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Treatment-Resistant Depression: Glutamate, Stress-Hormones and their Role in the Regeneration of Neurons

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Treatment-Resistant Depression: Glutamate, Stress-Hormones and their Role in the Regeneration of Neurons

Monday, March 25, 2013

The New York Academy of Sciences

Presented By

 

Clinical depression, (major depression) is a devastating illness, which occurs in about 15% of the population, and leads frequently to death by suicide or organic consequences, such as increased cardiovascular risk. Only around one in ten patients treated with the current standard of care antidepressant medication, like SSRIs or SNRI, demonstrate clinical response that extends beyond the effects of placebo. Therefore the current paradigm, which has been in use for the past 50 years and is based on specific effects on monoamines, shows drastic limitations. A paradigm shift is on the way focusing on a completely different neurotransmitter system, namely glutamate and its receptors. A model compound, ketamine, has demonstrated unusually fast improvements in patients, who did not respond to other treatments. The molecular basis for this phenomenon has been partially characterized. The glutamatergic system is integrated in the well-established stress machinery, and the involvement of stress hormones in the regulation of this system has become apparent. Importantly, the older paradigm of the role of serotonin can also be integrated into this new perspective, which seems to be valid in a subset of patients. Astonishingly one overlap between the stress system and the glutamatergic system is the regulation of electrolytes, and in particular magnesium. Both ketamine and magnesium can lead to a sprouting of neuronal synapses in the brain and by this reverse stress-induced changes. The importance of these changes in the structure of neurons and their functional consequences for the amelioration of defective brain function and the related depressive symptoms will be highlighted.

*Reception to follow.

This event will also be broadcast as a webinar.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker’s presentation will be broadcast in full via the webinar. To access all speakers’ presentations in full, we invite you to attend the live event in New York City where possible.

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The Biochemical Pharmacology Discussion Group is proudly supported by




Mission Partner support for the Frontiers of Science program provided by Pfizer

Agenda

* Presentation titles and times are subject to change.


Monday, March 25, 2013

12:00 PM

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
Harald Murck, MD, PhD, Covance Neuroscience Medical and Scientific Services

12:10 PM

Treatment Refractory Depression — Needs and Opportunities from the Industry Perspective
Jorge Quiroz, MD, Roche

12:50 PM

Ketamine Treatment as the New Paradigm for the Treatment of Affective Disorders — Clinical Aspects
Carlos Zarate, MD, National Institute of Mental Health, NIH

1:30 PM

Neurobiology of Stress, Depression, and Antidepressants: Remodeling Synaptic Connections
Ronald S. Duman, PhD, Yale University School of Medicine

2:10 PM

Coffee break

2:40 PM

NMDA-ergic Overactivity as a Model for Unraveling Biochemical Pathways Contributing to Enhanced Depression-Related Behavior
Simone Sartori, PhD, University of Innsbruck, Austria

3:20 PM

Promotion of Synaptogenesis in Prefrontal Cortex and Hippocampus by Elevation of Brain Magnesium and its Implications for Treatment of Anxiety
Guosong Liu, MD, PhD, Tsinghua University, China

4:00 PM

Networking reception

5:00 PM

Close

Speakers

Organizers

Robert Martone

Covance Biomarker Center of Excellence

Robert Martone is Neuroscience Therapeutic Area Lead for the Covance Biomarker Center of Excellence. He has extensive experience in the pharmaceutical industry leading neuroscience drug discovery and technology teams through all phases of discovery from target identification through clinical trials with expertise in both small molecule and protein therapeutics. He also has several years of academic research experience in molecular neurobiology, with a focus on the molecular genetics of familial neuropathies, and CNS tumor biomarker development.

Harald Murck, MD, PhD

Covance Neuroscience Medical and Scientific Services

Dr. Harald Murck studied Physics and Medicine and Philipps-University of Marburg and the Georg-August University in Göttingen, Germany. He conducted his scientific and clinical training in Psychiatry at the Max-Planck-Institute of Psychiatry, Munich; Germany. He has over 12 years of large and small pharma experience in clinical research, medical affairs and translational medicine (Lichtwer Pharma, Amarin, Novartis, BMS) and is at present Senior Medical Director at Covance, Princeton and Associate Professor at Philipps-University Marburg. He is author or co-author of more than 70 peer reviewed articles, several of them related to glutamatergic mechanisms of depression.

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Ronald S. Duman, PhD

Yale University School of Medicine

Dr. Duman is Professor of Psychiatry and Neurobiology, Director of the Abraham Ribicoff Research Facilities, and is the Elizabeth Mears and House Jameson Professor of Psychiatry at Yale University School of Medicine. Studies from Dr. Duman’s laboratory have contributed to the characterization of the molecular and cellular actions of antidepressants and stress, providing the basis for a neurotrophic hypothesis of depression. Recent studies also demonstrate that the rapid antidepressant actions of NMDA receptor antagonists are dependent on synaptogenesis and new protein synthesis. These findings represent major advances in our understanding of the effects of antidepressants and provide a framework for the development of novel therapeutic agents. Dr. Duman has received several prestigious awards for his work, including the Anna-Monika Prize, the Nola Maddox Falcone Prize, the Janssen Prize for Research in Psychopharmacology, a NIMH MERIT Award, a NARSAD Distinguished Investigator Award, and the College of International Neuropsychopharmacology Basic Research Award. He is author of over 300 original articles, reviews and chapters and has given over 200 invited lectures.

Guosong Liu, MD, PhD

Tsinghua University, China

Dr. Liu is a Professor of Neuroscience at Tsinghua University. He received his PhD in Physiological science from the University of California, Los Angeles in 1990. He completed post-doctoral scientific training at Stanford University. From there he went onto a faculty position at Picower institute of learning and memory, department of brain and cognitive science at Massachusetts Institute of Technology, where he remained from 1996–2005. In 2005, Dr. Liu founded a biotechnology company ("Magceutics, Inc."), which is developing novel anti-brain-aging therapy. In 2006, Liu moved to Tsinghua University, where he continues to teach and maintain a vigorous scientific laboratory. Dr. Liu's research focuses primarily on deciphering organization principle that regulate synapse density in brain under physiological and pathological conditions. These understandings result in novel strategies for designing molecular targets for treating neurodegeneration such as Alzheimer and Parkinson's diseases and psychiatric disorders such as anxiety and depression.

Jorge Quiroz, MD

Roche

Dr. Jorge Quiroz is Head of Psychiatry in Neuroscience Translational Medicine at Hoffmann-La Roche. After receiving his Medical Degree from the Pontifical Catholic University of Chile and board certification in Psychiatry, Dr. Quiroz completed his post-graduate training at the Laboratory of Molecular Pathophysiology, National Institute of Mental Health (NIMH) in Bethesda, Maryland. Dr. Quiroz's research efforts at the NIMH in translational neuroscience focused on clinical research and Magnetic Resonance Spectroscopy (MRS) in populations with severe mood disorders resistant to conventional pharmacological treatments. His achievements while at the NIMH included the NARSAD Young Investigator Award (National Alliance for Research on Schizophrenia and Depression), the NCDEU New Investigator Award (New Clinical Drug Evaluation Unit), the Fellows Award for Research Excellence, and the Clinical Center Director's Award for Quality of Work and Diversity. Dr. Quiroz then joined Johnson & Johnson Pharmaceutical Research and Development where he successfully filed New Drug Applications with the FDA (phase III studies) for the treatment of Bipolar Disorder. Subsequently, he joined Roche in 2009 focusing his research on the development of novel interventions for treatment resistant forms of Major Depression, particularly targeting pre and post-synaptic metabotropic glutamatergic receptors. Dr. Quiroz is currently a 2014 Master of Business Administration candidate at Columbia University & London Business School.

Simone B. Sartori, PhD

University of Innsbruck, Austria

Dr. Simone Sartori graduated in Pharmacy at the University of Innsbruck in 2000. She established her interest in the pharmacology of neurotransmitters as a research assistant during a temporary stay with Professor Trevor Sharp in the Department of Pharmacology at the University of Oxford, GB. Dr. Sartori joined the group by Professor Nicolas Singewald in the Department of Pharmacology and Toxicology at the University of Innsbruck where she obtained her PhD in 2005 and spent the next four years as a post-doctoral fellow. She was appointed to the departmental staff in 2009. Throughout her time in Innsbruck, Dr. Sartori's research has focused on the pathophysiology and pharmacology of various CNS transmitters, in particular of neuropeptides and the glutamate system, in terms of potential novel strategies for the treatment of mood and anxiety disorders.

Carlos Zarate, MD

National Institute of Mental Health, NIH

Carlos A. Zarate, MD is Chief Experimental Therapeutics & Pathophysiology Branch and of the Section on Neurobiology and Treatment of Mood and Anxiety Disorders, Division Intramural Research Program, National Institute of Mental Health. Dr. Zarate completed his residency training in psychiatry at the Massachusetts Mental Health Center/Brockton VAMC division. He later completed a fellowship in Clinical Psychopharmacology at McLean Hospital of the Consolidated Department of Psychiatry, Harvard Medical School and remained on staff at McLean Hospital as the Director of the Bipolar and Psychotic Disorders Outpatient Services and Director of the New and Experimental Clinic. From 1998 to 2000 Dr. Zarate was the Chief of the Bipolar and Psychotic Disorders Program at the University of Massachusetts Medical School. In 2001, he joined the Mood and Anxiety Disorders Program at NIMH. His achievements and awards include the Ethel-DuPont Warren Award and Livingston Awards, Consolidated Department of Psychiatry, Harvard Medical School; Outstanding Psychiatrist Research Award, Massachusetts Psychiatric Association; Program for Minority Research Training in Psychiatry, APA; the National Alliance for Research on Schizophrenia and Depression Young Investigator Award; National Alliance for Research on Schizophrenia and Depression Independent Investigator Award; the National Institutes of Health Director's Award Scientific/Medical, and the Brain & Behavior Research Foundation Award for Bipolar Mood Disorder Research. Dr. Zarate has been elected to membership to the American College of Neuropsychopharmacology, to the Board of Councilors for the International Society for Bipolar Disorders. He is also a member of the Society of Biological Psychiatry and the Society for Neuroscience. Dr. Zarate's research focuses on the pathophysiology and development of novel therapeutics for treatment-resistant mood disorders as well as the study of biomarkers and neural correlates of treatment response.

Sponsors

Bronze Sponsor

Roche

Academy Friend

Bristol-Myers Squibb

Webinar Sponsor

Covance

Promotional Partners

American Academy of Neurology

The Dana Foundation

Nature

Society for Neuroscience — Neuroscience Nexus


The Biochemical Pharmacology Discussion Group is proudly supported by




Mission Partner support for the Frontiers of Science program provided by Pfizer

Abstracts

Ketamine Treatment as the New Paradigm for the Treatment of Affective Disorders — Clinical Aspects <br/ > Carlos Zarate, MD, National Institute of Mental Health, NIH

Despite adequate treatment, many patients with mood disorders continue to have functional impairment, psychosocial disability, and significant medical and psychiatric comorbidity. Another limitation of existing therapeutics is that they are associated with a considerable lag of onset of action; only a small number of patients respond by the end of the first week of treatment. Eliminating this delay in therapeutics effects is now a major goal in mood disorders research. Recently, diverse new targets/compounds have been specifically tested in preclinical models and in proof-of-concept studies, with potential relevance as treatments for mood disorders. Several converging lines of evidence suggest that dysfunction of the glutamatergic system—particularly the N-methyl-D-aspartate (NMDA) receptor complex—may play an important role in the pathophysiology of mood disorders. This talk will review clinical translational studies conducted at the National Institute of Mental Health (NIMH). In particular, our studies targeting the glutamatergic systems found that the NMDA antagonists ketamine, MK-0657 (oral NR2B antagonist), and AZD6765 (low trapping non-selective NMDA antagonist) were found to have rapid antidepressant effects in TRD. These targets may be of substantial interest in defining future directions in drug development, as well as in developing the next generation of therapeutic agents for the treatment of mood disorders. Overall, further study of these and similar drugs may lead to a better understanding of relevant and clinically useful drug targets in the treatment of these devastating illnesses.

Neurobiology of Stress, Depression, and Antidepressants: Remodeling Synaptic Connections
Ronald S. Duman, PhD, Yale University School of Medicine

Recent molecular and cellular studies have demonstrated that stress and antidepressants exert opposing effects on the expression of neurotrophic factors, which results in structural alterations of neurons, including regulation of dendrite length and branching and spine density in the prefrontal cortex (PFC) and hippocampus. The deleterious effects of stress could contribute to the reduced volume of PFC and hippocampus in depressed patients. Conversely, the actions of antidepressants could be mediated in part by blocking or reversing the atrophy caused by stress and depression. Recent studies demonstrate that ketamine, an NMDA receptor antagonist, produces a rapid (within hours) antidepressant response in treatment resistant depressed patients, addressing a major limitation of currently available agents (i.e. delayed onset of action and low response rates). We have found that ketamine causes a rapid induction of synaptogenesis and spine formation in the PFC via stimulation of mTOR signaling and increased synthesis of synaptic proteins. These effects of ketamine rapidly reverse the atrophy of PFC neurons caused by chronic stress and underlie rapid behavioral responses in models of depression. We have also found that the atrophy of neurons caused by stress occurs via inhibition of mTOR signaling and synaptogenesis. Further characterization of the mechanisms underlying the effects of stress and rapid antidepressants will identify new targets for the development of rapid and efficacious antidepressants without the side effects of ketamine.

NMDA-ergic Overactivity as a Model for Unraveling Biochemical Pathways Contributing to Enhanced Depression-related Behavior<br/ > Simone B. Sartori, PhD, University of Innsbruck, Austria

An increasing number of clinical and preclinical studies propose that the N-methyl-D-aspartate (NMDA) receptor plays a role in the pathophysiology and treatment of mood disorders. For example, increasing NMDA receptor function by feeding mice a magnesium (Mg)-restricted diet results in an enhanced depression- and anxiety-related phenotype while dietary Mg-supplementation causes antidepressant effects in HAB mice selectively bred for high trait anxiety and co-occurring depression. In addition, the NMDA receptor antagonist ketamine exerts acute antidepressant effects in Mg-depleted mice similar to chronic treatment with clinically established selective serotonin re-uptake inhibitors. To gain insight into neuronal substrates underlying the enhanced mood and emotionality, data will be presented providing first evidence of deranged molecular-biological pathways in response to dietary-induced hypomagnesaemia and their modulation following successful antidepressant treatment.

Promotion of Synaptogenesis in Prefrontal Cortex and Hippocampus by Elevation of Brain Magnesium and its Implications for Treatment of Anxiety
Guosong Liu, MD, PhD, Tsinghua University, China

Recent studies indicate that the reduction of glutamatergic synapse density in prefrontal cortex (PFC) might contribute significantly to pathological mechanisms underlying Depression. Restoration of synapse density in PFC might represent a novel therapeutic strategy for treating Depression. Our laboratory has been studying the organization principles and molecular mechanisms governing synapses density in CNS. Our early works suggest that synapse density and plasticity might be regulated by ratio of correlated vs uncorrelated neural activities within neural networks (Slutsky, et al, 2004). Elevation of extracellular Mg2+ lead to optimization of this ratio and increase in synapse density and plasticity in vitro and in vivo. In this workshop, I present the overview of our works and present preclinical data demonstrating that elevation of brain Mg2+ in intact animal is effective in increase in synapse density in PFC (Abumaria et al, 2011) and hippocampus (Slutsky, et al, 2010), promoting fear memory extinction, resulting in reduction of anxiety and depression-like behavior in animal. To highlight our long-term goal of translating findings from basic research to clinical application, I will also present preliminary observations in our human clinical trial, in which we are testing the efficacy of newly developed, highly brain bioavailable, magnesium compound for enhancement of cognitive abilities and improvement of emotional control.

* Additional abstracts to follow.

Travel & Lodging

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The New York Academy of Sciences

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