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A new antidepressant

October 5, 2011
by William M. Glazer, MD
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Vilazodone (Viibryd) introduces a new and unique mechanism of action

Just when you thought that you understood how we classify the myriad of antidepressant medications available today, along comes one with a new mechanism of action. In June, Forest Labs launched Vilazodone (Viibryd), a drug that is thought to work via two mechanisms of action, one of them novel. Let's develop a context by reviewing the major classes of antidepressants currently available, as shown in Figure 1.


Figure 1: Major classes of antidepressant medications

First, there are the SSRIs (selective serotonin reuptake inhibitors), which are thought to work by increasing serotonin levels at the synapse by blocking its reuptake into the nerve terminal. Second, there are the SNRIs (serotonin-norepinephrine reuptake inhibitors), which increase both norepinephrine and serotonin levels. Third, there are the “Atypical Antidepressants,” which work in ways that we really don't yet understand.

The 5-HT1A Receptor: A target for treating behavioral disorders

Serotonin (5-HT) receptors are involved in many functions of the body and brain, including aggression, anxiety, learning, thinking, memory, mood, nausea, regulation of body temperature, and sleep. The 5-HT1A receptor is the most widespread of the 14 known serotonin receptors and is prominent in all sorts of mood/anxiety-relevant places like the cerebral cortex, hippocampus, and the amygdala.

Partial agonists of 5-HT1A receptors have been the subject of investigation for the treatment of behavioral conditions. Prior to the introduction of Vilazodone, there have been two available agents with 5-HT1A receptor partial agonist activity: buspirone (Buspar) for anxiety and aripiprazole (Abilify), an antipsychotic that has also been approved as an adjunct with antidepressants for major depressive disorder.

While Vilazodone asserts a classic selective serotonin reuptake inhibition effect, it is also a 5-HT1A receptor partial agonist.

Relevance of Vilazodone's 5-HT1A receptor partial agonist effect

In the case of the pure SSRIs, once the correct dose level is reached, it takes 10 to 14 days to work. This time lag is thought to be the result of the fact that reuptake inhibition initially feeds back to autoreceptors that shut down release of serotonin-and it takes 10 to 14 days for these autoreceptors to recalibrate.

It is thought that Vilazodone's partial 5-HT1A receptor agonist activity asserts an effect on these autoreceptors that could speed up the patient's response time.

Results of studies submitted to the FDA

ABOUT the author william m. glazer, md, is president of glazer medical solutions (www.glazmedsol.com) of key west, fla., and menemsha, mass. he is a clinician, researcher, lecturer, and consultant, and has been a member of faculty of the departments of psychiatry at the yale and harvard schools of medicine.
William M. Glazer, MD, is President of Glazer Medical Solutions of Key West, Fla., and Menemsha, Mass. He is a clinician, researcher, lecturer, and consultant, and has been a member of faculty of the departments of psychiatry at the Yale and Harvard schools of medicine.

The FDA has approved Vilazodone for the treatment of major depressive disorder. The efficacy of Vilazodone was established in two, eight-week placebo-controlled trials. The recommended dose is 40 mg/day, attained via titration, based on a recommended initial dose of 10 mg/day for seven days, followed by 20 mg/day for seven days, then 40 mg/day.

While there are as yet no studies proving that Vilazadone speeds up the antidepressant response rate, one of the two placebo-controlled studies showed a statistically greater reduction in depressive symptomatology in Vilazodone treated patients after one week.

Safety was evaluated in over 2,000 patients (aged 18 to 70) from these two studies and a 52-week, open-label study. Overall, 7.1 percent of patients who received Vilazodone discontinued treatment because of an adverse reaction, compared with 3.2 percent of placebo-treated patients in the double-blind studies.

As would be expected with drugs that alter serotonin function, the most common side effects were diarrhea, nausea, and headache. The studies indicated that Vilazodone might not have a propensity for causing weight gain and sexual side effects.

Controversy: Do antidepressants work?

Recently, articles in the public press have questioned the effectiveness of antidepressant medications in general. This discussion is complicated and is part of a trend in which themes that are usually the purview of the scientific process become politicized. Here, I want to discuss Vilazodone within the context of this controversy.

The scientific basis for the recent controversy is a recent meta-analysis by the psychologist Irving Kirsch. He selected 42 clinical trials and found that the average difference between drug and placebo was 1.8 points on the Hamilton Depression Rating Scale.