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A Decade of Penn Medicine Research Translates into a New Drug for Depression

Translational Research in Action

Smilow Center for Translational Research

In the spring of 2011, Penn is celebrating the opening of the Smilow Center for Translational Research – a new home for Penn Medicine's emphasis on translating breakthroughs in the lab to clinical therapies for patients. The story profiled here is just one example of such research at Penn.

See more stories in this series.

It takes a long time for a new drug to get approved for patients, usually about 10 years. Tucked away in two separate labs at the Department of Psychiatry at Penn Medicine, researchers have spent more than a decade researching and testing a new treatment for depression. The drug became the first new medicine to treat depression in more than a decade when it received FDA approval in January

The drug, vilazodone, packs a one-two punch, preventing serotonin reuptake like traditional SSRIs, as well as activating an impaired receptor, targeting the underlying pathology of depression. The drug’s mechanism was initially studied in the basic science labs at Penn, which led to clinical trials for major depressive disorder (MDD), also conducted by Penn Medicine researchers. The result: a truly translational effort, from bench to bedside.

There is a great need for effective depression treatments. Standard medicines, called selective serotonin reuptake inhibitors (SSRI), are effective but limited treatments for MDD. Impairing side effects – including weight gain, sexual dysfunction and tiredness – are the most common reason for treatment discontinuation, especially in the first month of treatment. And the cost is tremendous: Suicide is the 10th leading cause of death in the United States, and claims the lives of more than 34 thousand people each year. There are nearly twice as many suicides in the U.S. as there are homicides. Serious mental illness costs society an excess of $300 billion per year, with $193.2 billion in lost earnings alone.

Second Mechanism Raises Seratonin Levels

Eleven years ago, the Behavioral Psychopharmacology Laboratory, under the direction of Irwin Lucki, PhD, professor in Psychiatry and Pharmacology at the University of Pennsylvania School of Medicine, found that vilazodone raised serotonin levels in animal models twice as high as the conventional selective serotonin reuptake inhibitor (SSRI) fluoxetine. The reason for the increased effect of vilazodone on serotonin was its additional action, antagonizing 5-HT1A receptors, which are functionally impaired in people with depression. 

Dr. Lucki’s laboratory is one of the leading laboratories investigating the role of serotonin in the effects of antidepressant drugs. From 1996-2007, he directed a multi-investigator NIMH-supported program on the neurobiology of 5-HT1A receptors. In other tests conducted in rats and mice, vilazodone produced behavioral changes (reduced immobility and increased activity) indicating that it could be an effective antidepressant. Their original findings were pivotal in generating interest that eventually led to vilazodone advancing to clinical testing.

“This is a productive example of translational research - groups at Penn worked on the basic pharmacology and then conducted pivotal clinical trials,” said Dr. Lucki. “The results were used in the FDA evaluation and helped the drug receive approval.”

Battling Major Depressive Disorder from a New Direction

On the clinical side, Karl Rickels, MD, professor of Psychiatry and founder of the Mood and Anxiety Disorders Section at Penn Medicine, led efforts to demonstrate why a combination of antidepressant treatment mechanisms early in the course of treatment might improve outcomes. He reasoned that offering broader and more potent pharmacologic activity would increase antidepressant efficacy. His group had previously shown that SSRIs and 5-HT1A receptor partial agonists like buspirone were effective in treating MDD individually. But could they be combined?

In a multi-site placebo-controlled trial led by Dr. Rickels, the new medication vilazodone, a drug that combined activity as a SSRI and 5-HT1A receptor agonist, was shown to produce remission from major depression at rates significantly above placebo. Importantly, vilazodone was well-tolerated and did not increase reports of sexual dysfunction, the leading reason for discontinuing therapy with SSRIs. The major side effects of vilazodone were diarrhea and nausea that disappeared after a few days.

This study was one of the key positive studies used in the evaluation of vilazodone by the FDA.

The approval of vilazodone gives physicians a new medication with a basic pharmacological profile that may lead to better treatment outcomes for MDD – one of the most prevalent and costly mental illnesses, affecting up to 20 percent of individuals. Only further clinical studies will show how vilazodone will eventually compare with other medications for MDD and for potential use in treating anxiety disorders as well as patients battling both anxiety and depression. Vilazodone will be marketed as Viibryd and be available in spring, 2011. 

Stay tuned for more examples of translational research from Penn Medicine. With teams of researchers tackling diseases from multiple perspectives, we’re working to bring effective diagnostics and treatments to patients as quickly as we can. Page ME, Cryan JF, Sullivan A, Dalvi A, Saucy B, Manning DR, & Lucki I (2002). Behavioral and neurochemical effects of 5-(4-[4-(5-Cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide (EMD 68843): a combined selective inhibitor of serotonin reuptake and 5-hydroxytryptamine(1A) receptor partial agonist. The Journal of pharmacology and experimental therapeutics, 302 (3), 1220-7 PMID: 12183683

Rickels K, Athanasiou M, Robinson DS, Gibertini M, Whalen H, & Reed CR (2009). Evidence for efficacy and tolerability of vilazodone in the treatment of major depressive disorder: a randomized, double-blind, placebo-controlled trial. The Journal of clinical psychiatry, 70 (3), 326-33 PMID: 19284933

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