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Sexual Dysfunction During Treatment of Major Depressive Disorder with Vilazodone, Citalopram, Or Placebo: Results from a Phase IV Clinical Trial Anita H

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Sexual Dysfunction During Treatment of Major Depressive Disorder with Vilazodone, Citalopram, Or Placebo: Results from a Phase IV Clinical Trial Anita H 216 Original article Sexual dysfunction during treatment of major depressive disorder with vilazodone, citalopram, or placebo: results from a phase IV clinical trial Anita H. Claytona, Carl Gommollb, Dalei Chenb, Rene Nunezb and Maju Mathewsb Sexual dysfunction commonly occurs with major depressive across groups [women: 2.35 (citalopram) to 4.52 disorder (MDD). Vilazodone, a selective serotonin reuptake (vilazodone 40 mg); men 2.83 (vilazodone 40 mg) to 6.43 inhibitor and 5-HT1A receptor partial agonist antidepressant (placebo)]. Across treatment groups, baseline sexual approved for the treatment of MDD in adults, was evaluated function improved in women and men, MDD responders, to determine its effects on sexual function. The primary and patients with baseline sexual dysfunction. Int Clin study was a double-blind, randomized, controlled trial Psychopharmacol 30:216–223 Copyright © 2015 comparing vilazodone 20 and 40 mg/day with placebo; Wolters Kluwer Health, Inc. All rights reserved. citalopram 40 mg/day was an active control (NCT01473381; International Clinical Psychopharmacology 2015, 30:216–223 http://www.clinicaltrials.gov). Post-hoc analyses evaluated change from baseline to week 10 on the Changes in Sexual Keywords: antidepressant, Changes in Sexual Functioning Questionnaire, post-hoc analyses, selective serotonin reuptake inhibitor, sexual dysfunction, Functioning Questionnaire (CSFQ); no inferential statistics vilazodone were performed. CSFQ scores increased for women [1.2 aDepartment of Psychiatry and Neurobehavioral Sciences, University of Virginia, (citalopram) to 3.0 (vilazodone 40 mg)] and men [1.2 Charlottesville, Virginia and bForest Research Institute, Jersey City, New Jersey, (vilazodone 40 mg) to 3.5 (placebo)] in all treatment groups. USA Greater changes in CSFQ scores were seen in responders Correspondence to Anita H. Clayton, MD, Department of Psychiatry and [women: 2.33 (citalopram) to 5.06 (vilazodone 40 mg); men: Neurobehavioral Sciences, University of Virginia, 2955 Ivy Rd Northridge, Suite 210, Charlottesville, VA 22903, USA 2.26 (vilazodone 40 mg) to 4.35 (placebo)] versus Tel: + 1 434 243 4646; fax: + 1 434 243 4743; nonresponders. CSFQ change from baseline was small for e-mail: [email protected] patients with normal baseline sexual function; in patients Received 14 November 2014 Accepted 26 February 2015 with baseline sexual dysfunction, CSFQ scores improved Introduction sildenafil, tadalafil). Successful management of the Sexual dysfunction and major depressive disorder complex interrelationship between sexual dysfunction, (MDD) appear to have a bidirectional relationship, depression, and antidepressant therapy is needed to (Atlantis and Sullivan, 2012) with sexual dysfunction improve clinical outcomes. increasing the risk of depression, and depression and its treatment frequently being cited as causes of sexual Vilazodone is an SSRI and 5-HT1A receptor partial ago- dysfunction. Up to 60% of patients treated with selective nist approved by the US Food and Drug Administration serotonin reuptake inhibitors (SSRIs) report some sexual for the treatment of MDD in adults. The efficacy of dysfunction (Kennedy and Rizvi, 2009). A leading cause vilazodone 40 mg/day was established in two short-term, of nonadherence to antidepressants, (Ashton et al., 2005) double-blind, placebo-controlled phase III trials sexual dysfunction is considered by patients to be one of (NCT00285376 and NCT00683592) (Rickels et al., 2009; the most unacceptable side effects of SSRI treatment Khan et al., 2011). In both studies, significantly greater (Hu et al., 2004). Strategies to improve sexual function improvement was seen for vilazodone 40 mg/day versus during antidepressant treatment include lowering drug placebo on the primary efficacy parameter, mean change dosage, switching to a new antidepressant from the same from baseline to week 8 in Montgomery–Åsberg or a different class, or adding a new agent such as bus- Depression Rating Scale (MADRS) total score pirone (a 5-HT1A partial agonist), bupropion (a (Montgomery and Asberg, 1979). Safety and tolerability norepinephrine-dopamine reuptake inhibitor), or a findings were supported in a 1-year, open-label trial of cGMP-specific phosphodiesterase type 5 inhibitor (e.g. vilazodone 40 mg/day (NCT00644358) (Robinson et al., 2011). In these three studies, sexual functioning was assessed by the Changes in Sexual Functioning This is an open-access article distributed under the terms of the Creative Questionnaire (CSFQ) (Clayton et al., 1997) or the Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work Arizona Sexual Experience Scale (Mcgahuey et al., 2000). cannot be changed in any way or used commercially. Prospectively defined outcomes in these studies showed 0268-1315 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/YIC.0000000000000075 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Sexual dysfunction during MDD treatment Clayton et al.217 that treatment with vilazodone 40 mg/day was associated (1 : 1:1 : 1) to placebo, vilazodone 20 mg/day, vilazodone with improvement from baseline in sexual function and 40 mg/day, or citalopram 40 mg/day. The MADRS was limited adverse impact on sexual function relative to administered at screening and weeks 0 (baseline), 1, 2, 4, placebo (Clayton et al., 2013). In addition, in preclinical 6, 8, and 10. The CSFQ was a protocol-specified outcome studies in rodent models, vilazodone, unlike the SSRIs measure that was administered at weeks 0, 4, 8, and 10; citalopram and paroxetine, was not associated with sexual CSFQ total score mean change from baseline to week 10 dysfunction in male rats (i.e. ejaculation frequency and/or was analyzed using a mixed-effects model for repeated copulatory efficiency) (Oosting et al., 2013). measures. CSFQ analyses were based on the CSFQ analysis population (patients with baseline and ≥ 1 In a recent phase IV study (NCT01473381; http://www.clin postbaseline CSFQ assessment); safety analyses were icaltrials.gov)(Mathewset al., 2015), the efficacy, safety, and based on the safety population (all randomized patients tolerability of vilazodone 20 and 40 mg/day versus placebo who received ≥ 1 dose of double-blind study drug). were evaluated in patients with MDD; the SSRI citalopram was included as an active control for assay sensitivity. Mean change in MADRS total score from baseline at week 10, the primary efficacy parameter, was significantly greater in Patient selection vilazodone 20 mg/day (P = 0.0073) and 40 mg/day Adult male and female outpatients (18–70 years of age, (P = 0.0034) patients versus placebo patients; citalopram inclusive) who met Diagnostic and Statistical Manual of Mental patients also had a significantly (P = 0.0020) greater decrease Disorders, 4th ed., text revision (DSM-IV-TR) (American in MADRS total score compared with placebo. Both vila- Psychiatric Association, 2000) criteria for MDD, with an zodone doses and citalopram were generally well tolerated. ongoing major depressive episode of at least 8 weeks and up The effect of vilazodone on sexual functioning was pro- to 12 months and a MADRS total score at least 26 were spectively measured by CSFQ mean score change from included. Key exclusion criteria included DSM-IV-TR- baseline to week 10. The CSFQ is a 14-item self-report defined axis I disorder other than MDD, suicide risk, and scalecomprisingdifferentdomains that evaluate various nonresponse to at least two antidepressants after adequate phases of the sexual cycle; the CSFQ is frequently used to treatment trials. Use of psychoactive drugs or required measure changes in sexual function related to the effects of concomitant treatment with certain medications was pro- antidepressant treatment, with lower scores indicating worse hibited; eszopiclone, zopiclone, zaleplon, zolpidem, or zol- sexual functioning (Clayton et al., 2014). Results from the pidem extended release were allowed for insomnia. prospective analyses indicated improved sexual functioning in each treatment group, with no statistically significant between-group differences. Post-hoc analyses of sexual function and depression Post-hoc analyses of CSFQ data from the phase IV study Post-hoc analyses evaluated CSFQ mean score change conducted from December 2011 through March 2013 from baseline to week 10 in male and female patient were used to further characterize the effects of vilazodone subgroups; relative to MADRS response status (MADRS ≥ on sexual function in adult patients with MDD. Analyses response was defined as 50% improvement from base- were conducted on patient subgroups to evaluate men line to end of treatment using the last observation carried and women, patients with normal sexual function and forward approach); and in patients with and without baseline sexual dysfunction, and MADRS responders baseline sexual dysfunction. CSFQ subscales evaluated versus nonresponders. Analysis of CFSQ domains allowed five domains and three phases of sexual function plus for sex-specific evaluation of the different phases of the satisfaction: pleasure, desire/frequency, desire/interest, sexual cycle. Because citalopram was included as an active arousal, and orgasm. CSFQ total scores range from 14 to control, the effects of this SSRI on sexual function were 70, with baseline sexual dysfunction defined as CSFQ noted; however, the study was not powered to make total score
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