Lehigh University
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Better mental health with fewer side effects

Neal Simon, professor of biological sciences, is developing a new class of antidepressants.

The blues. The dumps. Melancholy. Moodiness. Depression wears many names and approximately 15 million faces in the United States, according to the National Institute of Mental Health. An additional 20 million American adults live with anxiety disorders, such as post-traumatic stress disorder, generalized anxiety disorder, and various phobias.

"These are very, very serious health problems," says Neal Simon, professor of biological sciences. "The number of people affected is large and growing. There is substantial impact on quality of life and family relationships, and productivity is lost."

Recent studies estimate that the economic burden of these disorders exceeds $150 billion a year, he adds.

The dominant class of pharmaceuticals for treating depressive disorders is Selective Serotonin Reuptake Inhibitors, which includes Prozac and Lexapro. These drugs, developed in the 1980s, cause several undesirable side effects such as a reduced sex drive.

"You can probably live with (the loss of libido) if the drug were effectively treating the disease," Simon says. However, "close to half the people who are given these drugs don’t respond to them clinically."

Those suffering from anxiety disorders receive slightly different drugs with similar mixed results.

"Given the number of people who suffer from these disorders, there really is a pressing need for new pharmaceuticals with a different mechanism of action," he says.

Simon founded Azevan Pharmaceuticals in 1999 to develop a potentially new class of antidepressants. For his work, he recently received a highly competitive Rapid Access to Interventional Development (RAID) award from the National Institutes of Health. RAID provides resources and experts to faculty members and small companies producing promising therapeutic drugs, such as Azevan’s.

The pharmaceutical prevents brain cells from responding to the peptide hormone vasopressin. In the kidneys, vasopressin reduces urine production, earning it the nickname antidiuretic hormone. The brain also secretes vasopressin as a response to chronic stress. This overabundance of vasopressin may lead to depression and anxiety. So, Simon’s team is testing four promising chemical compounds that prevent nerve cells from absorbing excess vasopressin.

"When we give animals these compounds, we see behaviors that are characteristic of depression and anxiety reversed," Simon says.

One of the compounds has already passed initial safety trials, the first of three trial phases necessary for drug approval. Next, Azevan must demonstrate that the drug effectively treats anxiety or depression before it can be tested in larger numbers of patients.

"We’ve been very fortunate," Simon says. "The fact that we are successfully in the clinic with a candidate molecule and that there are other clinical candidates in the pipeline means that our hit rate for producing potential therapeutics has been quite high—it’s very promising."

Aside from his interest in vasopressin, Simon is also studying dehydroepiandrosterone (DHEA), a major hormone produced by the adrenal gland. People taking supplemental DHEA for its reputed anti-aging properties noticed that the hormone also has mild antidepressant effects.

Simon has found that DHEA influences the expression of orexin, a peptide associated with improved appetite, energy use, sleep quality, and libido.

"You can see how people might have an improved sense of well-being," he says. "To the best of our knowledge, it’s the first identification of a molecular basis for some of the claimed therapeutic benefits of DHEA."

Simon hopes that this discovery may also lead to more antidepressant treatments.

Photography by Nick Ruechel

Story by Becky Straw

Posted on Friday, September 18, 2009

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