Three-time NARSAD Grantee talks about his groundbreaking work on depression since the 1980s

From The Quarterly, Fall 2012



When did your research career begin, and what made you pursue research on depression in particular?



My research career began in 1980 as a graduate student with Dr. Sam Enna at the University of Texas in Houston. I was fascinated by neurotransmitter receptor signaling pathways that were being elucidated at the time and there was very little known about how adaptations of these pathways contributed to the actions of antidepressants. My interests have evolved over the years to studies of gene expression and alterations of neuronal and glial morphology and function, but are still focused on identifying the mechanisms by which antidepressants work and how we might produce safer, faster acting and more effective agents.



You have been a recipient of each of the Brain & Behavior Research Foundation NARSAD Grants—Young, Independent and Distinguished Investigator. Can you tell us what this funding meant to you and your career?



To go beyond the monoamine theories of depression and antidepressant response that were being studied in the 1980’s and 1990’s we had to consider novel areas of research that were sometimes difficult to get funded. Fortunately, this is exactly the type of research that NARSAD Grants have supported. This has had an enormous impact on my work as well as the research of hundreds of other young research scientists.



What research discovery have you made that you are the most proud of?



The work that we have done on neurotrophic factors, particularly brain derived neurotrophic factor (BDNF) has been the most interesting and maybe the most important. We started this work in the early 1990’s in collaboration with my colleague and friend Eric Nestler when he was here at Yale. We found that antidepressant treatments increase the expression of BDNF in brain regions implicated in depression, and that infusions of BDNF into these brain regions produced antidepressant actions in rodent models. At the same time, other labs reported that stress decreases the expression of BDNF and clinical brain imaging studies were reporting that depression is associated with a decrease in the volume of brain regions such as the hippocampus and prefrontal cortex that contribute to depression. Together these studies have  contributed to a neurotrophic hypothesis of depression and treatment response, and we are still conducting studies to test and extend this work.



Over the course of the past 25 years, what role do you think NARSAD Grant funding has played in helping evolve the field overall – i.e., what we know about the brain and how to treat, prevent and cure mental illness?



The biggest impact of NARSAD Grant funding is to support novel, cutting edge research that has the potential to lead to completely new ideas about the pathophysiology and treatment of depression and other brain and behavior disorders. This is particularly important for young investigators, who are often the most likely to have fresh, new research ideas, but might have trouble getting funded because they don’t yet have a proven research track record. Funding problems have been exacerbated over the past several years with the downturn in the economy, which has had a truly devastating effect on many of our young investigators who are struggling to survive professionally.



What are the most exciting and promising areas of depression research for the coming ten years? What do you hope to see?



The biggest discovery for the treatment of depression is ketamine, a glutamate NMDA receptor antagonist that produces rapid (within hours) antidepressant actions in patients who have failed to respond to conventional antidepressants (i.e., are considered treatment resistant). The ability of ketamine to produce a rapid and efficacious antidepressant response by a completely different mechanism represents the most important finding in the depression field in over 50 years. Studies aimed at characterizing the mechanisms by which ketamine works rapidly and effectively could lead to novel targets and agents that are safer and more long-lasting, and could revolutionize the treatment of depression. Our recent work*, in collaboration with George Aghajanian here at Yale, demonstrating that ketamine increases synaptic connections in brain regions that control mood and emotion also raises the possibility that behavioral therapies, as well as pharmacological agents, could reinforce and sustain these new connections and the antidepressant response to ketamine. I have no doubt that NARSAD Grants will continue to support young investigators who are conducting this type of exciting new research.



* Paper entitled ‘Synaptic Dysfunction in Depression: Potential Therapeutic Targets,’ authored by Drs. Duman and Aghajanian published in Science magazine is available online at sciencemag.org.

 

Ronald S. Duman, Ph.D.

Scientific Council Member

1989 NARSAD Young Investigator

1997 NARSAD Independent Investigator

2005 NARSAD Distinguished Investigator

2002 Brain & Behavior Research Foundation Falcone Prize for Outstanding Achievement in Mood Disorders Research

Elizabeth Mears and House Jameson Professor of Psychiatry

Professor of Psychiatry and Neurobiology

Director, Division of Molecular Psychiatry and Abraham Ribicoff Research Facilities

Yale University School of Medicine