Evidence for Efficacy and Tolerability of Vilazodone in the Treatment of Major Depressive Disorder:  A Randomized, Double-Blind, Placebo-Controlled Trial

Background:  There is a desire to fulfill an unmet therapeutic need for a novel antidepressant agent.

Objective:  The objective of the study was to assess the efficacy and tolerability of vilazodone in adult patients with major depressive disorder (MDD).

Methods:  This study was a randomized, double-blind, placebo-controlled, multicenter, 8-week trial.  The study involved patients from 10 investigative sites comprising 18 main and satellite sites in the United States.  Inclusion criteria were adult patients, ages 18 to 65, with a MDD diagnosis based on DSM-IV guidelines (single or recurrent episode), and the duration of their current episode was at least 4 weeks and no longer than 2 years.  Patients were required to have a HAM-D-17 score of at ≥ 22 and a HAM-D-17 item 1 (depressed mood) score ≥ 2.  Exclusion criteria involved the following:  current Axis I disorder or within 6 months (GAD, social/simple phobias allowed), history of schizophrenia, schizoaffective disorder, bipolar I/II, substance abuse within 3 months, substance dependence within 6 months, MDD with psychotic features, postpartum onset or seasonal pattern of MDD, current psychotherapy or within 12 weeks of screening, serious suicidal/homicidal risk, previous suicide attempt, inadequate response to at least 2 consecutive antidepressants from different classes given at an adequate dose for adequate time, ECT, patients taking psychotropic drugs and/or migraine meds with serotonergic MOA; known hypersensitivity to an SSRI of 5-HT1A agonist, history of clinically significant cardiac, renal, neurologic, cerebrovascular, hepatic, hematologic, metabolic, or pulmonary disease, Sicca syndrome, taken an investigational drug or participated in drug trial in past 30 days.  410 patients underwent randomization.  205 patients were enrolled in each study group.  Patients received either placebo or a vilazodone titration.  Vilazodone 10mg tablets were given for the first 7 days, then the dose was increased to two 10mg tablets for the next seven days.  Patients who experienced side effects at 20mg could stay at that dose.  Others were increased to taking two 20mg tablets daily for the remainder of the study.  Patients with intolerable side effects at the 40mg dose could decrease back to 20mg daily and remain at this dose for the remainder of the study.  The primary outcome measure was mean change from baseline to week 8 on the MADRS (Montgomery-Asberg Depression Rating Scale) total score.  Secondary Measures were response, defined as a ≥ 50% decrease in total score from baseline to week 8 on the MADRS and HAM-D-17 total scores, or a score of 1 or 2 on the CGI-I at week 8.  A power greater than 90% was targeted in the study, and an intent-to-treat method was used.

Results:  397 patients were included in the intent-to-treat population, 198 and 199 patients in the vilazodone and placebo groups, respectively.  From baseline to week 8, the mean change in MADRS score was greater with vilazodone compared to placebo (95% CI, -12.9 vs. -9.6, p=0.001).  Mean change from baseline to week 8 on the HAM-D-17 score was greater in the vilazodone group (95% CI, -10.4 vs. -8.6, p=0.022), and the mean change from baseline to week 8 on the CGI-S showed greater improvement in the vilazodone group (95% CI, -1.4 vs. -1.0, p=0.001).  The mean CGI-I score was significantly improved in the vilazodone group (95% CI, 3.0 vs. 2.6, p=0.001).  Reductions in the HAM-A total score were greater in the vilazodone group (95% CI, -6.6 vs. -5.1, p=0.045).  The author’s concluded that vilazodone was found to produce a statistically and clinically significant reduction in depressive symptoms during short-term treatment of MDD in adults.  They feel as though consistent responses across multiple rating scales supports the efficacy of vilazodone.  The author’s concluded vilazodone to be safe and generally well-tolerated, and it may offer an effective treatment option for use in depressive disorders and possibly those associated with anxiety.

Strengths:  Consistent blinding, standardization of adverse event terms, a high power, and a consistency of response across multiple depression rating scales act as positive study assets.

Weaknesses:  Inequalities in baseline demographics, an unspecified length of washout period, patient ability to control dosing, length of study, high number of dropouts, neglecting to address compliance, extent of exclusion criteria, and a lack of meeting predefined secondary outcome measures act as limitations within the study.

Conclusion:  Vilazodone displayed efficacy and tolerability that was similar to other antidepressants used to treat MDD.  Vilazodone seems as though it would be a successful antidepressant agent in the trial population.  However, the trial population is very limited in nature due to a very extensive exclusion population.  Further studies are needed to determine the true efficacy and safety in a more broad patient population.  Also, longer studies are needed in order to address topics such as remission rates, weight gain, and sexual dysfunction.  Although targets for secondary endpoints were significantly different for vilazodone compared to placebo, the study did not reach its true secondary endpoint of a 50% decrease in total scores on the MADRS and HAM-D-17 rating scales.  Furthermore, there were several significant differences in the treatment groups at baseline.  It is possible that these differences could have influenced study results.  In further studies, a definite washout period should be specified for individual drugs based upon half-life and current practice titration guidelines.  Vilazodone appears to be a an effective treatment option for MDD, and it may, upon further study, show that it can have an even greater effect on MDD accompanied by anxiety due to its dual mechanism of action.

Rickels K, Athanasiou M, Robinson D, Gibertini M, Whalen H, and Reed CR.  Evidence for Efficacy and Tolerability of Vilazodone in the Treatment of Major Depressive Disorder:  A Randomized, Double-Blind, Placebo-Controlled Trial.  Journal of Clinical Psychiatry.  2009;70:326-33.

Bradley Evans
PharmD. Candidate