Translational Neuroscience in Psychiatry: Light at the End of the Tunnel

Translational Neuroscience in Psychiatry: Light at the End of the Tunnel

Tuesday, April 8, 2014

The New York Academy of Sciences

Presented By

 

Progress developing new and more effective treatments for psychiatric disorders, particularly depression and schizophrenia, has been stymied in part because of a lack of quantitative endpoints (biomarkers) to measure disease progression and response to therapy. Additional factors delaying the development of new drugs include a lack of mechanistic understanding of standard treatments and the complexity, and often long time course, of disease which makes disease modeling in laboratory animals challenging. Fortunately, developments along several fronts are providing new hope for a better understanding of disease progression and tractable mechanisms for drug discovery. The following topics will be explored in this symposium: progress in validating use of event-related potentials and other electrophysiological means to measure sensory deficits that are increasingly recognized as features of disease pathology; improved methods for brain imaging in patients to monitor illness progression and treatment effect; development of panels of blood biomarkers that reflect ongoing CNS disease pathology. Additionally, speakers will address strategies for 'back-translating' findings in humans to animal models. Ultimately, combinations of approaches, reflecting a variety of specific endophenotypes, may pave the way toward a better understanding of disease and improved therapies.

*Reception to follow.

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Agenda

* Presentation titles and times are subject to change.


April 8, 2014

8:30 AM

Registration and continental breakfast

9:00 AM

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
Ken Jones, PhD, Allergan

9:10 AM

Time Frequency Analysis of Sensory Deficits in Schizophrenia: Beyond the Phase Reset
Daniel C. Javitt, MD, PhD, Columbia University and Nathan Kline Institute

9:50 AM

Using EEG Biomarkers to Inform Diagnosis, Guide Treatments, and Track Response to Interventions in Psychotic Illnesses
Gregory Light, PhD, University of California, San Diego

10:30 AM

Coffee break

11:00 AM

EEG-based Translational Measures for Psychiatric Drug Discovery
Siva Digavalli, PhD, Bristol-Myers Squibb

11:40 AM

EEG Biomarkers of Target Engagement, Therapeutic Effect and Disease Process
Steven J. Siegel, MD, PhD, University of Pennsylvania

12:20 PM

Lunch break

1:20 PM

Rapid-Acting Glutamatergic Antidepressants: The Path to Ketamine and Beyond
John H. Krystal, MD, Yale University

2:00 PM

Rhythms and Blues: Change in Oscillatory Synchrony as an Intermediate Phenotype for Remission during Medication Treatment of Major Depression
Andrew F. Leuchter, MD, University of California, Los Angeles

2:40 PM

Coffee break

3:10 PM

Blood Biomarker Panels for Major Depressive Disorders
Eva E. Redei, PhD, Northwestern University

3:50 PM

Structural and Spectroscopic Neuroimaging Correlates of Treatment Outcome in Mood Disorders
Dan V. Iosifescu, MD, MSc, Icahn School of Medicine at Mount Sinai

4:30 PM

Networking reception

5:30 PM

Close

Speakers

Organizers

Siva Digavalli, PhD

Bristol-Myers Squibb

Siva Digavalli is a Senior Research Investigator at the Experimental Biology and Genomics group in Bristol Myers Squibb Co where one of his areas of focus has been to enable seamless translation of EEG-based biomarker use from preclinical to early clinical development. He has a Ph.D in Pharmacology and Experimental Therapeutics from LSU Medical School, New Orleans and a postdoctoral fellowship from Harvard Medical School.

Ken Jones, PhD

Allergan

Ken is currently a Principal Medical Writer with Allergan in Bridgewater, NJ, where he is preparing regulatory submission documents for novel biological and chemical entities for their neurology portfolio. He has over 20 years of preclinical drug discovery and clinical development experience in the area of CNS disorders. Ken received his PhD in Physiology at Rutgers University and postdoctoral training at the Harvard Medical School Department of Neurobiology where he developed mammalian primary cell culture techniques to map NMDA and AMPA receptors at synaptic and extrasynaptic sites. His subsequent contributions to research include the deorphanization of several G-protein-coupled receptors, including the elucidation of the dimeric nature of GABAB receptors, and the co-discovery of a non-visual photoreceptor that regulates circadian rhythms. Prior to joining Allergan, Ken was a Senior Clinical Scientist within the Department of Psychiatry at Forest Research Institute.

Frank Menniti, PhD

Mnemosyne Pharmaceuticals, Inc.

Dr. Menniti is a founder of Mnemosyne Pharmaceuticals, Inc. and as Chief Scientific Officer is the architect of the Mnemosyne’s new therapeutic platform, the Subunit-selective NMDA Receptor Modulators. Prior to founding Mnemosyne, Dr. Menniti was a research scientist in the CNS Discovery group at Pfizer, Inc. in Groton CT (1992-2009). While at Pfizer Inc., Dr. Menniti was a principal in developing the scientific rationale for use of NMDA receptor NR2B antagonists for stroke, neuropathic pain, Parkinson’s disease, and depression and in the clinical development of the prototype NR2B antagonist CP-101,606. Dr. Menniti also was involved in developing the therapeutic utilities of phosphodiesterase inhibitors for neuropsychiatric disease. This includes the identification of PDE10A inhibitors for schizophrenia and Huntington’s disease, with PF-02545920 as the first PDE10A inhibitor to reach Phase II development. Dr. Menniti also led the discovery teams that advanced the first PDE9A inhibitor into Phase II testing for the treatment of Alzheimer’s disease and the first PDE5A inhibitor into Phase II testing to improve functional recovery after stroke. Dr. Menniti received his Ph.D. in Pharmacology from the University of North Carolina, Chapel Hill in 1987 and was a Staff Fellow in the laboratory of Dr. James W. Putney at the National Institute of Environmental Health Sciences from 1988-1992, participating in research elucidating the fundamentals of intracellular calcium signaling.

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Siva Digavalli, PhD

Bristol-Myers Squibb

Siva Digavalli is a Senior Research Investigator at the Experimental Biology and Genomics group in Bristol Myers Squibb Co where one of his areas of focus has been to enable seamless translation of EEG-based biomarker use from preclinical to early clinical development. He has a Ph.D in Pharmacology and Experimental Therapeutics from LSU Medical School, New Orleans and a postdoctoral fellowship from Harvard Medical School.

Dan V. Iosifescu, MD, MScPhD

Icahn School of Medicine at Mount Sinai

Dr. Dan Iosifescu is the Director of the Mood and Anxiety Disorders Program and Associate Professor of Psychiatry and Neuroscience at the Icahn School of Medicine at Mount Sinai. His research is focused on novel pharmacological treatment modalities (such as ketamine and other glutamatergic drugs), and device based treatments (such as novel forms of magnetic stimulation) for patients with mood disorders. Dr. Iosifescu also investigates treatments for cognitive deficits in mood disorders and biological markers of treatment outcome, using neuroimaging (MRI, MRS) and neurophysiology (quantitative EEG) techniques to evaluate structural, biochemical, and functional brain abnormalities in mood disorders and their impact on clinical treatment. Dr. Iosifescu has continuously received independent funding from the National Institutes of Health (NIH) since 2003, as well as funding from private foundations.

After receiving his medical doctor (M.D.) degree from the Institute of Medicine and Pharmacy in Bucharest, Romania, Dr. Iosifescu completed his internship and psychiatry residency at Massachusetts General Hospital (MGH) and McLean Hospital, serving as chief resident in consultation-liaison psychiatry. His research training included a neuroimaging fellowship in the Neuroscience Laboratory at Harvard Medical School, a psychopharmacology fellowship in the MGH Mood and Anxiety Disorders Institute, and a fellowship in the Clinical Investigator Training Program at Harvard and MIT. In parallel Dr. Iosifescu received a Master of Medical Science degree from Harvard University. Until April 2010 Dr. Iosifescu was Associate Professor of Psychiatry at Harvard Medical School and Director of Translational Neuroscience in the Depression Clinical and Research Program and Site Director of the Bipolar Trials Network, both at Massachusetts General Hospital.

Daniel C. Javitt, MD, PhD

Columbia University and Nathan Kline Institute

Dr. Javitt is Professor of Psychiatry and Neuroscience at Columbia University College of Physicians and Surgeons where he directs the Division of Experimental Therapeutics and the Columbia Conte Center for Schizophrenia Research. In addition, he serves as Director of Schizophrenia Research at Nathan Kline Institute for Psychiatric Research. Dr. Javitt received his BA, magna cum laude from Princeton University in 1979 and his MD from Albert Einstein College of Medicine in 1983. He completed his residency in Psychiatry in 1987, and earned a PhD in Neuroscience from Einstein in 1990.    He has published over 250 articles on issues related to normal brain function, cognitive neuroscience, NMDA receptors and schizophrenia. He has received awards for his research from organizations including the American Psychiatric Association, the Society for Biological Psychiatry, the American College of Neuropsychopharmacology, the American College of Psychiatrists, and the Child Welfare League of America. His research is supported by the NIMH, the Stanley Medical Research Institute, and other philanthropic organizations. He is a Fellow of the American College of Neuropsychopharmacology, and a standing member of the Institute of Medicine Neuro Forum.

John H. Krystal, MD

Yale University

Dr. Krystal is the Robert L. McNeil, Jr., Professor of Translational Research and Chair of the Department of Psychiatry of the Yale University School of Medicine and Chief of Psychiatry at Yale-New Haven Hospital. He is a graduate of the University of Chicago, Yale University School of Medicine, and the Yale Psychiatry Residency Training Program. He has published over 400 papers and reviews on the neurobiology and treatment of schizophrenia, alcoholism, post-traumatic stress disorder, and depression. His research program unites psychopharmacology, neuroimaging, and molecular genetics. His work on brain glutamate systems contributed to the identification of novel treatment mechanisms for depression, alcoholism, and schizophrenia that are now in development. He is the Director of the NIAAA Center for the Translational Neuroscience of Alcoholism and the Clinical Neuroscience Division of the VA National Center for PTSD. Dr. Krystal received a number of awards including the Joel Elkes Award of the American College of Neuropsychopharmacology, the Anna-Monika Foundation Prize for Depression Research, and the NIAAA Jack Mendelson Alcoholism Research Award. He is also a member of the Institute of Medicine of the U.S. National Academy of Sciences. He was Chairman of the NIMH Board of Scientific Counselors (2004-2007), served on the NIAAA National Alcohol Advisory Council (2008-2012), and president of the American College of Neuropsychopharmacology (2012). Since 2006, he edited a leading psychiatry and neuroscience journal, Biological Psychiatry (IF=9.25).

Andrew F. Leuchter, MDPhD

University of California, Los Angeles

Andrew F. Leuchter, MD, is a Professor of Psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA. He also is Director of the Laboratory of Brain, Behavior, and Pharmacology, and a Senior Research Scientist at the Semel Institute. As a Board certified electroencephalographer, he has unique expertise for integrating neurophysiologic measures into clinical trials, and development of biomarkers to inform diagnostic and treatment decisions. Dr. Leuchter’s research studies indicate that changes in the electrical rhythms of the brain early in antidepressant treatment are a sensitive and specific predictor of remission, and can be used to direct the selection of a medication that is most likely to benefit an individual patient. An internationally recognized expert on the treatment of mood disorders, he is the author of over 100 articles in peer-reviewed scientific journals. In addition to his research, Dr. Leuchter has for more than 20 years led a research training program that educates the next generation of psychiatric researchers, many of whom now are on faculty at the nation’s top universities. Dr. Leuchter also maintains an active clinical practice, specializing in consultation for and care of patients suffering from treatment-resistant depression. Dr. Leuchter is a graduate of Stanford University and received his medical degree from the Baylor College of Medicine in Houston, Texas. Dr. Leuchter performed his residency and fellowship training at UCLA before joining the faculty.

Gregory Light, PhD

University of California, San Diego

Gregory Light has a joint appointment at the UCSD School of Medicine and the VA San Diego Healthcare System. At UCSD he serves as an Associate Professor of Psychiatry and co-directs the Schizophrenia Research Program. At the San Diego VA, he serves as the Administrative Director of both Mental Health Research as well as the Mental Illness, Research, Education and Clinical Center (MIRECC). He co-directs the MIRECC Clinical Neuroscience and Genomics Unit and oversees advanced post-doctoral fellowship programs for physicians and clinical psychologists.

His research focuses on the development of objective, laboratory-based biomarkers for improving our understanding and treatment of psychotic illnesses. For the past decade, he has directed the daily activities of the UCSD site in the Consortium on the Genetics of Schizophrenia (COGS). In this capacity, he provides national training, quality assurance, and data management of clinical, cognitive, and biomarker characterizations of schizophrenia patients and their family members. He has approximately 90 publications. Dr. Light’s research is funded by the National Institutes of Health and the National Alliance for Research on Schizophrenia and Depression (NARSAD) and Department of Veteran’s Affairs.

Eva Redei, PhD

Northwestern University

Eva E. Redei, PhD, is the David Lawrence Stein Professor of Psychiatry and Behavioral Sciences and a Professor of Physiology in the Feinberg School of Medicine at Northwestern University. She holds an MS in chemical engineering and a Ph.D. in organic chemistry. Subsequently, Dr. Redei joined the Brain Research Institute of UCLA as a postdoctoral fellow and remained at UCLA, Department of Anatomy as research faculty. She joined the Department of Psychiatry and Pharmacology at the University of Pennsylvania, where she remained until recruited to Northwestern University.

She has received numerous honors including visiting professorships, invited lectureships and two endowed chairs sequentially. She has over 90 peer-reviewed publications and numerous other invited communications. Redei’s research is funded by NIH and private foundations; she is a member of the Molecular Neurogenetics NIH study section and reviews grants for other NIH study sections, federal and international granting agencies. She has continuously been on editorial boards.

The research in Dr. Redei’s laboratory is focused on the genetic and molecular mechanisms that underlie vulnerabilities to depression and neurodevelopmental disorders. Efforts have been directed toward developing animal models and map the genetic, epigenetic and transcriptomic processes that characterize these models. These explorations led to the search, over the past 10 years, to identify blood-based diagnostic markers for major depression.

Steven J. Siegel, MD, PhD

University of Pennsylvania

Steven Siegel is a Professor of Psychiatry and Director of the Translational Neuroscience Program in the School of Medicine at the University of Pennsylvania. He is also Director of the Clinical Neurosciences Track and Associate Director of Educational Programs for the Institute for Translational Medicine and Therapeutics (ITMAT). He received his MD and PhD in Neurobiology at the Mount Sinai School of Medicine in 1996 after completing an undergraduate degree in Neuroscience at Colgate University in 1986. He later completed residency in Psychiatry and a Fellowship in Neuropsychiatry at the University of Pennsylvania before joining the faculty in 2001. He is a practicing Psychiatrist specializing in the treatment of Schizophrenia.

Work in his laboratory investigates the neurobiology of schizophrenia, autism, drug abuse and nicotine dependence using animal models to evaluate EEG and event related brain activity in mice. Additionally, his laboratory has invented and helped develop new methods for the treatment of schizophrenia and Parkinson’s Disease using biodegradable long-term delivery systems. He has published approximately 120 scientific manuscripts, reviews, editorials, book chapters and books addressing the clinical management of schizophrenia, the use of electrophysiological animal models in psychiatric disorders and the use of biodegradable polymers in pharmaceutical delivery systems.

His laboratory has trained more than 100 undergraduate, graduate and post doctoral students in the Neurobiology of Psychiatric illness and Biomedical Engineering. Work in the group has been supported by the National Institutes of Health, The Commonwealth of Pennsylvania, The Stanley Medical Research Institute, NARSAD, The IES Brain Research Foundation and several pharmaceutical companies.

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Abstracts

Time-frequency Analysis of Sensory Deficits in Schizophrenia: Beyond the Phase Reset
Daniel C. Javitt, Columbia University and Nathan Kline Institute

Neurophysiological measures based upon the local field potential are among the most powerful tools in translational neuroscience. Such measures are obtained cross-sectional across-patients to stratify subgroups, longitudinally within-patients to monitor treatment outcome and translationally across species to link human findings to both primate and rodent models. In traditional neurophysiological studies, stimuli are presented repetitively and averaged across presentations to give rise to the time-domain event-related potential (ERP). Several ERP measures, such as auditory N1, mismatch negativity (MMN), steady-state response and P3, and the visual P1 and closure negativity (Ncl) are now well-established measures of neurophysiological dysfunction and have been linked to underlying pathophysiological processes in disorders such as schizophrenia. Moreover, measures such as MMN and visual P1 are modulated by agonists at N-methyl-D-aspartate-type glutamate receptors, and may therefore be effective in translational drug development models. More recent neurophysiological approaches utilize time-frequency analyses, as reflected in the event-related spectral perturbation (ERSP) response. Separate measures are obtained for intertrial coherence (phase locking) of responses across trials and power within trials. Power measures, moreover, can be assessed at either the average (“evoked”) or single-trial (“induced”) level, permitting detection of both stimulus-induced increases and decreases of spectral power. As opposed to phase-locked components which reflect primarily the interplay between pyramidal neurons and parvalbumin-type (PV) interneurons, alterations in induced power most likely reflect engagement of other classes of inhibitory interneuron. In schizophrenia, severe deficits are observed in both intertrial coherence and power consistent with emergent glutamatergic models, and providing novel measures for future translational research.
 

Using EEG Biomarkers to Inform Diagnosis, Guide Treatments, and Track Response to Interventions in Psychotic Illnesses
Gregory Light, University of California, San Diego

Investigations into the neural substrates of neurocognitive and psychosocial impairments have transformed our understanding of intact and impaired brain functions in psychotic illnesses. Despite substantial progress, current diagnosis and treatment decisions are largely based on subjective patient report, clinician inference about patient inner experiences and behavioral observation rather than informed by objective laboratory tests. Many laboratory-based candidate biomarkers have already provided critical insights into the pathophysiology of psychosis. In this presentation, one example of a simple, low-cost, and translatable EEG test will be described: mismatch negativity (MMN). This measure, already considered a “breakthrough” biomarker, offers great promise for improving our understanding and treatment of psychotic illnesses. MMN is automatically elicited in response to unattended, infrequent sounds embedded in a sequence of frequently presented stimuli. Since MMN does not require sustained effort or even consciousness, it is thought to reflect an initial step from auditory sensory processing to the engagement of higher cognitive operations. In fact, MMN accounts for substantial portions of variance in cognition, psychosocial functioning, and level of independence in community living, and is sensitive to some pharmacologic and non-pharmacologic interventions. MMN exhibits utility as a repeated measure with reliability levels that are comparable to or even exceed those obtained from common clinical neuropsychological tasks. Lastly, MMN improves the prediction of which individuals at high clinical risk actually develop a psychotic illness. These attributes suggest that MMN can contribute to future biomarker-informed diagnostic or treatment stratification algorithms.
 

EEG-based Approaches for Translation in Psychiatric Discovery
Siva Digavalli, PhD, Bristol Myers Squibb Co.

Pharmacodynamic biomarkers provide an objective and functional basis to evaluate effects of a drug treatment. Such functional markers are vital for hypothesis testing in the absence of direct target engagement. Electroencephalography (EEG)-based approaches such as quantitative EEG and event related potentials (ERPs) offer a convenient and relatively inexpensive means of monitoring drug response on large neuronal population activity in clinical as well as preclinical subjects. However, such approaches are not suitable for all molecular targets. The presentation will review several examples from the literature and from author’s work where qEEG and ERP techniques were used to seamlessly translate drug response across multiple species. We will also discuss variables that may determine the suitability of EEG approaches as translational tools.
 

EEG Biomarkers of Target Engagement, Therapeutic Effect and Disease Process
Steven Siegel, MD, PhD, University of Pennsylvania

Recent studies suggest that abnormalities in glutamate and GABA signaling contribute to the constellation of deficits in schizophrenia and related conditions. These deficits can be measured using electroencephalographic (EEG) including both event related potentials (ERPs) and power within specific frequency ranges. Furthermore, clinical studies suggest that a subset of these EEG biomarkers is associated with symptoms. This presentation will address the relationship between gamma-band activity and social/cognitive behaviors in preclinical models of NMDA-receptor hypofunction as well as how these models can be used to screen therapies.
 
Data from patients with schizophrenia or autism will be juxtaposed with data from animal model mice. Subsequently, EEG and behavioral data from of mice with disruption of the NMDA receptors in excitatory and/or inhibitory neurons will be compared to the pattern of deficits in schizophrenia and autism. Data following exposure to potential therapeutic agents will also be presented.
 
Elevated resting gamma power was associated with deficits in social interactions. Consistent with an elevated baseline noise, excitatory neurons from transgenic mice showed increased intrinsic excitability in patch studies. A GABAB-receptor agonist reduced pyramidal cell excitability, improved gamma-band responses, and reversed behavioral deficits in model mice.
 
Data suggest that baseline gamma power is associated with disruption of social function and that GABAB agonists may be useful for schizophrenia.
 

Rapid-acting Glutamatergic Antidepressants: The Path to Ketamine and Beyond
John H. Krystal, MD, Yale University

This presentation will briefly review the emergence of strategies to treat depression by targeting glutamate neurotransmission, a pursuit that identified the first rapid-acting antidepressant medication, ketamine. This presentation will highlight current hypotheses about disturbances in glutamate synaptic function associated with depression, particularly glial deficits in glutamate uptake, potentially resulting in overstimulation of presynaptic inhibitory glutamate receptors (mGluR2) and overstimulation of postsynaptic NMDA receptors.   It will suggest ways that NMDA receptor antagonists transiently ameliorate the consequence of excessive suppression of glutamate release by disinhibiting glutamate release and to reduce NMDA receptor overstimulation by blocking NMDA receptors. The presentation will then review evidence of the rapid antidepressant efficacy of ketamine as a short-term treatment for depression; highlighting the emergence of clinical improvement within hours rather than weeks. It will also briefly discuss other putative rapid-acting antidepressant drugs/mechanisms including Glyx-13, AZD6765, scopolamine, AMPAkines, and mGluR2 antagonists.
 

Rhythms and Blues: Change in Oscillatory Synchrony as an Intermediate Phenotype for Remission during Medication Treatment of Major Depression
Andrew F. Leuchter, University of California, Los Angeles

The linkage between the relief of symptoms of Major Depressive Disorder (MDD) and the mechanism of action of antidepressant medications remains obscure. Research therefore has focused on identification of intermediate phenotypes (IPs) that could identify subgroups of patients with similar responses to treatment and could constitute biomarkers of medication effectiveness. Recent research indicates that antidepressants may modulate rhythmic brain oscillations, and the resultant shifts in oscillatory synchrony during antidepressant treatment may constitute an IP for treatment response. Our data indicate that a shift in oscillatory synchrony from a low frequency (theta) to a higher frequency (alpha) band constitutes a reliable and specific IP for remission during medication treatment. Data from two independent cohorts of subjects show that the degree of shift from theta to the alpha band is a strong predictor of remission in medication-treated, but not placebo-treated subjects. Preliminary data also suggest that these shifts in oscillatory synchrony may be mediated by changes in extracellular serotonin levels. Our findings are consistent with the theory that some patients with MDD suffer from a syndrome of thalamocortical dysrhythmia, and that antidepressant medications may exert therapeutic effect through resolution of dysrhythmia.
 

Blood Biomarker Panels for Major Depressive Disorders
Eva Redei, PhD, Northwestern University

Depression is one of the leading causes of disability in the United States and its prevalence is increasing steadily. Primary care physicians treat one half to two third of patients suffering from Major Depressive Disorder (MDD), of which less than half diagnosed clinically. A laboratory blood test, based on specific biomarkers, would increase diagnostic accuracy and initiation of treatment. We approached the identification of MDD biomarkers via an integrative method of using animal models of both the genetic and the environmental/stress etiologies of depression. Examining genome-wide expression differences between each model and its control, in their brain and blood, we identified transcripts that show expression differences that are parallel in relevant brain regions and blood. Gene ontology revealed their function ranging from cellular metabolism to neurodevelopment. In the first pilot study, 26 human ortholoques of these transcripts were analyzed quantitatively in the blood of 15-19 year old antidepressant-free adolescents with MDD and not depressed (ND) age, sex and race-matched controls. Transcript abundance of 11 blood markers differentiated subjects with early onset MDD from the ND group. Based on an interacting protein network analysis, overlapping and separate set of transcripts might characterize subjects with MDD vs. MDD and co-morbid anxiety disorder. Thus, our approach can be developed into clinically valid diagnostic panels of blood transcripts for early onset MDD, which could reduce diagnostic heterogeneity in this population and has the potential to advance individualized treatment strategies.
 

Structural and Spectroscopic Neuroimaging Correlates of Treatment Outcome in Mood Disorders
Dan V. Iosifescu, Icahn School of Medicine at Mount Sinai

Emerging evidence suggests that treatment-resistant depression (TRD) might be associated with biological features distinct from other forms of major depressive disorder (MDD). We will review in this presentation data from structural magnetic resonance imaging studies (sMRI) suggesting specific volumetric, cortical thickness and white matter abnormalities associated with TRD. We will also review data collected with magnetic resonance spectroscopic imaging (MRS), a method for in-vivo chemical analysis, suggesting that treatment response in MDD might be associated with metabolic changes in specific brain areas. Several neuropharmacological agents with impact on glutamate metabolism (including ketamine, memantine and minocycline) have recently emerged as potential treatments in mood disorders. We will review new data for ketamine, a glutamate NMDA receptor antagonist, as a rapid-acting treatment for TRD, and new data on its effects on neurocognitive and neuroplasticity parameters (such as BDNF). We will also discuss data on memantine (a weaker glutamate NMDA receptor antagonist) for the treatment of cognitive deficits in bipolar disorder. Adjuvant memantine was associated with acute improvements on several cognitive domains (attention, short-term memory and delayed memory) and with increased hippocampus neuronal viability (as measured with MRS). In a preliminary study with minocycline, an antibiotic with glutamate modulation and antioxidant effects, antidepressant activity was associated with decreases in glutamate-glutamine (Glx) and increased glutathione (GSH) on MRS. Collectively, these studies highlight the emerging evidence linking neuroplasticity (as measured by MRI and MRS) with the mechanism of antidepressant treatments, including promising novel agents impacting glutamate metabolism.
 

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