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Clinical Utility of Vilazodone for the Treatment of Adults with Major Depressive Disorder and Theoretical Implications for Future Clinical Use

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Clinical Utility of Vilazodone for the Treatment of Adults with Major Depressive Disorder and Theoretical Implications for Future Clinical Use Neuropsychiatric Disease and Treatment Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Clinical utility of vilazodone for the treatment of adults with major depressive disorder and theoretical implications for future clinical use Mandeep Singh Background: Vilazodone is the latest approved antidepressant available in the United States. Thomas L Schwartz Its dual mechanism of action combines the inhibition of serotonin transporters while simultane- ously partially agonizing serotonin-1a (5-HT1A) receptors. This combined activity results in SUNY Upstate Medical University, Psychiatry Department, Syracuse, serotonin facilitation across the brain’s serotonergic pathways, which has been termed by the NY, USA authors as that of a serotonin partial agonist and reuptake inhibitor, or SPARI. Objective: The authors to review laboratory, animal model data, and human trial data to synthesize a working theory regarding the mechanism of antidepressant action of this agent and regarding its potential for additional indications. Methods: A MEDLINE and Internet search was conducted and the resultant evidence For personal use only. reviewed. Results: Vilazodone has randomized, controlled empirical data which has garnered it an approval for treating major depressive disorder. It combines two well-known pharmacodynamic mechanisms of serotonergic action into a novel agent. Although no head-to-head studies against other antidepressants are published, the efficacy data for vilazodone appears comparable to other known antidepressants, with associated gastrointestinal side effects similar to serotonin selective reuptake inhibitor and serotonin norepinephrine reuptake inhibitor antidepressants, but potentially with a lower incidence of sexual side effects and weight gain. Discussion: As a new option for the treatment of major depressive disorder, vilazodone, due to its unique SPARI mechanism of action, may hold promise for patients who cannot tolerate or have not responded to previous antidepressant monotherapies. Additionally, its use may extend to the treatment of other mental health conditions similar to those treated by serotonin selective reuptake inhibitors. Neuropsychiatric Disease and Treatment downloaded from https://www.dovepress.com/ by 54.191.40.80 on 06-Jul-2017 Keywords: major depressive disorder, vilazodone, antidepressants Introduction Vilazodone is now a US Food and Drug Administration (FDA)-approved antidepres- sant treatment (ADT). This paper will review preclinical pharmacokinetic information, pharmacodynamic information, current publicly available clinical data for this product, as well as reviewing animal models and mechanism of action data that would suggest potential use in other realms of psychiatric illness. Correspondence: Thomas L Schwartz Clinicians have been using the same catecholamine treatments for major depressive SUNY Upstate Medical University, disorder (MDD) since the 1950s, mostly by blocking reuptake transporters (dopamine, Psychiatry Department, 750 East Adams Street, Syracuse, NY 13210, USA norepinephrine, and serotonin). Originally utilizing the tricyclic antidepressants, Tel +1 315 464 3166 and in recent years, more so with serotonin selective reuptake inhibitors (SSRIs) Fax +1 315 464 3163 Email [email protected] and serotonin norepinephrine reuptake inhibitor (SNRIs). The National Institute of submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2012:8 123–130 123 Dovepress © 2012 Singh and Schwartz, publisher and licensee Dove Medical Press Ltd. This is an Open Access http://dx.doi.org/10.2147/NDT.S20683 article which permits unrestricted noncommercial use, provided the original work is properly cited. Powered by TCPDF (www.tcpdf.org) 1 / 1 Singh and Schwartz Dovepress Mental Health’s STAR*D trial suggests that remission from This makes potential efficacy and tolerability comparisons a prototypical agent of the SSRI class occurs one-third of to known ADT agents difficult. What is known about the the time with initial monotherapy in MDD patients, and each pharmacokinetics, pharmacodynamics, and clinical trial subsequent ADT yields less favorable outcomes as treat- results of vilazodone and animal models could suggest further ment resistant depression increases. After four successive applications for this novel mechanism. This information will ADTs, about two thirds of patients finally remit, but many be reviewed shortly. of these do not sustain their remission for more than a few months.1 Therefore, one third of MDD patients continue to Vilazodone pharmacokinetics have significant symptoms after treatment with a sequence According to the official FDA-sanctioned package of agents for about a year, and many of those who remit do insert,14 this drug is initially dosed at 10 mg per day in not sustain their improvement. Given these modest results, the morning for 1 week then dose escalated to 20 mg per researchers continue to investigate ways to treat MDD with day for week 2 with the final titration to the 40 mg per novel pharmacologic mechanisms. day as a usual daily dose. It comes in 10 mg, 20 mg, and In the absence of a remarkable breakthrough drug in 40 mg tablet strengths. This drug must be taken with food the area of nonmonoamine agents, ie, hormonal, peptide, or 50% of its bioavailability is lost. There are no dosing genetic, neuromodulation,2 clinicians have resorted to higher changes required in renal or hepatic patients and a gradual levels of polypharmacy to gain full remission when mono- withdrawal is suggested to avoid serotonin discontinuation therapies fail. Combination drug treatment might be being syndrome. Its moderate half-life makes withdrawal deployed earlier and earlier in treatment as an option.1,3,4 To possible, but likely with a low severity of symptoms. boost antidepressant efficacy in patients who fail to respond It is clinically contraindicated for use with monoamine adequately to a SSRI, second generation atypical antipsychot- oxidase inhibitors. Vilazodone is metabolized extensively ics are FDA-approved (aripiprazole, quetiapine, quetiapine by the hepatic CYP450 3A4 enzyme system. Its dose XR, olanzapine-fluoxetine combination), but with potential should be reduced to 20 mg/day with concomitant use of For personal use only. additional side effect burden (metabolic and movement potent 3A4 inhibitors (erythromycin, amiodarone, protease disorders) and cost.5,6 A unique mechanistic approach occurs inhibitors, ketoconazole). Vilazodone’s therapeutic activity with vilazodone, an agent that combines two mechanisms in is due primarily to the parent drug and there are no known a single drug, namely that of a SSRI with 5-HT1A receptor active metabolites. The pharmacokinetics of vilazodone partial agonist actions serotonin partial agonist reuptake (5 mg–80 mg) are dose-proportional. Steady-state is often inhibitor (SPARI).7 Specifically, this agent increases the achieved in days. Vilazodone has a terminal half-life of availability and activity of the neurotransmitter serotonin and approximately 25 hours. It is 96%–99% protein-bound so it its neuropathways. Vilazodone blocks the serotonin reuptake may disrupt digoxin- or coumadin-binding temporarily as it pump (serotonin transporter), desensitizes serotonin receptors displaces these drugs into a nonprotein-bound, free plasma (especially serotonin 1A autoreceptors), and therefore pre- state which increases their availability and activity. sumably increases serotonergic neurotransmission. Its partial Neuropsychiatric Disease and Treatment downloaded from https://www.dovepress.com/ by 54.191.40.80 on 06-Jul-2017 agonist actions at presynaptic somatodendritic 5-HT1A Vilazodone pharmacodynamics autoreceptors may theoretically enhance serotonergic activity Vilazodone is a combined serotonin reuptake inhibitor (SRI) and contribute to antidepressant actions as well.1,8,9 This par- and 5-HT1A receptor partial agonist.15 The authors use the tial agonist action also occurs at the level of the postsynaptic term SPARI to define this class of ADT.7 This mechanistic 5-HT1A receptor which may theoretically diminish sexual way of treating MDD is similar to the common depres- dysfunction.8,9 This effect has been noted in studies utilizing sion treatment strategy of augmenting SSRI monotherapy the 5-HT1A receptor partial agonist, buspirone.10 In support (fluoxetine, sertraline, paroxetine, etc) with the commer- of this theoretical information, similar animal models suggest cially available 5-HT1A receptor partial agonist anxiolytic, potential for rapid onset antidepressant efficacy, given more buspirone.16 The latter is approved for treating generalized robust serotonergic actions suggesting greater antidepressant anxiety disorder (GAD).7 In fact, the STAR*D trial has efficacy compared to SSRIs.11–13 However, these preclinical studied nonremitters to treatment with citalopram, comparing suggestions have yet to be confirmed specifically for vila- augmentation with either buspirone or with bupropion SR, zodone in human clinical trials. Currently there is a lack of finding no significant differences in remission rates between head-to-head comparative trials with other antidepressants. these two combination treatments.17 124 submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2012:8 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Dovepress Clinical use of vilazodone for MDD SRI mechanisms yield an increase in synaptic 5-HT administered early in treatment.19,20
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