In January 2011, the FDA approved vilazodone for the treatment of major depressive disorder (MDD) (Table 1).
Vilazodone was discovered by Merck KGaA in Germany.1 In February 2001, Merck KGaA licensed vilazodone to GlaxoSmithKline. In April 2003, GlaxoSmithKline returned all rights to Merck KGaA because phase IIb clinical data did not support progression to phase III clinical trials. In September 2004, Genaissance Pharmaceuticals Inc. acquired an exclusive worldwide license from Merck KGaA to develop and commercialize vilazodone for depression treatment.2 Subsequently, Clinical Data Inc. acquired Genaissance Pharmaceuticals Inc., including vilazodone, and proceeded with 2 phase III trials and a large safety trial resulting in FDA approval. In February 2011, Forest Laboratories Inc. acquired Clinical Data Inc. and will launch vilazodone in second quarter of 2011.
Table 1
Vilazodone: Fast facts
| Brand name: Viibryd |
| Class: Serotonin reuptake inhibitor and 5-HT1A receptor partial agonist |
| Indication: Major depressive disorder |
| Approval date: January 24, 2011 |
| Availability date: Second quarter of 2011 |
| Manufacturer: Forest Laboratories Inc. |
| Dosage forms: 10 mg, 20 mg, and 40 mg tablets |
| Starting dose: 10 mg/d |
| Target dose: 40 mg/d |
How it works
Similar to all antidepressants, vilazodone’s mechanism of action is not fully understood, but is thought to be related to its inhibition of serotonin (ie, 5-HT) reuptake and partial agonism of 5-HT1A receptors.3 Vilazodone technically is not a selective serotonin reuptake inhibitor (SSRI) because it has greater affinity for the 5-HT1A receptor (0.2nM) than it does for the 5-HT reuptake pump (0.5nM).4
Vilazodone was developed based on the theory that inhibition of 5-HT1A autoreceptor inhibition was responsible for SSRIs’ delayed (approximately 2 weeks) onset of antidepressant efficacy. Briefly, this theory is as follows: In humans, 5-HT1A receptors are primarily presynaptic in the raphe nuclei and postsynaptic 5-HT1A receptors predominate in the neocortex and limbic regions of the brain.5 Presynaptically, 5-HT1A are autoreceptors, ie, serotonin stimulation of these receptors results in inhibition of firing of 5-HT neurons, while postsynaptically they may be involved in downstream serotonergic effects such as sexual function.5 SSRIs are thought to work as antidepressants by increasing 5-HT concentration in the synapse but their initial effect is to turn off 5-HT neuronal firing as a result of increased concentration of 5-HT at the presynaptic 5-HT1A autoreceptor. Subsequently, these 5-HT1A autoreceptors subsensitize such that 5-HT neuronal firing rate returns to normal. The time course for this subsensitization parallels the onset of SSRI antidepressant efficacy. For several years, efforts have been made to antagonize the 5-HT1A presynaptic autoreceptors as a means of potentially shortening SSRIs’ onset of efficacy.6-8
Pharmacokinetics
Vilazodone is absorbed in the gastrointestinal tract and reaches peak concentration at a median of 4 to 5 hours. Its bioavailability increases when taken with food such that Cmax (maximum concentration) is increased by 147% to 160%, and area under the curve is increased by 64% to 85%. Its absolute bioavailability in the presence of food is 72%.4 In systemic circulation, the drug is 96% to 99% protein-bound.3 Vilazodone is eliminated primarily through cytochrome P450 (CYP) 3A4 metabolism in the liver.3
Terminal half-life of vilazodone is 25 hours. In general, steady state is achieved in 4 to 5 times the half-life at a stable dose. However, dosing guidelines for vilazodone recommend titration over 2 weeks to achieve a target of 40 mg/d. Thus, steady state will not be achieved until the patient has been on the stable target dose for approximately 2.5 weeks.3
Efficacy
Vilazodone’ efficacy for MDD treatment was established in 2 pivotal 8-week, randomized, double-blind, placebo-controlled, but not active-controlled, trials (Table 2).9-11 Study participants were outpatients age 18 to 65 who met DSM-IV-TR criteria for MDD. Patients were required to have a 17-item Hamilton Rating Scale for Depression (HAM-D-17) score >22 and a HAM-D-17 item 1 (depressed mood) score >2.
In the first clinical trial, 410 patients were randomly assigned to vilazodone or placebo. In the vilazodone group, patients were started on 10 mg/d for 1 week, titrated to 20 mg/d for a second week, and then 40 mg/d for the remainder of the study. At week 8, the mean change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS), HAM-D-17, Clinical Global Impression-Improvement scale (CGI-I), Clinical Global Impression-Severity scale (CGI-S), and Hamilton Anxiety scale (HAM-A) was statistically greater with vilazodone than placebo (P <.05).9 Compared with placebo, vilazodone-treated patients showed a statistically significant (P <. 05) improvement in MADRS and HAM-D-17 scores at week 1. Approximately 12% more vilazodone-treated patients achieved response (defined as ≥50% decrease in total score at end of treatment) on the primary efficacy measure, which was MADRS (40.4% vs 28.1%, P=.007), and the 2 secondary efficacy measures, which were HAM-D-17 (44.4% vs 32.7%, P =.011) and CGI-I (48.0 vs 32.7, P =.001). Remission rates (MADRS <10) were not reported in this study, but the authors stated that there was no statistical difference in remission rates between the vilazodone and placebo groups.9