Vilazodone: A landmark antidepressant approval or another “me-too” drug?

Major depressive disorder (MDD) is defined as a debilitating and chronic psychiatric disorder that is generally characterized by mood symptoms (e.g., depressed or sad mood), cognitive symptoms (e.g., inability to concentrate or difficulty with decision-making), and physical symptoms (e.g., lethargy, fatigue, insomnia) that has the potential to significantly impact quality of life, the performance of activities of daily living, and day to day functioning.¹ If left untreated, MDD may lead to detrimental outcomes.²³ The cost of this disabling condition is considerable, both on an individual (e.g., reduced quality of life), and on a societal level (e.g., lost productivity).⁴⁵ While the current pharmaceutical market is saturated with many antidepressants, most people do not achieve an adequate treatment response with initial antidepressant therapy. This was demonstrated in the four-phase Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which examined the use of the selective serotonin reuptake inhibitor citalopram for 12 weeks.⁶ The initial remission rates on step one of the STAR*D study with citalopram alone were 36.8% which decreased after each round of either augmentation or switching medications. The participants of the study that did not achieve remission were asked to participate in the second phase of the trial of augmentation or replacement therapy. In step 2, an additional 30.6% of patients remitted. At step 3, 13.7% remitted, and after step 4, 13% went into remission. After four different regimens, the cumulative remission rate was 67%. The group that did not remit until after four treatments experienced the highest relapse rates. Only 4% remained well during the follow-up. Relapse rates were lowest among those who went into remission during the earlier phases of the study.⁶ The STAR*D study indicated that combination therapy or multiple antidepressant trials might be needed to achieve remission in many patients.⁷⁸ The selective serotonin reuptake inhibitors (SSRIs) are considered first line treatment in MDD due to their efficacy, tolerable side effect profile and low risk of fatality with overdose.⁸ SSRIs generally take 3–4 weeks or more to achieve therapeutic effect. According to Celeda and colleagues, the ongoing proposal has been for the availability of an antidepressant that is able to overcome the adaptive mechanisms that can delay the therapeutic onset of antidepressant activity to yield a quicker onset of action.⁷⁸ This proposal lead to the Food and Drug Administration approval of vilazodone (Viibryd) in January 2011.⁶⁷⁸

PHARMACODYNAMICS AND PHARMACOKINETICS

Vilazodone is a novel antidepressant that is placed under the pharmacologic category of an SSRI and Serotonin 1A (5HT-1A) receptor partial agonist which is indicated for the treatment of MDD in adults.⁹ Vilazodone has little to no effect on norepinephrine or dopamine.¹⁰¹¹¹²

The absorption of vilazodone is significantly dependent on food, as taking the drug under fasting conditions can reduce its plasma level by 50% compared to the postprandial condition.¹²¹³ It undergoes extensive hepatic metabolism primarily via cytochrome P450 (CYP) 3A4, with a minor pathway via CYP 2D6, as well as non-CYP-mediated metabolism (possibly by carboxylase).¹³¹⁴ The elimination of vilazodone is primarily via hepatic metabolism with a mean elimination half-life of about 25 hours. The pharmacokinetic properties of vilazodone have not been extensively evaluated in patients with severe renal or hepatic impairment. Dosage adjustment is not required in patients with renal impairment, and a specific dosage adjustment has not been recommended for those with severe hepatic impairments based on the lack of available studies in this population.14.¹⁵ The recommended starting dose of vilazodone is 10mg once daily to be taken with food for seven days, then 20mg daily for seven days, then 40mg once daily thereafter.¹¹¹⁴¹⁵ Higher doses of vilazodone have not been assessed for safety and efficacy.¹⁵¹⁷

CLINICAL TRIALS WITH VILAZODONE

The approval of vilazodone was based on its efficacy being shown in two 8-week randomized, double-blind, placebo-controlled studies in adults with MDD. In these two studies combined, study participants were randomized to vilazodone (titrated up to 40mg daily over 2 weeks; n=435) or placebo (n=433).¹⁸ Both studies evidenced efficacy for vilazodone as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). The number needed to treat for response vs. placebo was 8 (95% CI 6–16) and for remission was 14 (95% CI 8–55). The primary end-point of a significant change from baseline at 8 weeks in the MADRS total score was compared to placebo (P=0.001).¹⁸ The least squares mean difference from placebo were −3.2 (95% confidence interval [CI], −5.2 to −1.3) for Study 1 and −2.5 (95% CI −4.4 to 0.6) for Study 2 with a statistically significant difference being observed at week 1. In addition, in both studies, vilazodone produced a clinically significant improvement in MADRS total scores in patients with a first episode MDD ((Least Squares Mean treatment difference vs. placebo, −2.1; p = not significant [n = 277]).]). The most commonly identified side effects were nausea and diarrhea which were generally mild to moderate, with occurrence most common in the first week and duration of 4–5 days.¹⁹ Overall, the studies indicate that 7.1% of patients discontinued participation in the clinical trials on vilazodone compared to 3.2% of placebo patients.⁹ The most commonly encountered adverse effects (incidence ≥ 5% and at least twice the rate of placebo) were diarrhea, nausea, vomiting and insomnia, with number needed to harm (NNH) values vs. placebo of 6 (95% CI 5–8), 6 (95% CI 5–8), 30 (95% CI 18–82) and 26 (95% CI 16–78), respectively. NNH vs. placebo for any sexual adverse effect was 12 (95% CI 9–18), but systematically collected data using rating scales of sexual function did not reveal treatment associated effects.²⁰

To date, vilazodone is only indicated for the treatment of MDD in adults.²⁰ In addition, vilazodone 40mg once daily demonstrated an improvement in depressive symptoms in a long-term, 52 week, non-comparative, phase III study. Based on a double blind randomized, placebo-controlled crossover study in 10 healthy male subjects, an assessment was performed on the effect of 20 mg vilazodone on sleep electroencephalography.²¹ Reduction in rapid eye movement as well as changes in slow wave sleep and wakefulness through central activation were observed.²¹

As it currently stands, the primary indication for vilazodone is treatment of MDD in adults; due to its unique mechanism of action, this may also show promise in patients who cannot tolerate or do not respond to previous trials of antidepressants. There are currently no comparative efficacy studies available, and therefore, this is a theoretical proposal. In the future, the use of vilazodone may extend to the treatment of other mental health disorders that are similar to those that are treated by selective serotonin reuptake inhibitors.²² Other agents with serotonin reuptake inhibition and 5HT-1A agonism also carry approved indications for generalized anxiety disorder (GAD), obsessive compulsive disorder, social anxiety disorder, posttraumatic stress disorder (PTSD), eating disorders, and premenstrual disorders. It is conceptually feasible that vilazodone's pharmacodynamic mechanism may also prove to be useful in alleviating the symptoms that can be associated with these disorders.²²²³²⁴

ONGOING RESEARCH

Presently, there are clinical trials that are undergoing recruitment for participants to evaluate the safety, efficacy, and tolerability of vilazodone for GAD in comparison to placebo, a double-blind placebo-controlled randomized trial of vilazodone for PTSD, a double-blind study of vilazodone for the treatment of social anxiety disorder, and the efficacy of vilazodone for reducing marijuana use in marijuana-dependent adults. Any one of these studies has the potential to produce an additional indication for the use of vilazodone based on the study's outcome, thus promoting the increased use of this newer antidepressant.²⁵ Table 1 describes the detailed information related to each ongoing vilazodone trial.

Table 1: Ongoing vilazodone randomized clinical trials

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Table 1:

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There are currently no available studies in which vilazodone has been studied in these other conditions and therefore there is the chance that it may not be effective in these conditions. Another observable advantage to vilazodone is the cost, which is the same for all strengths (10mg, 20mg, and 40mg) at $5.52 per dose or approximately $165.86 per month.²⁵²⁶²⁷ The number needed to treat for vilazodone is 8 and with its cost of $5.52/day to treat, it would cost $44.16/day (over $16,000/year) to have an additional responder vs. placebo.

The cost of vilazodone is somewhat comparable to the brand versions of two prominent antidepressants on the market, compared to Prozac (fluoxetine) which is priced at $8.22 per dose (10mg), $8.44 per dose (50mg), and $16.88 per dose (40mg), and Paxil (paroxetine) which is priced at $4.88 per dose (10mg), $5.09 per dose (20mg), $5.24 per dose (30mg), and $5.55 per dose (40mg). A current disadvantage with vilazodone is the lack of a generic equivalent on the market which may offer cost savings that are already available with generic versions of other antidepressants.²⁶²⁷ The generic versions of the SSRIs are usually much cheaper and are often included on discount drug lists that are offered by many chain pharmacies.

Vilazodone serves as an alternative antidepressant for those who may not respond to other antidepressant treatments. While the combined 5-HT reuptake inhibition and 5-HT1A receptor partial activity of vilazodone is presumed to yield more rapid and specific desensitization of the somatodendric 5HT-1A autoreceptor, leading to a quicker onset of action, this has not been evaluated in comparative research with other antidepressants.²²²⁷ In a current market filled with various antidepressant classes, vilazodone appears to offer a different and alternative mechanism of action to assist with providing remission of depressive symptoms. Since up to 50% of patients may not respond to initial pharmacotherapy, they may achieve some benefit from another agent that does not belong to the same therapeutic class.²⁷²⁸ While some patients may have an enhanced response due to the unique mechanism of action of vilazodone, it has not been compared with existing therapies on the market which may have lower costs to patients.