A Possible New Class of Antidepressants

Neuroscientific advances are leading to new treatments for depression.

Posted Jul 06, 2016

Over the last several years, remarkable progress has been made in clinically relevant brain research. This work is leading to the development of new types of medications for the treatment of psychiatric disorders.

In a study published in the journal Molecular Psychiatry, Maurizio Fava and colleagues describe the results of early human testing of a newly developed medication that can increase the growth of new cells in the hippocampus, a brain region involved in memory, learning, and emotional regulation. These investigators are evaluating this drug as a potential antidepressant medication.

The process by which new brain cells are made is called neurogenesis. Decades ago, medical students were taught that new cells were not made in the brain after childhood. This neuroscience dogma was shown later to be false when scientists found that there are a few regions in the brain where new cells are continuously being generated throughout life. The dentate gyrus of the hippocampus is one such region.

Over the past 15-20 years, scientists have discovered that one of the many actions of various antidepressants is to enhance the growth of new neurons in the hippocampus. Some have wondered whether agents that specifically augment neurogenesis in the hippocampus would yield a new class of antidepressants.

Dating to the 1980’s, methods have been developed that allow the growth of hippocampal cells in a cell culture dish, i.e., outside the brain. Growing cells in culture provides a technique that lends itself to rapidly screening agents that might stimulate the growth of new hippocampal cells. Of course, if such drugs are found to work in cell cultures, they must be tested in animals for safety and in animal models of depression for potential efficacy. Only after positive results in animal studies can such drugs begin the extensive FDA-approved process for testing new medications in human subjects.

Fava and his colleagues are studying a drug called NSI-189, which is being developed for clinical use by a small company. This drug had been discovered previously to stimulate neurogenesis in hippocampal cell cultures and in the hippocampus of living mice. It also had been shown to be effective in a mouse model of depression. NSI-189 is said to be a novel compound, presumably a different type of drug than current antidepressants, although peer-reviewed mechanistic data about the drug are lacking and other information is proprietary.

In the article in Molecular Psychiatry, Fava’s group reports the results of a phase 1b study of NSI-189. (Note that the authors of this paper have potential conflicts of interests:  one of the authors is employed by the company that is developing NSI-189 and the others have received research support from the company.) A phase 1b study involves testing the study medication in a very small group of volunteers suffering from the illness you are trying to treat, in this case major depressive disorder. The purpose of this phase 1b study is to examine how the human body handles different doses of the drug and to see if it appears to be safe. Since the study involves only a small number of people, it may be difficult to determine if the drug also has an efficacious, in this case antidepressant, effect. Nevertheless, the study involves persons with the illness under study in order to see if there might be a suggestion of an effect.

In this study of NSI-189, the drug’s safety profile was satisfactory and its absorption and metabolism were appropriate. Of course, the safety profile might change in larger studies. Interestingly, there was a strong suggestion of antidepressant efficacy even in this very small sample. Furthermore, although the drug was administered daily for 28 days, the antidepressant effects were still evident at the last time point examined - about two months after the drug was stopped.

A somewhat larger “phase 2” clinical trial began in 2016. Will this larger study confirm the drug’s safety and effectiveness? If this next study yields encouraging results, then much larger phase 3 studies would likely follow. Several phase 3 studies are generally required before the FDA will consider approving a new drug. 

The purpose of this post is to demonstrate how current advances in basic neuroscience research have the potential to open new avenues for the development of novel therapeutics. Very few innovative advances in psychopharmacological drug development have occurred during the last 30 or more years, but recently this has been changing.

We predict that there will be exciting advances in diagnostic approaches and treatment for psychiatric illnesses in the coming years. This optimism is supported by an increase in the number of research-oriented medical students who are entering the field of psychiatry.

This column was written by Eugene Rubin MD, PhD and Charles Zorumski MD.