Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.
Many kinds of antidepressant drugs are available, but their overall effectiveness is limited (Rush, 2007). Many patients do not have a satisfactory response to available drugs, because of limited efficacy, tolerability, or both. As a result, new drug therapies for depression are always needed. Although a new drug may not necessarily be more effective on average compared with other available drugs, it might be relatively more efficacious or better tolerated for certain patients. In this article, I review the newly approved novel atypical antidepressant drug vilazodone (Viibryd™).
What Is Vilazodone?
Vilazodone has been investigated in preclinical and clinical studies as an antidepressant drug for the treatment of major depression (Dawson & Watson, 2009; Khan, 2009). Based on studies conducted in the United States (see http://clinicaltrials.gov, trials NCT00644358, NCT00683592, NCT00285376, and NCT00290914), vilazodone was approved by the U.S. Food and Drug Administration (FDA) in January 2011. Vilazodone is a phenylpiperazine chemical derivative. Other phenylpiperazine derivative drugs include the antidepressant drugs trazodone (Desyrel®) and nefazodone (Serzone®). The particular structure of vilazodone was also based on a preliminary compound that was obtained by synthetically incorporating the main structure of azapirone drugs. The prototypical azapirone drug is buspirone (Buspar®).
Buspirone is a non-benzodiazepine azapirone drug indicated for the treatment of generalized anxiety disorder. Buspirone is a partial agonist at post-synaptic serotonin-1A type (5-HT1A) receptors, modulating serotonin activity, and it has antidepressant properties at higher doses (e.g., up to 60 to 90 mg per day). It is often combined with antidepressant drugs to treat adverse sexual effects or to augment their antidepressant effects. Some controlled studies have found buspirone augmentation to be effective in treatment-resistant depression (Howland, 2010). In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the efficacy and tolerability of various antidepressant therapies were evaluated through four sequential treatment levels (Howland, 2008). During the first level of STAR*D, all patients were treated with the selective serotonin reuptake inhibitor (SSRI) drug citalopram (Celexa®). In the augmentation arm of the second level of STAR*D, non-remitters to citalopram were randomized to receive augmentation with bupropion (Wellbutrin®) or buspirone. The bupropion and buspirone groups had similar rates of remission and response. Bupropion, however, was associated with a significantly greater reduction in depression scores (from baseline to the end of Level 2) than buspirone, and it was associated with a significantly lower dropout rate due to intolerance than was buspirone.
Interest in the clinical effects of 5-HT1A receptor modulation extends to other drugs. More than a dozen beta-adrenergic receptor antagonist drugs (beta-blockers) are currently FDA approved. As a beta-blocker, pindolol (Visken®) is somewhat unusual. Under conditions of increased adrenergic (nor-epinephrine) activity, it blocks postsynaptic beta-1 and beta-2 adrenergic receptors. However, when basal levels of adrenergic activity are lower, it has weak partial agonist (partially stimulating) effects on these receptors, referred to as intrinsic sympathomimetic activity. In addition, pindolol blocks presynaptic 5HT-1A receptors, an effect that increases the presynaptic release of 5HT. Because of the usual delayed onset of effect and less-than-optimal response rates associated with antidepressant monotherapy, adding a second medication at the beginning of antidepressant treatment is one approach to induce a more rapid, efficacious, and sustained response. Because of its unique adrenergic and 5HT effects, pindolol has been used successfully to accelerate (hasten) the therapeutic effects of antidepressant drugs in placebo-controlled studies, although most controlled studies have not shown it to be very effective for treatment-resistant depression when added later in treatment for partial responders or nonresponders (Howland, 2010).
Based on the known clinical benefits of drugs that block the serotonin reuptake transporter and of drugs that influence 5-HT1A receptor activity, vilazodone was specifically designed to have dual activity as an SSRI and as a 5-HT1A receptor agonist (de Paulis, 2007). Preclinical studies have demonstrated that it does have SSRI and 5-HT1A receptor partial agonist effects, without significant effects on other neurotransmitter transporters or receptors. The pharmacology of vilazodone is therefore unique and distinct compared with other antidepressant drugs, although its mechanism of action is based on the known pharmacological and clinical effects of other SSRI drugs and 5-HT1A receptor agonist drugs.
The FDA approval of vilazodone for major depression was based on two randomized, double-blind studies. A published 8-week study involving 410 patients (ages 18 to 65) compared vilazodone and placebo (Rickels et al., 2009). Patients took vilazodone 10 mg per day for the first week, 20 mg per day for the second week, and then 40 mg per day for the remainder of the study. Based on the main outcome measure (change in the Montgomery-Asberg Depression Rating Scale [MADRS] score from beginning to end of treatment), vilazodone was significantly more effective than placebo. Secondary outcomes included response rate (defined as a 50% or greater reduction in MADRS score at Week 8) and remission rate (defined as a MADRS score of less than 10 at Week 8). Response rates for vilazodone (40.4%) and placebo (28.1%) were significantly different, but remission rates (vilazodone 23.2% versus placebo 15.6%) were not significantly different. The overall rate of treatment-emergent adverse events (TEAEs) was higher for vilazodone (80%) than for placebo (63.7%). Most adverse events were experienced as mild to moderate in severity. Dropout rates due to TEAEs were higher for vilazodone (9.3%) than for placebo (4.9%). The most commonly reported adverse events (AEs) that were significantly greater for vilazodone versus placebo were diarrhea (23.9% versus 7.3%) and nausea (18.5% versus 4.4%), but headaches were not significantly different (13.2% versus 14.2%). Rates of other AEs for vilazodone versus placebo included dizziness (7.8% versus 5%), dry mouth (6.8% versus 6.4%), fatigue (4.9% versus 3.5%), and somnolence (4.9% versus 2%). No significant differences were found between the groups with respect to sexual effects, weight changes, cardiovascular effects, or laboratory studies.
A second, unpublished 8-week study involving 481 patients (ages 18 to 70) also compared vilazodone and placebo (Khan et al., 2010). Patients took vilazodone 10 mg per day for the first week, 20 mg per day for the second week, and then 40 mg per day for the remainder of the study. Based on the main outcome measure (change in the MADRS score from beginning to end of treatment), vilazodone was significantly more effective than placebo. Response rates for vilazodone (43.7%) and placebo (30.3%) were significantly different, but remission rates (vilazodone 27.3% versus placebo 20.3%) were not significantly different. Because this study has only been presented in abstract form, information about TEAEs is limited. Most AEs in each group were described as mild to moderate in severity. Dropout rates due to TEAEs were higher for vilazodone (5%) than for placebo (1.7%). The reported AEs were said to be similar to those described in Rickels et al.’s (2009). There were no reported significant findings or differences between the groups with respect to sexual effects, weight changes, cardiovascular effects, or laboratory studies.
The effectiveness of vilazodone has been investigated in only one unpublished, 52-week, open-label study (Robinson et al., 2010). In this study, 616 patients (ages 18 to 70) were treated openly with vilazodone 10 mg per day for the first week, 20 mg per day for the second week, and then 40 mg per day for up to 50 weeks. MADRS scores improved during the course of the 52-week study. Of the original 616 patients, 313 (51%) completed 6 months, and 254 (41%) completed 52 weeks. The reasons for dropping out of the study included AEs (20%), loss to follow up (17%), withdrawal of study consent (10%), lack of efficacy (6%), and noncompliance (2%). Because this study has only been presented in abstract form, information about TEAEs is limited. Most AEs were described as mild to moderate in severity. The reported AEs were said to be similar to those described in the short-term studies; diarrhea and nausea were most common. Again, there were no reported significant findings with respect to sexual effects, weight changes, cardiovascular effects, or laboratory studies.
Clinical Use of Vilazodone
The expected therapeutic dose of vilazodone is 40 mg per day. Because diarrhea and nausea were common, patients in the studies took 10 mg per day for the first week, 20 mg per day for the second week, and then 40 mg per day. Taking it with food may be helpful for the initial nausea. The drug is also better absorbed when taken with food. As with the use of buspirone and most SSRI drugs, morning dosing is recommended to avoid insomnia. As expected from its pharmacological profile, vilazodone may be less likely to cause adverse sexual effects compared with SSRIs and certain other antidepressant drugs. However, because it has inherent SSRI effects, it is still possible that adverse sexual effects might become apparent with more widespread use in real-world practice.
Abruptly stopping vilazodone might be associated with a discontinuation syndrome similar to that of SSRIs and other serotonergic antidepressant drugs, although this phenomenon has not been systematically investigated or reported. Vilazodone has not been associated with significant weight gain, although the available data from two short-term and one long-term study are insufficient to adequately assess this. Experience with some SSRI drugs during long-term use in real-world practice has suggested a significant minority of these patients gain weight. Possible side effects of vilazodone include diarrhea, nausea, headache, dizziness, dry mouth, and sleepiness. It does not appear to have adverse cardiac effects (e.g., electrocardiogram or blood pressure changes). Animal and human studies have not identified significant toxicity, but the clinical consequences of high dose use or overdoses are not known.
Vilazodone is metabolized primarily by the cytochrome-P450-3A4 enzyme (CYP3A4) in the liver, and secondarily by the hepatic CYP2C19 and CYP2D6 enzymes. It is a significant inhibitor of CYP2C8 and a moderate inhibitor of CYP3A4/5 enzymes. Hence, there is the potential for drug-drug interactions involving drugs that are inhibitors, inducers, or substrates for these particular hepatic enzymes, and careful clinical monitoring is prudent when patients are taking vilazodone together with other medications. Vilazodone has metabolites, but their pharmacological activity has not been clearly characterized. The effect of impaired liver function or renal function on the metabolism or clearance of vilazodone is not known. As a result, it should be used cautiously (if at all) in patients with liver or kidney disease.
Based on its pharmacology, vilazodone may be effective for the treatment of anxiety disorders, but it has not been studied for these conditions. Vilazodone has not been studied in children or adolescents, nor has it been well studied in patients older than 65. There are no specific data on its safety during pregnancy, but animal studies have not suggested any risk.
Vilazodone is a novel dual-acting antidepressant drug with putative pharmacological properties that are similar to the combined use of SSRI drugs and the drug buspirone. Vilazodone does not have major efficacy advantages compared with other antidepressant drugs, although there have been no head-to-head comparisons. With the exception of sexual effects, vilazodone may have a tolerability profile more similar than not to the SSRI drugs. However, because of its unique pharmacology and relatively benign tolerability profile, it may be an appropriate alternative for patients who do not respond to or cannot tolerate currently available antidepressant drugs. Because vilazodone is a newly approved drug, nurses should become familiar with its pharmacology and clinical profile compared with other antidepressant drugs.
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- Robinson, D.S., Kadjdaz, D.K., Gallipoli, S., Whalen, H., Wamil, A. & Reed, C.R. (2010, May). A 1-year open-label study assessing the safety and tolerability of vilazodone in patients with major depressive disorder. Paper presented at the 163rd annual meeting of the American Psychiatric Association. , New Orleans, LA. .
- Rush, A.J. (2007). Limitations in efficacy of antidepressant monotherapy. Journal of Clinical Psychiatry, 68(Suppl. 10), 8–10.