias.”* The MAOIs can produce
`orthostatic hypotension and edema.”!° Moreover, becauselevels of the
`A form of the enzyme MAOarehighin thegutandliver, inhibition of
`MAOrequires dietary restrictions to reduce the risk of a serious and
`potentially fatal adverse event, hypertensivecrisis.'' There was thusa clear
`motivation to develop newer, moreselective antidepressant medications,
`and, by the late 1980s, research led to the introduction of a newclass of
`antidepressants, the selective serotonin reuptake inhibitors (SSRIs). As
`comparedwiththefirst-generation antidepressants, SSRIs were found to
`be generally similarin efficacy for the treatmentofdepressed outpatients,
`with a better tolerability profile.? Moreover, the SSRIs were profoundly
`safer in overdose than the TCAs.Asa resultof these differences, the SSRIs
`rapidly supplanted the TCAs and MAOIsasthe antidepressantclass of
`first choice for both psychiatrists and primary care providers. Indeed, by
`the end ofthefirst decadeof the “SSRI first” era, primary care physicians
`were prescribing more antidepressants than psychiatrists.’
`Shortlyafterthe introduction ofthe SSRIs, anotherclass ofantidepressants
`knownas the serotonin-norepinephrine reuptake inhibitors (SNRIs)
`was introduced, As suggested by the name, these medications inhibit the
`reuptakeof norepinephrinein addition to serotonin and,as such,directly
`affect both serotonergic and noradrenergic neurotransmission. However,
`it should be noted that most of these compounds show muchgreater
`inhibition of serotonin reuptake than norepinephrine reuptake (10-fold
`
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`Pierz and Thase
`
`|
`
`
`ie|®Vilazodoneisanovelantidepressantmedicationthatmay
`
`offerclinical benefits with regard to onset of action and side
`effect profile.
`® Serotonin 1A (5-HT,,) receptors have an importantrole in
`modulating the serotonergic system.
`@ Drugsthat target 5-HT,, receptors,particularly in
`combination with inhibition of serotonin transporters, may
`be of value in the treatment of mood disorders.
`
`=
`“A
`
`|
`
`for duloxetine and 30-fold for venlafaxine), such that at
`normaltherapeutic doses, most of their activity very likely
`results from their serotonergic effects.!*!* Although notas
`widely prescribed as the SSRIs, several SNRIs are also now
`consideredtobefirst-line treatment options for MDD.It was
`proposedthat the property of dual reuptake inhibition might
`convey an efficacy advantage for the SNRIs over SSRIs’;
`however, few studies have foundlarge,statistically significant
`differences between the 2 drug classes, and meta-analyses
`generally documentrelatively small average differences
`that fall below proposed marginsofclinical relevance.!>~'®
`Moreover, no evidence of a difference in efficacy has been
`found in comparisons of venlafaxine and/or duloxetine
`versus the mostselective SSRI, escitalopram.!>!®!9 For these
`reasons,in light of the pharmacologic profile of the novel
`antidepressantvilazodone,”thisarticle focuses on alternate
`serotonergic mechanismsthat may be drawn uponto try to
`address the unmetneedsof antidepressant therapy.
`
`METHOD
`
`A PubMedsearch of all English-language articles
`from January 1990 to January 2013 was conducted using
`the search terms depression and 5-HT,,, depression and
`buspirone, depression andpindolol, and vilazodone. We found
`47 articles and abstracts that were selected for inclusion
`on the basis of information about the pharmacology of
`serotonin (5-hydroxytryptamine) 1A (5-HT,,) receptors
`and the clinical data on pindolol, buspirone, andvilazodone
`in depression.
`This review summarizes currentliterature involving
`antidepressantactivity, the role of 5-HT,, autoreceptors,
`andclinicaltrials involving serotonin reuptake inhibition in
`conjunction with 5-HT,, agonists andpartial agonists, with
`a focus on vilazodone.
`
`THE SEROTONERGIC SYSTEM
`AND MAJOR DEPRESSIVE DISORDER
`Although the discovery of the first antidepressants was
`serendipitous, developmentof the SSRI drug class resulted
`from the deliberate and concerted efforts ofscientists working
`in drug discovery. Asearly as the 1960s, hypotheses began to
`circulate about the role of serotonin in the pathophysiology
`of depression and as a target for antidepressant drugs.”
`Research on the SSRIs began in the 1970s, with zimelidine
`beingthefirst such drug to reachclinicaltrials and fluoxetine
`becomingthefirst to be approved by the US Food and Drug
`
`e2 © PrimaryCARECOMPANION.COM
`
`Administration (FDA) in 1987.2?4 The other SSRIs were
`subsequently introduced:paroxetine,sertraline,fluvoxamine,
`citalopram, andescitalopram.
`Serotonergic pathways in the brain all emanate from
`the raphe nuclei, branching out to nearly every region of
`the central nervous system (Figure 1). Serotonin plays
`an important role in many brain functions, including
`contributingto the regulation of mood,fear responses,sleep,
`appetite, and sexual behavior.”>6 Serotonergic neuronsalso
`project to the hippocampus,a region in whichthe generation
`of new neurons(“neurogenesis”) and synaptic plasticity have
`been implicated as possible factors in the development and
`treatment of MDD.”
`
`SEROTONIN BIOCHEMISTRY
`AND PHARMACOLOGY
`
`Serotonin is a monoamine neurotransmitter that is
`synthesized from the aminoacid tryptophan.Like tryptophan
`and the other aminoacids, serotonin containsa positive and
`negative charge at physiologic pH, makingit hydrophilic and
`unableto easily cross cellular membranesorthe blood-brain
`barrier. This property makes it unable to diffuse back into
`neuronsafter its release, thereby necessitating a specific
`transport mechanism for its removal from the synaptic
`cleft. Serotonergic uptake occurs through the serotonin
`transporter (SERT), an integral membraneprotein located in
`the presynaptic neuron. Thus,serotonin is transported from
`the synaptic space back into the presynapticcell from which
`it was released (Figure 2A), whereit is either repackaged
`into synaptic vesicles for subsequentre-release or degraded
`by MAO.Thetherapeutic efficacy of MAOIs is believed
`to be initiated by inhibiting the enzymatic degradation of
`serotonin, while the efficacy of the SSRIs is presumed to be
`initiated by inhibition of the SERT (Figure 2B,step 1).
`Onceserotoninis released into the synapse, it can bind
`approximately 20 different endogenousreceptor subtypes.”*”
`These receptorsfall into 7 distinct families based on their
`aminoacid sequence, drug response, andcellulareffects, In
`the serotonergic pathwaysthat originate in the raphe nuclei,
`these serotonin receptor subtypes can be found on various
`postsynaptic, non-serotonin-containing neuronsthroughout
`the brain; these receptors are known asheteroreceptors (Table
`1). A few ofthe receptors, notably subtypes 5-HT4, 5-HTjp,
`5-HT)p, and 5-HT),, are also expressed on the serotonin-
`containing raphe neurons themselves as autoreceptors, where
`they regulate further serotoninrelease. Generally, serotonin
`activation ofautoreceptorsleadsto the inhibition ofneuronal
`firing and serotonin release through negative feedback
`mechanismswithin the raphe neuron (Table 1). The 5-HT4
`receptors are the primary 5-HT autoreceptor expressed
`on the cell body and dendrites (“somatodendritic”) of the
`raphe neurons and regulate 5-HT via modulation ofaction
`potential activity. The 5-HT,, receptors are the primary
`terminal autoreceptors, expressed on the axonaltermini; they
`modulate 5-HTactivity via inhibition of 5-HT synthesis and
`release from the raphe neurons.Finally, the 5-HT, receptors
`have more recently been proposed as autoreceptors given
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`Prim Care Companion CNS Disord
`2014;16(1):doi:10.4088/PCC.131r01554
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`

`Vilazodone, Serotonin, and Major Depressive Disorder
`
`Figure 1. Serotonergic Pathways and Depression-Related Symptoms?”
`
`Striatum
`psychomotor
`
`
`
`Prefrontal cortex
`mood,suicide
`
`
` Nucleus
`
`Hypothalamus = pope
`weightloss, insomnia
`Yeni
`
`ri
`
`accumbens
`ri
`3
`fh
`2= anhedonia
`Rostral
`Amygdala
`raphe nuclei
`suicide,
`anxiety
`
`Hippocampus
`memory
`
`4
`
`Caudal
`raphe nuclei
`
`Adapted with permission from Bergeretal.”
`ball serotonin in the central nervous system is produced by neurons emanating from the raphe nuclei, which project to nearly every
`brain region. Serotonin-innervated brain structuresthatare closely associated with MDDare shownin bold,followed by MDD-
`related behavioral symptomsand physicaleffects.
`Abbreviation: MDD = major depressive disorder.
`
`apparentcross-talk with 5-HT,, receptors and modulation
`of the serotonin transporter.*° Additional investigation is
`needed to morefully understand the expression pattern and
`activity of 5-HT, autoreceptors.
`
`5-HT,, AUTORECEPTORSIN DEPRESSION
`A growing body of evidence suggests that 5-HT,,
`receptors are involved in depression and antidepressant
`activity.”* In patients with MDD,5-HT), receptor expression
`and activity are altered in raphe nuclei, hippocampus,
`and manycortical regions.*!-** The activation of 5-HT,,
`autoreceptors, through the binding of serotonin (orfull or
`partial receptor agonists), initially produces an inhibition
`of serotonin release by the neuron (Figure 2B, step 2).°°
`However,current theorypredicts that sustained, long-term
`5-HT,, receptorstimulation soon leadsto a desensitization
`and/or down-regulation of the autoreceptors so that, over
`time, serotonin release is no longer inhibited (Figure 2B,
`step 3).”° The time required for this process of inhibition
`
`followed by disinhibition of the serotonergic system may
`partially explain whyserotonergic antidepressant drugs**-**
`often require several weeks or more to achieve maximal
`symptomatic improvement.
`Initially, drugs like SSRIs and SNRIs inhibit serotonin
`reuptake through SERT, producing an increase in synaptic
`serotonin, which binds postsynaptic receptors found
`proximal to the synaptic cleft to increase serotonergic
`signaling (Figure 2B, step 1). However, the increased
`serotonin also begins to bind more distal 5-HTj,
`autoreceptors, for example, those found back on the
`raphe neuroncell bodies, which ultimately inhibit further
`neuronalfiring and result in decreased serotonin release
`(Figure 2B, step 2). Eventually, 5-HT,, autoreceptors
`desensitize or are down-regulated, removing the inhibitory
`signal and permitting synaptic serotonin levels to rise in
`the presence of sustained blockade of SERT by the SSRI
`(Figure 2B, step 3). The netresult over timeis the sustained
`increase of serotonergic neurotransmission madepossible
`
`PRIMARYCARECOMPANION.COM&]e3
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`

`Pierz and Thase
`
`PE
`
`Figure 2. Effects of SSRIs and 5-HT,, Partial Agonists on Serotonergic Transmission
`
`A. Basal Serotonergic Neurotransmission (No Drug)
`sermon
`Transporter
`Serotonin
`eow
`
`
`
`
`
`oa
`Presynaptic Celt
`
`» SHTy 9
`{Raphe Neuron)
`
`
`Receptor
`
`B. Effect of SSRI Treatment on Serotonergic Neurotransmission
`Step 1: Inhibition of Serotonin Reuptake by Serotonin Transporter
`
`
`
`2
`
`
`
`'
`
`ti Bote sit PPataa
`
`C. Effect of Vilazodone on Serotonergic Neurotransmission
`
`Vilazodone
`\
`
`(A) Serotonin released from the presynaptic cell (orange) activates 5-HT heteroreceptors, causing a biological responsein
`postsynaptic cells (indicated by +). Serotonin is removed from the synaptic cleft and other extracellular space by the serotonin
`transporter, located on the presynapticcell. In MDD,synaptic levels of serotonin are lower than in a nondepressed state.
`(B) Effect of SSRI treatment on serotonergic neurotransmission.Step 1, immediate effects: an SSRI blocks the reuptake of serotonin
`through the serotonin transporter, increasing thelevels of serotonin in the synapse and increasing the activation of nearby
`postsynaptic receptors (+). Step 2, activation of presynaptic negative feedback loop: the increase in extracellular serotonin also
`leads to stimulation of the presynaptic 5-HT 4 autoreceptors, creating a negative feedback loop (-) that decreases neuronal
`activation (indicated by a smaller yellow arrow)andserotonin release (indicated by fewer serotonin moleculesin the synapse).
`Step 3, long-term effects: the negative feedback pathwaytriggered bythe activation of 5-HT), autoreceptors attenuates over time
`following the desensitization or down-regulation of 5-HT), autoreceptors, which takes approximately a few weeks with standard
`SSRI treatment. Neuronalfiring and serotonin release are then restored, while serotonin transporter reuptake remains blocked.
`(C) Vilazodoneis both an SSRI and a 5-HT, partial agonist. As an SSRI,it blocks serotonin reuptake by the serotonin transporter
`to increase serotonin accumulation in the synapse,indirectly leading to nonspecific 5-HT receptoractivation. As a 5-HT\,
`partial agonist,it directly activates 5-HT 4 autoreceptorsas well as postsynaptic heteroreceptors and mayalso potentially hasten
`the desensitization of the 5-HT,, autoreceptors. Accordingto this theory, the faster autoreceptor desensitization maylead to a
`more rapid onset of therapeutic efficacy.
`Abbreviations: 5-HT, = serotonin 1A, MDD = major depressive disorder, SSRI = selective serotonin reuptake inhibitor.
`
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`

`
`
`Table 1. Serotonin Heteroreceptors and Autoreceptors?
`Heteroreceptors (“other” receptors)
`¢ Found on nonserotonergic neurons
`For example, neuronsthat produce andrelease glutamate
`(or another neurotransmitter) may express receptors for serotonin;
`such receptors would be classified as heteroreceptors
`¢ Includeall of the known serotonin receptor subtypes
`(including those subtypes that can also be foundas autoreceptors)
`« Mediate the broad and globaleffects of serotonin (see Figure 1)
`Autoreceptors(“self” receptors)
`«¢ Serotonin receptors located on neuronsthat produceserotonin
`(eg, neuronsofthe raphenuclei)
`« Activation of these receptors inhibits the neuron andis generally involvedin
`negative feedback loops that decrease synaptic serotonin (self-regulation)
`Exception: 5-HT autoreceptors are proposed to increase synaptic serotonin via
`inhibition of the serotonin transporter
`e 5-HT, autoreceptors: located on presynaptic cell bodies and dendrites
`Inhibit neuronalfiring, leading to decreased serotonin release
`¢ 5-HT)g and 5-HT)p autoreceptors: located on presynaptic axonal termini
`Decrease the numberof serotonin moleculesreleased by the cell
`Increase serotonin transporteractivity, leading to increased serotonin clearance
`« 5-HT, autoreceptors: proposedto also be located on presynaptic axonal termini
`Decrease serotonin transporteractivity; the downstream effect is not yet known
`Based on Carr and Lucki,”* Pytliak et al,2® and McDevitt and Neumaier.”
`
`Vilazodone, Serotonin, and Major Depressive Disorder
`
`with buspirone augmentation of SSRIs, however,
`have shown mixedresults. In patients with severe
`depression whofailed to respondto fluoxetine or
`citalopram, buspirone augmentation compared
`with placebosignificantly reduced Montgomery-
`Asberg Depression Rating Scale (MADRS)scores
`at endpoint; early onset of action was observed for
`augmentation with buspirone versus placebo in
`patients with less severe depression,but differences
`at endpoint were not significant.*” Conversely,
`buspirone combined with fluoxetine did not show
`faster onset or increased responseratesrelative to
`fluoxetine alone in patients with non-treatment-
`resistant depression.*®
`In the largest depression study conductedto date,
`the Sequenced Treatment Alternatives to Relieve
`Depression (STAR*D), buspirone augmentation was
`one of multiple second-step treatmentstrategies in
`patients whofailed to achieve remission with up to
`14 weeksofcitalopram treatment.” In this study,”
`augmentation with buspirone wasassociated with a
`30% remission rate, which was similar to the rate seen with
`sustained-release bupropion augmentation.”
`Multiple double-blind trials have shown efficacy for
`pindolol augmentation of SSRIs to both hasten onset of
`therapeutic action and/or improve symptom resolution at
`endpoint.>°°° The effectiveness of pindolol augmentation,
`however, wasnot supportedin otherstudies.°”~™ Discrepant
`results may be dueto differences between studies in regard
`to patient selection, study design, and pindolol dose.®
`Meta-analyses of pindolol augmentation studies suggest
`that the addition of pindolol to SSRI treatment waseffective
`in accelerating the onset ofclinical action, with significant
`benefits versus placebo observed in the initial weeks of
`treatment.°-°
`
`by the removal of the 5-HT), receptor-mediated negative
`feedback loop (“disinhibition”).
`Ligands that bind to 5-HT,,4 autoreceptors and
`heteroreceptors, as antagonists (which block serotonin
`activity), full agonists (which mimic serotoninactivity), or
`partial agonists (which mimic and compete with serotonin
`binding, but only produce a partial response relative to
`endogenous serotonin), have shown beneficial effects
`on depression symptoms, both clinically and in research
`situations.*>*” Buspirone, a drug used to treat generalized
`anxiety disorder, is a full agonist at presynaptic 5-HT,
`autoreceptors, where it initially inhibits both serotonin
`synthesis and neuronal firing. Buspironeis also a partial
`agonist at 5-HT,, heteroreceptors in the hippocampus and
`frontal cortex, where it can help attenuate dysfunctional
`serotonergic transmission in MDD.** Pindolol, a B-adrenergic
`receptorantagonist and a partial agonist of5-HT|, receptors,
`showssimilareffects.*>°? Both compoundshave been shown
`to enhancetheeffects of SSRIs, possibly by directly binding
`to 5-HT,, autoreceptors and hastening their desensitization
`and down-regulation (Figure 2B, step 3)???
`
`5-HT,, AGONISTS/PARTIAL AGONISTSIN
`TREATMENT OF DEPRESSION
`
`It has been hypothesized that pharmacotherapy with
`5-HT,, agonists or partial agonists alone could beeffective
`in the treatment of depression and anxiety, while avoiding
`the typical side effects of many SSRIs (eg, nausea, sexual
`dysfunction, sleep disturbances); however, the effectiveness
`of 5-HT}, agonists and partial agonists as monotherapy for
`MDDhasbeen modest, and they are primarily used only as
`augmentingagents in combination with SSRIs.*”*9
`Preliminarystudies using case reports, chart reviews, and
`open-labeltrials suggested that buspirone augmentation was
`effective in improving depression symptomsin patients who
`were refractory to SSRI treatment.**-“ Double-blind studies
`
`Prim Care Companion CNS Disord
`2014;16(1):doi:10.4088/PCC.13r01554
`
`VILAZODONE
`
`Vilazodone was approved by the FDAfor the treatment
`of MDDin January 2011. Pharmacologically, vilazodone
`increases serotoninlevels by inhibiting SERT,with additional
`partial agonist properties at 5-HT,, receptors.It has been
`hypothesized that this dual mechanism of action has the
`potential to shorten the onset of antidepressantactivity,
`decrease side effects attributed to serotonin reuptake
`inhibition (eg, sexual dysfunction), and provide enhanced
`benefits for symptomsof anxiety.*!
`Asa result of the partial agonist activity at autoreceptors,
`the desensitization or down-regulation of 5-HT),4
`autoreceptorsthat purportedly underlies the delayedefficacy
`of SSRIs is hypothesized to occur with vilazodone over a
`shorterperiod of time (Figure 2C). Studies in animal models
`supportthis hypothesis, as vilazodone appearsto desensitize
`5-HT;, autoreceptors more rapidly than conventional
`SSRIs.Additionally, vilazodone has also been shown to
`increase serotonin levels in rat cortex and hippocampusto
`an extent greater than other SSRIs, as measured by in vivo
`microdialysis.”
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`Pierz and Thase
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`Clinical Trials of Vilazodone for MDD
`The clinical efficacy of vilazodone was demonstrated
`through the results of two 8-week, phase III, randomized,
`double-blind, placebo-controlled trials*!®® in adult
`outpatients diagnosed with MDD according to DSM-IV-TR
`criteria.© In both studies, vilazodone compared with placebo
`demonstratedstatistically significant improvement on the
`primary outcome measure, change from baseline to week 8
`in MADRS”total score, as well as on the 17-item Hamilton
`Depression Rating Scale (HDRS-17)total score.”!
`In thefirst study,significant improvements in MADRS
`and HDRS-17 total scores were observedin patients treated
`with vilazodone compared with placeboas early as week 1,
`suggesting a rapid onsetof action. In the secondtrial,*! a
`significant difference in MADRStotal score for vilazodone
`compared with placebo was observed after 6 weeks of
`treatment, with a trend for improvement (P=.051) noted as
`early as week 4.
`These individual studies were not powered or designed
`to evaluate the clinical relevance of the effects at time
`points earlier than 8 weeks; however, post hoc analyses of
`the pooled data (436 vilazodone-treated and 433 placebo-
`treated patients) indicated significant treatmentdifferences
`favoring vilazodone at week 1 in MADRStotal score change
`from baseline,as well as in rates of response (defined as = 50%
`improvement on the MADRS).”
`The most commonlyreported adverse events that occurred
`with significantly (P<.05) greater incidence in vilazodone-
`treated versus placebo-treated patients were diarrhea (28.0%
`vs 9.2%, respectively), nausea (23.4% vs 5.1%, respectively),
`dizziness (8.5% vs 4.6%, respectively), insomnia (6.0% vs
`2.1%, respectively), vomiting (4.6% vs 1.2%, respectively), and
`abnormaldreams(4.1% vs 1.2%, respectively).2”73 Adherence
`to the recommended dosetitration schedule (10 mgdaily for
`1 week, increased to 20 mg daily for 1 week and 40 mg daily
`thereafter) is important to minimizegastrointestinal adverse
`events and to achieve the full recommended dose of 40 mg
`per day.
`Sexual dysfunctionis a well-recognized side effect ofsome
`antidepressant drugs. However, patients often underreport
`sexual problemswith the spontaneousadverseeventcollection
`methodsusedin traditional clinical trials. While most SSRI
`trials generally report a low incidence of sexual dysfunction
`adverse events, some studies that used specific metrics to
`evaluate sexual dysfunction have reported a significantly
`higherrate ofsexual dysfunction (up to 63% and 41% of men
`and women,respectively) associated with SSRI treatment
`compared with placebo or non-SSRI antidepressants.”*”°
`Therefore,it is important to include validated, standardized
`evaluations of sexual function in trials of drug classes that
`are knownto affect sexual functioning to ensure that this
`importantside effect is systematically assessed.
`In the phase III studies of vilazodone, sexual function
`was evaluated using validated scales; the Arizona Sexual
`Experiences Questionnaire wasusedin thefirst studyandthe
`Changesin Sexual Functioning Questionnaire was used in the
`secondstudy.*! Changesin sexualfunction,as reported using
`
`e6 @ PrimaryCARECOMPANION.COM
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`these measures, were found to be minimal over the 8-week
`treatmentperiodin the vilazodone group and were generally
`similar to placebo,” although these studies did not include
`an active SSRI comparatorand werenotspecifically designed
`to test for differences in sexual functioning.It is hypothesized
`that treatment-emergent sexual dysfunction was minimized
`due to the partial agonist activity of vilazodone at 5-HT),4
`receptors. This hypothesis is consistent with the amelioration
`of SSRI-induced sexual dysfunction observed in studies of
`coadministration of an SSRI with 5-HT,, receptorpartial
`agonists (for example, buspirone or pindolol).’””-*° Future
`clinical trials that include an active SSRI comparator would
`be necessaryto test this hypothesis.®!
`
`THE ROLE OF VILAZODONE IN CLINICAL PRACTICE
`
`The pharmacologic profile of vilazodone may address
`several unmet needs inherent in the pharmacotherapy
`of depression. First, the proposed mechanism ofaction is
`consistent with a rapid onsetof clinical efficacy, whichis
`supported by the results of the pooled analysis suggesting
`effects of vilazodone as early as week 1.°*’? Perhaps equally
`important, vilazodone mayfill the void for a serotonergic
`antidepressant that has a low incidenceofsexualsideeffects;
`it has been recommendedthat this claim be tested using a
`noninferiority trial versus placebo and including anactive
`comparator known to increase the incidence of sexual
`dysfunction.*! It also remains to be seen whetherpatients
`who develop significant sexual side effects on other SSRIs
`can bereadily switched to vilazodone, with preservation
`of response and restoration of sexual function. If such
`advantages are confirmed, it would represent a significant
`advantage over current practice, which includes either
`switching to nonserotonergic antidepressants such as
`bupropion or adding “antidotes” such as sildenafil. Another
`unmetneedfor antidepressanttherapyis better remediation
`of comorbid anxiety symptoms. Indeed, the negative impact
`of anxiety on treatment outcomefor a rangeoffirst-line and
`second-line therapies was oneofthe strongest findings in the
`STAR*Dstudy.®” Beyondthetheoretical rationale underlying
`the pharmacologiceffects of vilazodone onanxiety,clinical
`evidence has supported the efficacy of concomitant
`administration ofan SSRI and 5-HT|, receptorpartial agonist
`(ie, buspironeor pindolol) in MDD,*2+3475°°It is important
`to note, however, that the completed clinical trials were not
`specifically designed to assess onset of efficacy, sexual side
`effects, or efficacy in patients with concomitant anxiety, so
`future studies will be needed to confirm these proposed
`mechanism-based benefits. Furthermore, the interpretation
`of the onsetofclinicalefficacy is confoundedbythetitration
`schedule;significant effects that were observed at week 1 in
`oneof the clinical studies occurred at a dose ofonly 10 mg/d,
`although the recommended therapeutic dose is 40 mg/d.
`
`CONCLUSIONS
`
`Vilazodone, a novel FDA-approved antidepressant, was
`specifically designed to function both as an SSRI,by inhibiting
`SERT,andas a partial agonist at 5-HT,, receptors, similar to
`
`Prim Care Companion CNS Disord
`2014;16(1):doi:10.4088/PCC.13101554
`
`

`

`buspirone and pindolol. It has been hypothesizedthatthis dual
`mechanism ofaction may shorten the onsetofantidepressant
`activity, decrease side effects attributed to serotonin reuptake
`inhibition (eg, sexual dysfunction), and provide enhanced
`benefits for symptomsof anxiety. The efficacy ofvilazodone
`in MDDhas been demonstrated in 2 large, randomized,
`double-blind, placebo-controlledtrials,*“®in which patients
`treated with vilazodone compared with placebo-treated
`patients showedsignificant improvement after 8 weeks. In
`1 study, significant improvement compared with placebo
`was observedasearly as week1,althoughthis rapid time
`courseofefficacy remainsto be validated.If clinical studies
`corroborate the theoretical advantages attributed to its dual
`mechanism of action, vilazodone may become a unique
`treatment option with a rapid onset, minimal sexual side
`effects, and anxiolytic properties.
`
`Drug names: bupropion (Wellbutrin, Aplenzin, and others), buspirone
`(BuSpar andothers), citalopram (Celexa and others), duloxetine
`(Cymbalta), escitalopram (Lexapro and others), fluoxetine (Prozac and
`others), fluvoxamine (Luvox andothers), paroxetine (Paxil, Pexeva, and
`others), sertraline (Zoloft and others), sildenafil (Viagra and Revatio),
`venlafaxine (Effexor and others), vilazodone (Viibryd).
`Authoraffiliations: Clinical Data, Inc, New Haven, Connecticut (Dr
`Pierz), and Perelman School of Medicine, University of Pennsylvania,
`Philadelphia (Dr Thase). Dr Pierz is now with Purdue Pharma, Stamford,
`Connecticut.
`Potential conflicts ofinterest: Dr Pierz is a former employee of Forest
`Research Institute, the current sponsorofvilazodone, andof Clinical
`Data Inc, the former sponsorof vilazodone, andhas served as a
`consultant to Transgenomic Inc. Dr Thase has served as a consultant
`to or on the advisory boards of AstraZeneca, Bristol-Myers Squibb,
`Cerecor, Dey, Eli Lilly, Forest, Gerson Lehman Group, GlaxoSmithKline,
`Guidepoint Global, H. Lundbeck, MedAvante, Merck, Neuronetics,
`Novartis, Ortho McNeil, Otsuka, PamLab,Pfizer, Shire, Sunovion,
`Supernus, Takeda, and Transcept; has received grant/research support
`from Agency for Healthcare Research and Quality, Alkermes,Eli Lilly,
`Forest, GlaxoSmithKline, NationalInstitute of Mental Health, Otsuka,
`PharmaNeuroboost, Roche, and Sepracor; has served on the speakers
`bureaus of AstraZeneca,Bristol-Myers Squibb, Dey, Eli Lilly,