2018-2019 Research Report
THE IMPACT OF YOUR GIFT
The Depression Task Force is an acclaimed collaboration of top neuroscientists who have been working together since 2012 to accelerate discovery of new and better treatments for depression.
We are pleased to provide you with an update of research accomplishments in the past year.
I. Accomplishments in 2018-2019
A. Clinical Trial for Novel Anti-Depressant Mechanism
The Depression Task Force has identified several molecular targets in the brain that represent new and entirely unique pathways for the diagnosis and treatment of depression.
We are thrilled to report that we will officially test one of the new pathway models in humans in a two-year clinical trial starting in 2020. All the necessary permits have been secured and patient selection will begin shortly. The three clinical sites are: 1) The New York Psychiatric Institute at Columbia University 2) Mount Sinai Medical Center and 3) Stony Brook Medical Center in Long Island. The planned study size is 75 patients, 25 at each site.
The pathway we are studying in this clinical trial is the brain’s natural pain management system of circuits and receptors. We believe this system will open a window into the biology of depression, such that we can start to break the condition down into clinical subtypes—a massive leap forward for medicine.
The compound we will test during the clinical trial is tianeptine. Tianaptine is an atypical antidepressant that has been used clinically in Europe for 30 years, but is not offered in the United States. The Task Force has identified for the first time how tianeptine works; unlike typical antidepressants that target the serotonin neurotransmitter, tianeptine works by activating receptors in the brain’s pain relief circuits.
Research shows that many patients with depression feel prolonged or exaggerated pain emotionally when they feel rejected by a loved one, friends, family or colleagues. This is known as high trait “rejection sensitivity” in the clinic, and it affects 30% of depressed patients. Research shows that patients with high trait rejection sensitivity also have a deficiency in their pain management circuits.
Our hypothesis is that there is a direct link between this deficiency in the brain’s pain management circuits and the exaggerated pain that a patient with high trait rejection sensitivity suffers. We also believe that patients with this deficiency will best be helped by a drug that directly targets the pain circuits. The tianeptine trial will allow us to test both hypotheses.
We are very excited to test this novel treatment pathway in patients, with the hopes of advancing a very real clinical subtype of depression.
B. Major Expansion of Task Force
HDRF is now at an inflection point, with several lines of research pointing to novel treatments. In 2019, we added three young leaders with new imaging tools and expertise that will be increasingly important to understanding depression. All three are physician-scientists who can help bridge the animal research in the lab (mice and rats) with human studies, so that we can expedite drug discovery. The new members are:
1. Elisabeth Binder, MD, PhD, Max Planck Inst. of Psychiatry, Munich
Binder’s lab has played a leading role internationally in studying the genetic basis of depression, with a particular focus on the body’s stress system and secretion of cortisol – a stress hormone. She has identified novel proteins that control this hormone and thereby strongly influence stress responses and risk for depression. Her expertise will complement the DTF’s ongoing work on stress and how the system gets unbalanced in depression.
2. Kafui Dzirasa, MD, PhD, Duke Institute for Brain Sciences, Durham, NC
Recipient of the 2019 Young Investigator Award from the Society for Neuroscience.
A biomedical engineer, Dzirasa and his lab have vastly expanded the field’s technical capability by using advanced technology to record electrical activity from multiple brain regions of mice simultaneously while they complete behavioral tasks. With this novel approach, Dzirasa has succeeded in identifying signatures of neural circuits that denote pre-existing vulnerability to depression. They have also identified electrical signatures that show us when an individual is depressed, suggesting a potential tool for diagnosis.
3. Conor Liston, MD, PhD, Weill Cornell, Brain & Mind Research Institute, NYC
The Liston lab uses related approaches as those described for the Dzirasa lab in mouse models, and complements them with studies of depression-related brain circuits in humans by use of advanced neuroimaging techniques. As just one example, Liston and his lab have identified several possible sub-types of human depression based on differential circuit abnormalities.
The DTF network now spans the US, Canada, Europe and Singapore. Working together, the team also plans to incorporate more studies of anxiety and PTSD, as these two syndromes, with depression, are seen as highly genetically related, and often develop together with major depression.
C. Publications of Note
Combined, in 2018-2019 the seven neuroscientists of the Depression Task Force published their findings in over two dozen articles in major publications such as American Journal of Psychiatry, Science, Biological Psychiatry and Proceedings of the National Academy of Sciences (PNAS). Significant articles include:
1. Multidimensional Predictors of Susceptibility and Resilience to Social Defeat Stress, Biological Psychiatry, July 2019
By Dr. Bruce McEwen and Dr. Eric Nestler,
with Dr. Carla Nasca, a postdoctoral fellow in the laboratory of Dr. McEwen
This study identified physical predictors of depression risk in the brain, and showed the efficacy of acetylcarnitine (LAC) to foster resilience and reduce this risk. LAC is a naturally-occurring protein in the brain that enhances the actions of the neurotransmitter glutamate, which helps cells recover after a major stressful event. This exciting paper suggest that LAC can rewire the brain to be pro-resilient and is a possible new treatment for depression.
For her work on this study, Dr. Carla Nasca was named as a finalist for the prestigious 2019 Blavatnick Award.
2. Adult-Born Hippocampal Neurons Bi-directionally Modulate Entorhinal Inputs in the Dentate Gyrus, Science, May 2019
By Dr. Rene Hen
Though few in number, neurons that are created in the brain during adulthood—through a process called ‘neurogenesis’—have a major impact on mood and memory because of their broad networking abilities. The study showed that these young neurons control circuits that keep bad memories from intruding on new memories. These findings could pave the way for more targeted treatments for conditions such as PTSD that are associated with hypervigilance and recurrent distressing memories.
3. Perinatal Maternal Depressive Symptoms as an Issue for Population Health, American Journal of Psychiatry, April 2018
By Dr. Michael J. Meaney
Dr. Meaney conducted a systematic review that explored the association between maternal depressive symptoms and child neurodevelopment outcomes, including in neuroimaging studies. The results strongly suggest that the influences of maternal depressive symptoms operate across a continuum to influence child outcomes, implying that maternal depression may appropriately be considered an issue of population health.
II. Research Strategy Overview
The ten powerful labs of the Depression Task Force have the unique capability of fully embracing a complex psychiatric syndrome like depression by employing not only state-of-the-art approaches in neuroscience, but also advanced chemistry, genetics and brain imaging, and does so in rodent models and in humans. Progress is clear and steady each year, with two lines of attack moving forward:
The DTF has identified numerous genes and gene families that are key to understanding depression. The genes are active in several brain circuits that regulate mood. We know that prolonged stress can tamper with these genes. Stress can switch them on or off, and that can spell trouble if not corrected.
By contrast, a different set of genes are affected in the brains of resilient individuals and these genes actively help the individuals cope with periods of stress. These are known as pro-resilient genes. The DTF is studying both sides of the coin: genes that increase our risk for depression, and genes that
Finding the key genes is just the start of the story, though. Now the team needs to figure out how the genes deep in the brain impact the complex circuitry that controls our emotions and coping behavior. Are we resilient and unfazed by major adversity? Or are we hyper-reactive to perceived stress and unable to cope?
Our newest DTF members are expert at recording circuit activity, thus enabling a study continuum from gene to molecule to cell to circuit and ultimately to behavior. This will allow us to map how small changes in genes involve the entire brain getting stuck in a downward spiral in susceptible individuals or maintaining health despite stress in those who are more resilient.
This continuum of research must be examined across the life cycle, because stress early in life and a host of other life experiences influence stress susceptibility versus resilience—and risk for depression—for a life time. Children exposed to trauma, for example, are subject to brain rewiring that puts them at greater risk for depression later in life.
This information will be essential in identifying new ways of preventing risk associated with susceptibility or instituting mechanisms of natural resilience in those who are inherently more susceptible—in both cases uncovering many new targets for treatment.