Potential use of NH neurotransmitters as novel source for psychiatric drugs

Physiologists and medical researchers have long recognized the important endocrine roles played by the pituitary hormones oxytocin (OT) and vasopressin (VP) on peripheral systems in lactation, uterine contraction and urine concentration.

Over the past few years, neuroscientists have begun reporting evidence solidifying the possible roles of OT and VP in social behavior, both normal (bonding, romance) and pathological (autism, aggression). In a recent human study, Swiss and American scientists have also reported that intranasal spray containing the hormone oxytocin increases trust between humans by reducing the anxiety of risks that arise through interpersonal interactions.

Robert Ring, a researcher with the Wyeth Discovery Neuroscience group, said that perhaps the time is right for drugmakers to take a closer look at the important roles these two substances play inside the brain. The pharmaceutical industry has been very successful in developing medicines aimed at regulating the hormonal effects of these two pituitary hormones on peripheral systems.  Pitocin, an oxytocin-like molecule, was developed and commonly used to induce contractions during birth.  Similarly, vasopressin receptors in the kidney and vascular smooth muscle have been targeted for the treatment of heart failure and other diseases.

Drug companies, however, may have “underappreciated the important roles that both the central vasopressinergic and oxytocinergic systems play in modulating neural-circuitry underlying many of the behavioral, neuroendocrine and autonomic features of psychiatric diseases,”

He noted that in the brain, oxytocin and vasopressin are not considered hormones, but act rather as “powerful neurotransmitters, regulating many of the same brain functions that are often disturbed in psychiatric disease.” Not surprisingly, drug companies relatively recently have begun to “reexamine their extensive experience with targeting the hormonal actions of these hormones and with a new eye toward central nervous system diseases,” Ring adds.

Studies point to OT role in anxiety, schizophrenia; novel treatments sought

Ring is speaking at the American Physiological Society’s 2005 Conference, “Neurohypophyseal Hormones: From genomics and physiology to disease,” plus the latest developments toward clinical applications, July 16-20 in Steamboat Springs, Colorado. 

In an effort to seek new approaches to treating psychiatric disorders, evidence is beginning to emerge “from preclinical animal models that point to the important role of oxytocin in the neurophysiology underlying anxiety and schizophrenia.”  Specific research from Wyeth, presented by Ring at the APS meeting this week, suggests that drugs might be developed to regulate OT function in the brain “as novel treatments for these debilitating psychiatric disorders. 

“The results from our studies and others, suggest that oxytocin serves as an endogenous anxiolytic substance, in addition to its well known role during birth,” Ring noted. The central vasopressin system also appears to be very important, Ring added. Drugs that act to block the effects of vasopressin on one of its receptors in the brain, the V3 or V1b receptor, are currently being developed as novel antidepressants and anxiolytics. The French pharmaceutical company, Sanofi-Synthelabo, has already begun to test the first V3 antagonist in human clinical trials for depression, Ring said.

Next? Gender-specific medicines for treating psychiatric disorders

The prevalence of psychiatric disorders often shows significant differences between the sexes. Depression, for example, is up to three times more common in women than men.  Ring noted that “there are some well-recognized differences between males and females in the organization and function of the VP and OT systems of the brain.” With this in mind, the effects of OT and VP on brain function may offer novel opportunities for psychiatric drug development.

Ring contends that “it’s reasonable to contemplate exploiting these observed sexual dimorphisms in the development of gender-specific drugs for specific psychiatric conditions.”  This may not be a crazy as it may sound.  Drugs are commonly designed and marketed specifically for treatment of pathological conditions in one sex or the other.  Ring recognizes that similar opportunities may exist in treating psychiatric disease, noting that “this could represent a potential paradigm shift in how we think about the development and marketing of future psychotropic drugs.”  This is totally consistent with a growing mantra of the drug industry which proposes to develop “the right drug for the right person.”

Robert H. Ring, Head of Molecular Neurobiology, Depression & Anxiety Disorders, Discovery Neuroscience, Wyeth Research, Princeton, New Jersey.

“The central vasopressinergic and oxytocinergic systems as targets for psychiatric drug development.”

Ring also is participating in the symposium, “Clinical utility of NH receptor analogs,” chaired by Joseph Verbalis of Georgetown University, and Maurice Manning of the Medical College of Ohio.

The other participants in the symposium are:

David P. Brooks, Vice President Biology U.S., Cardiovascular and Urogenital Drug Discovery Centre, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania

“Development of non-peptide oxytocin receptor antagonists for the treatment of preterm labor.” 

Patrice Collins, Medical Affairs, Astellas Pharmaceuticals Inc.

“Effects of a novel vasopressin V1a/V2 antagonist conivaptin on serum sodium concentration and effective water clearance in hyponatremia clinical trials.”