A team of investigators led by two-time NARSAD Distinguished Investigator Grantee René Hen, Ph.D., of Columbia University, and including 2010 NARSAD Young Investigator Grantee Denis J. David, Ph.D., in the lab of Alain Gardier, Ph.D., Pharm.D., University of Paris-Sud in France, report important progress on development of a medication that may rapidly alleviate the symptoms of depression and co-morbid anxiety.

The medication, known as RS67333, affects the brain serotonin neurotransmitter system by activating the serotonin-4 receptor (5-HT4). However, unlike commonly prescribed antidepressant medications such as Prozac®, Paxil®, and Celexa®—selective serotonin reuptake inhibitors (SSRIs) that target the serotonin transporter SERT—RS67333 shows a therapeutic effect in animal models of anxiety/depression after only seven days of treatment. By contrast, SSRIs usually take three to six weeks to display beneficial therapeutic effects, and many patients don’t respond at all.

Drs. Hen, David and colleagues report in a paper published online in the journal Neuropsychopharmacology on November 28th that RS67333, like Prozac®, has both antidepressant and anti-anxiety effects in an animal model of anxiety/depression. In addition, RS67333 stimulates neurogenesis in the hippocampus of the adult brain and facilitates maturation of newborn neurons.

Interestingly, the investigators also found that the beneficial effects of SSRIs on behavior and neurogenesis require activation of serotonin-4 receptors. Previously only serotonin-1A receptors (5-HT1A) were known to be necessary for the effects of SSRIs. Importantly, the authors find that the rapid-acting anti-anxiety effects of RS67333 are not dependent upon the birth of new neurons in the hippocampus. This is an exciting finding in the search for faster-acting antidepressant medications as some hypotheses suggest that the delay in the effects of SSRIs is due to the lag between the birth of new neurons and their maturation and integration into functional brain circuits, suggesting that RS67333 acts rapidly through a previously unknown mechanism of action.

The scientists note that RS67333 may have unwanted side effects in other peripheral tissues including the heart, gastrointestinal tract, and urinary bladder. However, targeting signaling molecules that interact with serotonin-4 receptor may be preferable to blockade of SERT when attempting to produce novel antidepressants with rapid therapeutic effects.

Read an abstract of the research paper.