Pathways THOUGHTS to the & INSIGHTS Future FROM FOUNDATION OUTSTANDING ACHIEVEMENT PRIZEWINNERS

BBRFOUNDATION.ORGbbrfoundation.org 1 BOARD OF SCIENTIFIC COUNCIL DIRECTORS PRESIDENT J. Raymond DePaulo, Jr., M.D. President & CEO Herbert Pardes, M.D. Ariel Y. Deutch, Ph.D. Jeffrey Borenstein, M.D. Wayne C. Drevets, M.D. VICE PRESIDENT EMERITUS Ronald S. Duman, Ph.D. President, Scientific Council Floyd E. Bloom, M.D. Stan B. Floresco, Ph.D. Herbert Pardes, M.D. Judith M. Ford, Ph.D. Ted Abel, Ph.D. Alan Frazer, Ph.D. Anissa Abi-Dargham, M.D. Robert R. Freedman, M.D. OFFICERS Schahram Akbarian, M.D., Fred H. Gage, Ph.D. Chairman Ph.D. Aurelio Galli, Ph.D. Stephen A. Lieber Huda Akil, Ph.D. Mark S. George, M.D. Vice President Susan G. Amara, Ph.D. Elliot S. Gershon, M.D. Anne E. Abramson Stewart A. Anderson, M.D. Mark A. Geyer, Ph.D. Nancy C. Andreasen, M.D., Jay N. Giedd, M.D. Secretary John B. Hollister Ph.D. Jay A. Gingrich, M.D., Ph.D. Amy F.T. Arnsten, Ph.D. David Goldman, M.D. Treasurer Gary S. Aston-Jones, Ph.D. Frederick K. Goodwin, M.D. Arthur Radin, CPA Jay M. Baraban, M.D., Ph.D. Joshua A. Gordon, M.D., Deanna Barch, Ph.D. Ph.D. DIRECTORS Jack D. Barchas, M.D. Elizabeth Gould, Ph.D. Carol Atkinson Samuel H. Barondes, M.D. Anthony A. Grace, Ph.D. Eric F. Bam Francine M. Benes, M.D., Paul Greengard, Ph.D. Donald M. Boardman Ph.D. Raquel Gur, M.D., Ph.D. J. Anthony Boeckh Karen F. Berman, M.D. Suzanne N. Haber, Ph.D. Susan Lasker Brody Wade H. Berrettini, M.D., Philip D. Harvey, Ph.D. Paul T. Burke Ph.D. Stephan Heckers, M.D. Suzanne Golden Bonnie D. Hammerschlag Randy D. Blakely, Ph.D. René Hen, Ph.D. John Kennedy Harrison II Pierre Blier, M.D., Ph.D. Fritz A. Henn, M.D., Ph.D. Carole H. Mallement Hilary Blumberg, M.D. Takao Hensch, Ph.D. Milton Maltz Robert W. Buchanan, M.D. Robert M.A. Hirschfeld, M.D. Marc R. Rappaport Peter F. Buckley, M.D. L. Elliot Hong, M.D. Virginia M. Silver William E. Bunney, Jr., M.D. Steven E. Hyman, M.D. Kenneth H. Sonnenfeld, Joseph D. Buxbaum, Ph.D. Robert B. Innis, M.D., Ph.D. Ph.D., J.D. William Byerley, M.D. Jonathan A. Javitch, M.D., Barbara K. Streicker William Carlezon, Ph.D. Ph.D. Barbara Toll Marc G. Caron, Ph.D. Daniel C. Javitt, M.D., Ph.D. Robert Weisman, Esq. William T. Carpenter, Jr., M.D. Dilip Jeste, M.D. Cameron S. Carter, M.D. Lewis L. Judd, M.D. PUBLICATION CREDITS BJ Casey, Ph.D. Ned Kalin, M.D. Editors Bruce M. Cohen, M.D., Ph.D. Peter W. Kalivas, Ph.D. Lauren Duran Jonathan D. Cohen, M.D., Eric R. Kandel, M.D. Peter Tarr Ph.D. Richard S.E. Keefe, Ph.D. Designer Peter Jeffrey Conn, Ph.D. Samuel J. Keith, M.D. Jenny Reed Edwin Cook, M.D. Martin B. Keller, M.D. Richard Coppola, DSc John R. Kelsoe, M.D. Rui Costa, Ph.D., HHMI Kenneth S. Kendler, M.D. Joseph T. Coyle, M.D. James L. Kennedy, M.D. Jacqueline N. Crawley, Ph.D. Robert M. Kessler, M.D. John G. Csernansky, M.D. Kenneth K. Kidd, Ph.D. Karl Deisseroth, M.D., Ph.D. Mary-Claire King, Ph.D.

JULY 2017 2 168 Members (4 Emeritus) 2 Nobel Prize Winners 4  Former Directors of the National Institute of Mental Health as well as the current Director 4  Recipients of the National Medal of Science 13  Members of the National Academy of Sciences 26 Chairs of Psychiatry & Neuroscience Departments at Leading Medical Institutions 55 Members of the National Academy of Medicine

Rachel G. Klein, Ph.D. Patricio O’Donnell, M.D., J. David Sweatt, Ph.D. John H. Krystal, M.D. Ph.D. John A. Talbott, M.D. Amanda Law, Ph.D. Dost Ongur, M.D., Ph.D. Carol A. Tamminga, M.D. James F. Leckman, M.D. Steven M. Paul, M.D. Laurence H. Tecott, M.D., Francis S. Lee, M.D., Ph.D. Godfrey D. Pearlson, Ph.D. Ellen Leibenluft, M.D. MBBS, M.D. Ming T. Tsuang, M.D., Robert H. Lenox, M.D. Mary L. Phillips, M.D. Ph.D., DSc Pat Levitt, Ph.D. Marina Piciotto, Ph.D. Kay M.Tye, Ph.D. David A. Lewis, M.D. Daniel S. Pine, M.D. Leslie G. Ungerleider, Ph.D. Jeffrey A. Lieberman, M.D. Robert M. Post, M.D. Rita J. Valentino, Ph.D. Irwin Lucki, Ph.D. James B. Potash, M.D., M.P.H. Jim van Os, M.D., Ph.D., Gary Lynch, Ph.D. Steven G. Potkin, M.D. MRCPsych Robert C. Malenka, M.D., Pasko Rakic, M.D., Ph.D. Susan Voglmaier, M.D., Ph.D. Ph.D. Judith L. Rapoport, M.D. Nora D. Volkow, M.D. Anil K. Malhotra, M.D. Perry F. Renshaw, M.D., Mark von Zastrow, M.D., Husseini K. Manji, M.D., Ph.D., M.B.A. Ph.D. FRCPC Kerry J. Ressler, M.D., Ph.D. Karen Dineen Wagner, J. John Mann, M.D. Carolyn B. Robinowitz, M.D. M.D., Ph.D. John S. March, M.D., M.P.H. Bryan L. Roth, M.D., Ph.D. Daniel R. Weinberger, M.D. Daniel Mathalon, Ph.D., M.D. John L.R. Rubenstein, Myrna M. Weissman, Ph.D. Helen S. Mayberg, M.D. M.D., Ph.D. Marina Wolf, Ph.D. Robert W. McCarley, M.D. Bernardo Sabatini, M.D., Jared W. Young, Ph.D. Bruce S. McEwen, Ph.D. Ph.D. L. Trevor Young, M.D., Ph.D. Ronald D.G. McKay, Ph.D. Gerard Sanacora, M.D., Ph.D. Jon-Kar Zubieta, M.D., Ph.D. James H. Meador-Woodruff, Akira Sawa, M.D., Ph.D. M.D. Alan F. Schatzberg, M.D. MEMBERS EMERITUS Herbert Y. Meltzer, M.D. Nina R. Schooler, Ph.D. George K. Aghajanian, M.D. Kathleen Merikangas, Ph.D. Robert Schwarcz, Ph.D. Dennis S. Charney, M.D. Richard J. Miller, Ph.D. Philip Seeman, M.D., Ph.D. Jan A. Fawcett, M.D. Karoly Mirnics, M.D., Ph.D. Yvette I. Sheline, M.D. Bita Moghaddam, Ph.D. Pamela Sklar, M.D., Ph.D. Dennis L. Murphy, M.D. Solomon H. Snyder, M.D., DSc, D.Phil. Charles B. Nemeroff, M.D., (Hon. Causa) Ph.D. Matthew State, M.D. Eric J. Nestler, M.D., Ph.D. Murray Stein, M.D., M.P.H. Andrew A. Nierenberg, M.D. John S. Strauss, M.D.

bbrfoundation.org 3 LETTER FROM THE PRESIDENT

As we celebrate our 30th anniversary, we are excited to share the thoughts and insights of our Outstanding Achievement Prizewinners. Together, they provide a rare glimpse into the future – visionary statements of men and women who are leaders in their respective specialties. Their assessments of where we are and where we are headed are comprehensive in scope.

There is universal acknowledgement of how far brain and behavior research has come since the Foundation’s inception, and excitement about recent technological advances that have made possible experiments that would have seemed like science fiction 30 years ago. However, there is recognition of how much remains to be learned about the brain’s workings.

The significant impact of the Foundation is only possible through the collaboration between scientists and our generous donors, who understand that investing in brain and behavior research will continue to bring better treatment and ultimately cures and methods of prevention. We are deeply appreciative of this collaboration.

Jeffrey Borenstein, M.D. President & CEO

4 The Brain & Behavior Research Foundation Outstanding Achievement Prizes These top prizes in psychiatric and neuroscience research recognize leading scientists for their innovation and productivity, and for achieving breakthrough discoveries that are bringing us closer to our goal of conquering mental illness.

These prizes not only recognize and award extraordinary leadership in key fields of psychiatric research; they provide models of accomplishment for younger scientists involved in brain and behavior studies.

The Outstanding Achievement Prizewinners are dedicated teachers and scientists who represent models of accomplishment for younger scientists in brain and behavior research.

Lieber Prize for Schizophrenia Research Established in 1987 by Constance E. Lieber, Foundation President Emerita, and her husband, Stephen A. Lieber, Chairman of the Foundation’s Board of Directors, to bring public recognition to the outstanding discoveries being made in schizophrenia research.

Colvin Prize for Mood Disorders Research Established in 1993, this prize was formerly known under the successive titles of the Selo Prize, Falcone Prize and Bipolar Mood Disorder Prize. The prize was renamed in 2012 in honor of the late Oliver D. Colvin, Jr., a great benefactor of the Foundation who left the largest single contribution in the Foundation’s history.

Ruane Prize for Childhood & Adolescent Psychiatric Research This prize was initiated in 2000 by philanthropists Joy and William Ruane to recog- nize important advances in understanding and treatment of early-onset brain and behavior disorders.

Goldman-Rakic Prize for Cognitive Neuroscience This prize was created by Constance and Stephen Lieber in memory of Patricia Goldman-Rakic, Ph.D., a distinguished neuroscientist renowned for discoveries about the brain’s frontal lobe, after her tragic death in an automobile accident in 2003.

Maltz Prize for Innovative & Promising Schizophrenia Research Established in 2005, the prize was renamed in 2016 in honor of Board Members Milton and Tamar Maltz. The Maltz Prize is given to an investigator who has under- taken innovative and promising research in schizophrenia. Winners of this prize are selected by the Lieber Prize recipient(s) of the same year.

bbrfoundation.org 5 The Lieber Prize for Schizophrenia Research Francine M. Benes, M.D., Ph.D. into the development of innovative new treatments Harvard Medical School by providing essential information from a studies that 2002 Lieber Prizewinner span the entire technological continuum of transla- tional neuroscience. Schizophrenia is a uniquely complex disorder affecting human cognition and emotion in the absence of any David L. Braff, M.D. diagnostic histopathology. Sophisticated new technolo- University of California, San Diego School of Medicine gies, however, are detecting microscopic and molecular 2014 Lieber Prizewinner alterations in regions of the brain that are likely related to the mediation of these abnormalities. The “high Schizophrenia is a profoundly complex disorder of the tech” capabilities of MRI technology to define relevant human brain that results in devastating levels of disabil- brain networks and “risk” genes for schizophrenia have ity. We have made progress in understanding schizo- been essential for understanding the pathophysiology phrenia in the context of the “gene-X-environment” of schizophrenia. Parallel PM studies are contributing to (GXE) paradigm. In terms of genomics, large−scale our understanding of this disorder by unmasking dis- projects have identified many common and de novo crete alterations in the wiring of complex microcircuitrs risk loci. One problem with this extensive work is that that can be explored under controlled conditions using the effect sizes of the many risk loci remain quite small. empiric models developed by basic neuroscientists. It These genetic risk loci do seem to tag long suspected has become clear that postmortem studies provide an aberrant CNS processes in schizophrenia vulnerability, essential bridge to studies in live human subjects with including glutamate dysfunction, neuronal pruning dys- experiments conducted in vitro and in vivo using neuro- regulation and inflammatory impacts. Also, while new biologic models. The latter make it possible to explore medications are being developed, cognitive and sensory the validity and relevance of findings in schizophrenia training interventions offer an exciting “non−drug” subjects. Postmortem studies of schizophrenia are a path to schizophrenia treatment. What will the future sine qua non for defining specific microcircuitry abnor- hold? There are three discovery pathways available: malities in schizophrenia, as they attain anatomical res- 1. A “game changing” serendipitous finding (e.g., the olutions and molecular sensitivities that are a thousand discovery of Thorazine as a treatment) 2. A dramatic times and a million times greater, respectively, than “Kuhnian” insight such as Darwin and Mendel’s con- those attainable in live human subjects. While postmor- cepts 3. Largely incremental advances (the most likely tem studies of schizophrenia are bringing us closer to path). For example, using biomarker endophenotypic understanding how microcircuitry abnormalities may be deficits of key, e.g., quantitative domains (e.g., in neu- related to ”risk” genes and abnormal brain networks, rocognition) offer powerful discovery pathways. As I say they also have the potential to translate brain findings to my students, “you are the luckiest people in science:

bbrfoundation.org 7 although we have learned a lot about schizophrenia, that are becoming more and more powerful as they are there is so much left to do.” The path to understanding combined with developments in artificial intelligence and developing more effective personalized treatments may be helpful in this regard. Thanks to the efforts based on genotype and biomarkers is inevitably going of many researchers, we have come a long way since to be long but will also be exciting, and hopefully 1987 in our understanding of schizophrenia. But we will eventually relieve the profound suffering of our won’t reap the benefits of our new knowledge without patients and their families. continued funding to support the army of researchers now dedicated to obtaining better treatments and, Benjamin S. Bunney, M.D. ultimately, prevention. Yale University 1987 Lieber Prizewinner Marc G. Caron, Ph.D. Duke University Medical Center Since 1987, when the first Lieber prize was awarded, 2013 Lieber Prizewinner the development of new techniques has fueled an exponential growth in schizophrenia research and Schizophrenia is an inherited and complex brain allowed investigation into many new areas of potential disorder likely resulting from a landscape of genetic etiology and pathogenesis. In 1987 the human genome mutations. Although each mutation explains only had not yet been mapped and techniques such as PCR a minute portion of disease burden, many of these and CRISPR-Cas9 had not been invented. Although mutants point to functional imbalances in neuronal the first gene transfer was performed in 1980, gene brain circuits as being responsible for both positive manipulation allowing for knock-in and knock-out and negative symptoms of the disease. Current anti- animal models did not exist. The “dopamine hypoth- psychotic therapies target the brain dopamine systems esis” of schizophrenia still provided the impetus for a via blockade of the G protein coupled receptor (GPCR) lot of the schizophrenia related research. Now, thanks D2 dopamine receptor (D2R) to lessen positive symp- to the work of thousands of researchers, funded by toms, but fail to correct the cognitive and executive NIMH and the Brain and Behavior Research Founda- function deficits associated with negative symptoms. tion, we are gaining confidence that schizophrenia is a Thus, better therapies are needed with broader effi- CNS developmental disorder. It is posited that mistakes cacy. To this end, we have leveraged the newly appre- in the piecing together, shaping and malfunctioning ciated concept that GPCRs can signal not only through of brain structures occur, which are caused by two, conventional G protein activation but also through the as yet unidentified, converging elements – genetic kinases and ß-arrestins components of the so-called predisposition and environmental events. Neither has desensitization pathway, to mediate distinct cellular been identified but reams of data are accumulating and physiological responses. We have recently provided regarding the possible genes involved, the proteins for proof-of-concept in animal models that a novel ß-arres- which they are responsible and environmental factors, tin-biased D2R ligand can, like antipsychotics, block the both pre- and post-natal. Relatively young fields such hyperdopaminergic tone presumably responsible for as neuroengineering are yielding powerful and ever the positive symptoms, but unlike typical antipsychot- improving techniques, optogenetics being an example, ics, can simultaneously enhance DA function in meso- to help us understand the function of specific neurons limbic neurons. Current work is testing the hypothesis within neuronal circuits. Given the growing plethora that this ß-arrestin-biased D2R ligand will ameliorate of possibly relevant research findings, it will take new cognitive and executive functions in preclinical models. techniques and continued research to determine their A therapeutic agent that can deliver multifaceted res- salience for biomarkers as well as etiology and patho- toration of dopamine brain functions should transform genesis. For example, techniques for mining Big Data the treatment of psychotic disorders.

8 William T. Carpenter, Jr., M.D. grail” for me. However, my experience directing a University of Maryland schizophrenia outpatient clinic convinced me early on 2000 Lieber Prizewinner that the dopamine hypothesis was not totally explan- atory. In a an experimental detour that changed the Advance in knowledge and concepts are rapidly chang- trajectory of my research career from focusing on cat- ing opportunities in science related to schizophrenia. echolamines to glutamate, Robbie Schwarcz, my first Of profound importance is the far more systematic fellow, and I drew from the observations of John Olney addressing of the heterogeneity of schizophrenia. that systemic glutamate killed neurons in the infant rat There is a recognition that there are many different brain. We also took advantage of the potent glutamate symptoms associated with the diagnosis and that peo- receptor agonist, kainic acid, characterized by Japa- ple with this diagnosis vary as to which symptoms are nese neuropharmacologists and showed that when present and when they developed. Science is redirected injected into the rat striatum it recreated the pathology from the diagnostic level to the actual pathology, with of Huntington disease. Searching to better understand implications that cross current diagnostic boundaries. how excessive activation of glutamate receptors might Brain mechanisms and their causes will vary across account for human neurodegenerative disorders such cases, and so too will therapeutic discovery. New dis- as Huntington disease and Alzheimer disease, my lab- covery in schizophrenia will be informative for other oratory isolated a neuropeptide implicated in negative disorders where some of the patients have the same modulation of glutamatergic neurotransmission. Our pathology. Perhaps the most promising area of science postmortem study demonstrated that its catabolism with clinical impact relates to prevention. Recent work was reduced in cortex in schizophrenia. This led to the has confirmed that young people with mild but clini- hypothesis that the fundamental deficit in schizophre- cally relevant symptoms are at increased risk for devel- nia was hypofunction of NMDA receptors. This pro- oping a psychotic disorder. Initial clinical trials suggest posal dovetailed with the results of human and animal that treatment can reduce symptoms and progression studies with the NMDA receptor antagonist, ketamine. to full psychosis. This sets the stage for detecting risk NMDA receptor hypofunction in cortex best accounted even earlier, before the onset of symptoms. It is hoped for the cognitive impairments and motivational deficits that current studies will yield information relevant to that accounted for persistent disability and was the identifying persons at risk in advance of symptoms proximate cause of psychosis. The last 15 years have and that knowledge on the genetic and environmen- been particularly productive as we have pursued this tal risk factors will provide a basis for primary pre- hypothesis in my laboratory and with collaborators in vention approaches. The study paradigm thus moves our NIMH Conte Center, taking advantage of molecular from treatment to primary prevention with the aim of techniques. To recreate NMDA receptor hypofunction, reducing the incidence of schizophrenia and related we silenced the gene, serine racemase, that is respon- psychotic disorders. sible for synthesizing the NMDA receptor co-agonist, D-serine, and showed that it reproduced the cortical Joseph T. Coyle, M.D. atrophy, synaptic pathology, cognitive deficits and the Harvard University neurochemical pathology of schizophrenia. Further- 2004 Lieber Prizewinner more, these deficits could be largely reversed by treat- ment in adulthood by restoring D-serine brain levels or Since commencing my involvement in neuroscience treating with a mGluR3 positive allosteric modulator. research 50 years ago as a medical student in Sol The results were validated by the genetic findings that Snyder’s laboratory, schizophrenia has been the “holy a dozen risk genes for schizophrenia including serine

bbrfoundation.org 9 racemase are within two degrees of separation from who have had functional challenges for most of their the NMDA receptor. As we look to the future, we must lives. However, we can envision a time when people recognize that having the risk gene does not guarantee with schizophrenia can maintain personal connections a rapid pathway to treatment (witness Huntington dis- to friends and family, find someone to love, attend ease). Nevertheless, we may be reaching a critical mass college, and a hold a job successfully. To accomplish of knowledge of brain disorders so that like in the case this, we need to know two things. First, we need a of cancer we may have achieved a tipping point that detailed understanding of what is holding back people leads to an accelerating discovery of more effective with schizophrenia from more complete integration. treatments. I want to emphasize that NARSAD played For example, we know at a general level that these a critical role at each stage of my journey. include problems in cognition (i.e., processing social and non-social information in their daily lives) and in Robert Freedman, M.D. motivation (i.e., a desire to engage community life and University of Colorado, Denver other people). Second, we need effective treatments 2015 Lieber Prizewinner for these problems. Such treatments will likely involve some combination of novel drugs, innovative train- The epidemiology of schizophrenia points to prena- ing methods, and perhaps new approaches such as tal brain development as a special period of risk, in neurostimulation. It is now abundantly clear that the which genes that are associated with schizophrenia functional disability associated with schizophrenia is are working to construct the brain. At this point, the persistent, substantial, and multifaceted. Similarly, the brain problems that later give rise to schizophrenia scientific approach to address this problem will need to are already being formed. Infection of the mother can be persistent, substantial, and multifaceted. compound the problems. To prevent schizophrenia in these children, we need to investigate how to prevent Paul Greengard, Ph.D. these brain abnormalities from ever forming. My own The Rockefeller University research has identified a promising treatment, increase 1996 Lieber Prizewinner of the mother’s intake of the nutrient phosphatidylcho- line, which ameliorates the effects of some genetic risk Until recently, remarkably little was known about the and infections. Children whose mothers received this causes of schizophrenia, or even about the regions of treatment are now reaching 4 years old and are less the brain involved in this disease. In recent decades, we likely to show attention and social problems seen in have learned that there are a large number of diverse children who develop schizophrenia as adults. I foresee types of nerve cells in the brain and that the differ- the field developing this treatment and others to pro- ent cell types have extremely varied compositions of duce children who are born resilient instead of prone the proteins that they express. Using this background, to mental illnesses. schizophrenia researchers are now able to identify the regions, and the cell types within those regions, that Michael F. Green are involved in schizophrenia. By manipulating the University of California, Los Angeles amount and function of specific proteins in specific 2016 Lieber Prizewinner brain regions, scientists are able, for the first time, to identify signaling pathways that lie at the basis of My impression is that the next phase of schizophre- schizophrenia. Genetic studies in which a given protein nia research will revolve around the idea of recovery. can be increased or decreased in amount in animal The goal will be to enhance the ability of people with models of schizophrenia enable us to test hypothe- schizophrenia to integrate fully into the community. We ses concerning the role of such proteins in causing or do not expect miracles – after all, these are individuals combating the disease process. Identification of such

10 proteins also permits the development of pharmaceu- tive new treatments that we need. tical compounds aimed at either increasing or decreas- ing the activity of such proteins. Through an iterative Kenneth S. Kendler, M.D. process, we can anticipate highly effective drugs with Virginia Commonwealth University minimal side effects within the next few years. 1995 Lieber Prizewinner

Eve C. Johnstone, M.D. I received the Lieber Prize in 1995, during another University of Edinburgh, Scotland era of research in the genetics of schizophrenia. To 2007 Lieber Prizewinner everyone’s satisfaction, twin and adoption studies had demonstrated that genetic factors made a major contri- I qualified in medicine in 1967 and I worked in aca- bution to the etiology of schizophrenia. Linkage studies demic psychiatry, principally in schizophrenia research were starting to get going, but no major successes had from 1972 until 2010 when I retired. Nowadays I am yet occurred (or were going to occur). Now, in 2017, only peripherally involved in research and not at all the field has been transformed in ways that would in clinical practice. From my own point of view my have been impossible to predict 22 years ago. While research career worked out very well – we made some genome-wide association studies took time to prove findings that I think are really worthwhile. I was lucky their utility, they have now been spectacularly success- to be in the right places at the right time and I had ful, although the effect size of the loci identified are some wonderful colleagues. The work I did essentially all small. We are beginning to clarify other parts of the depended upon three main methods of investiga- genetic architecture. Sequencing is still in early days but tion-imaging, treatment trials and clinical/outcome the broad outlines are becoming evident. The impact studies. Non-invasive imaging was just coming in at an of large genome anomalies – copy number variants – ideal time for me and it has lasted as a useful investi- are also increasingly understood. The greatest question gative technique for more than 40 years. Nowadays ahead of us now is to find the biological stories con- it is probably most useful in combination with other tained in all these statistical signals. Can we translate techniques such as genetic work. Clinical trials are these findings into increased understanding of biolog- less fashionable now probably because we need ical mechanisms of illness? And, if so, can we new treatments and new theories to drive the used these biological insights to develop new development of such treatments. Clinical/out- ways to prevent or treat these disorders? I am come studies are very labor-intensive and you cautiously optimistic. The problem is a very need a really worthwhile question to justify the complex one. But our tools are improving level of investment. Other techniques are now and the research community is growing, in providing new possibilities and I am particu- size and sophistication. larly interested in stem cell work using blood and skin samples from people whose psychoses are associated Joel E. Kleinman, M.D., Ph.D. with minor genetic anomalies. This work is particularly National Institute of Mental Health valuable in relation to extended families with individual 2011 Lieber Prizewinner members with and without the anomalies and with and without the psychoses. We have such families from The identification of genetic variants that increase our large clinical/outcome studies and while I could not risk for schizophrenia is one of the major advances for do the lab work, I am fascinated by the findings and research on this syndrome. In so far as these variants happy to see my case material of ongoing value. I hope are species-specific, postmortem human brain tissue that the testing of batteries of drugs against the dishes has been critical for identifying the molecular mecha- of relevant stem cells may ultimately give use the effec- nisms associated with these genes. The identification of

bbrfoundation.org 11 specific molecular mechanisms has the potential to help Stephen R. Marder, M.D. us elucidate how environmental factors interact with University of California Los Angeles genes to cause schizophrenia. Moreover, this approach 2016 Lieber Prizewinner will hopefully give us new targets for improved treat- ments for schizophrenia, especially for cognitive defi- I anticipate advances in the treatment of schizophre- cits. Postmortem human brain studies have been one nia that will occur in the next decade and beyond. The of the areas of my expertise for 40 years allowing me most important advances that can affect people who the opportunity to contribute to this line of research are currently living with schizophrenia may emerge in schizophrenia. from research focusing on non-pharmacological treat- ments. In this area, strategies for improving cognition, Jeffrey A. Lieberman, M.D. negative symptoms, positive symptoms, and social Columbia University cognition have been shown to be effective, with effect 2006 Lieber Prizewinner sizes indicating that the amount of improvement is meaningful. Unfortunately, these findings have not We may be approaching a tipping point in our historic affected clinical care. Advances are likely to emerge efforts to elucidate the causes of schizophrenia and from studies that implement these interventions and alleviate its symptoms and prevent disability. Three deliver them to the most appropriate patients at the areas of research are leading the way. Genetic studies right time. New pharmacological strategies or neuro- are revealing the architecture of schizophrenia’s heri- modulation may facilitate the effects of these inter- tability and causation. Findings of genetic mutations ventions, but they will not be the primary treatment. (inherited and sporadic) that have large effects and I am most excited about treatment research that will high penetrance can point to therapeutic agents tar- be disease-modifying. That is, pharmacological or geting gene products outside of the scope of psycho- non-pharmacological interventions that target the tropic drugs and that would never have been consid- underlying pathology in the brain – perhaps an inflam- ered. At the same time biomarkers, using imaging and matory process or a defect in synaptic plasticity – that electrophysiological procedures in particular, are being would be delivered before the illness emerges or at the used to identify people who are at imminent risk of early stages of the illness and would change the course developing schizophrenia and signaling the need for of the illness. This is a very ambitious goal and one that intervention. These also are highlighting the neural will require developments in genetics, basic neurosci- circuitry of schizophrenia and potential therapeutic ence, and clinical science. Fortunately, BBRF has played approaches using neuromodulation. In this context, a major role in supporting the development of scientists collaborative multi-specialty care provided to individu- who are involved in all of these research areas. als at the initial stages of their illness are now capable of enabling recovery and limiting the damage caused Patrick McGorry, M.D., Ph.D., FRCP, FRANCZP by schizophrenia or even preventing its onset. All in Orygen & University of Melbourne, Australia all, we can do more to help people with schizophre- 2015 Lieber Prizewinner nia than ever before. It’s now a matter of providing these services in a timely fashion and enabling their The future of schizophrenia research is dependent access. Moreover, with continued research, improved upon a paradigm shift to a transdiagnostic approach to treatments and even eventual cures can be expected aetiology, neurobiology and treatment. Schizophrenia to follow. researchers have led the psychiatric world in moving from a late− or end−stage focus to early diagnosis and a focus on the earliest stages of illness. This has shown that the course of illness is plastic and can be greatly

12 improved if timely evidence−based care is provided. available agents which can be used as first−line and In doing so we have learned that the need for care maintenance treatments, rather than reserved for precedes diagnostic “clarity” according to a diagnostic treatment failures and to avert suicide. Rapastinel, as system that was constructed over a century ago, based my lab has shown, has potential to also address the on late macrophenotypes. The early microphenotypes cognitive impairment present in mood disorders, which are fluid, can lead in many directions and comorbid- would address a major unmet need in their treatment. ity is the rule rather than the exception at all stages of Indeed, I expect future research to clarify how stress illness. So phenotypic diagnostic clarity may ultimately contributes to both mood symptoms and cognitive be a mirage, or at least a matter of degree in a more impairment in the major mood disorders. We can also dimensional sense. Our psychosocial and biological expect advances in pharmacogenetics to extend current treatments generally lack specificity for the current knowledge about biomarkers for suicide, e.g., a muta- diagnostic categories, especially early in the course. tion in the cholesterol synthesizing gene, ACP1, which Later on, the ubiquity of comorbidity underpins what we and others have shown to be the top biomarker is often derided as “polypharmacy.” A transdiagnos- for suicide risk in bipolar disorder and schizophrenia. tic clinical staging model could be validated both by Pharmacogenetic research will also lead to diagnostic clinical trial data, and also by key biomarkers which, tests to facilitate diagnosis and choice of medication in in reflecting potential mechanisms of disease (genetic mood disorders. research will guide this search), are likely to extend across diagnostic boundaries and hence redraw bound- Sir Robin M. Murray, M.D., F.R.S. aries. This implies the critical need to study and follow King’s College, London early−stage samples across the diagnostic spectrum 2003 Lieber Prizewinner accessed via primary care and youth mental health plat- forms. I expect genetic as well as biomarker research For a UK psychiatrist, one troubling development in to increasingly support the transdiagnostic approach the USA is the increasing use of cannabis (marijuana). and the search for mechanisms, rather than, as once Marijuana is like alcohol; the majority of people who hoped, the validation of flawed and historical concep- use it sensibly come to no harm, but heavy users tions from the age of steam. A crucial feature of future increase their risk of adverse effects. It is now clear successful research, and indeed a civilized society, is that heavy use of high potency varieties of cannabis dramatically increased global investment to guarantee increases risk of psychosis; in London, one quarter of evidence−based care for all people with schizophrenia the patients we see with schizophrenia would not have and mental illness across the spectrum. developed it but for their heavy use of marijuana. Can- nabis is more potent than it used to be. In the 1960s, Herbert Y. Meltzer, M.D. marijuana contained only about 3−4% of tetrahydro- Northwestern University, Feinberg School of Medicine cannabinol (THC), but now high potency varieties often 1992 Lieber Prizewinner contain 16−20%. Furthermore, in some states one can legally buy preparations with 40% or 60% THC, and of The most important advance in mood disorder research course synthetic cannabinoids such as K2 and spice are in the near term will be the further development of available on the internet. In the UK the average psychi- mood−altering and suicide−preventing drugs for major atrist, and indeed the average young person, is aware depression and bipolar disorder, based upon rapasti- of the risks, and consumption of cannabis has declined nel (GLyx 13) and ketamine−related formulations. We over the last 10 years. As cannabis use becomes more can expect more effective and safer drugs than these common in the USA, it is vital to study the mechanisms breakthrough agents, based upon further research underlying cannabis-associated psychosis, and to moni- into their mechanisms of action. These will be orally tor the effects of legalization on mental health.

bbrfoundation.org 13 Michael J. Owen, M.D., Ph.D. are alleviated by antipsychotic medication, the negative Cardiff University, UK signs are less responsive to medication. All the antipsy- 2012 Lieber Prizewinner chotic drugs act by a similar mechanism of interfering with the transmission of dopamine within the brain, We now stand at a point of great opportunity aris- either by blocking the type 2 dopamine receptor or by ing from the confluence of three streams of scientific competing with the natural dopamine in the brain. The endeavor. First, recent genomic studies have identi- dopamine type 2 receptor, known as the D2 receptor, fied a substantial number of risk alleles for psychiatric can exist in either a state of high affinity for dopamine disorders including schizophrenia, bipolar disorder and or a state of low affinity for dopamine, analogous to autism, and we can expect further advances over the hemoglobin that has red and blue states of existence. next 5 years. One of the key discoveries has been that Although animal models of schizophrenia do not prop- genetic risk does not obey current diagnostic boundar- erly reflect this uniquely human disease of schizophre- ies, with many risk variants instead increasing suscep- nia, all animal models show an elevation in the number tibility across a range of disorders. Pathways of risk are of high-affinity states of the brain’s dopamine type 2 beginning to emerge from the genomic findings from receptor. For the future measurement of D2High states within disorder, and cross-disorder studies. Although in humans, the current work is to develop markers to these are currently rather broad and do not provide for label D2High states for diagnosis and treatment. clear mechanistic understanding, the findings point to the importance of particular synaptic proteins, immu- Solomon H. Snyder, M.D. nological pathways and epigenetic regulators. Second, Johns Hopkins University advances in stem cell biology and genome engineering 2001 Lieber Prizewinner now allow human disease risk to be modeled with high construct validity in neuronal cells. Third, advances Much of the research that has given insights into brain in neuroscience allow us to probe disease mechanisms mechanisms of schizophrenia has involved studies across development and at neuronal and systems levels elucidating the mechanisms of action of antipsy- in animal as well as cellular models, and in humans. chotic and psychotomimetic drugs. Thus, blockade The challenge now is to integrate advances across these of dopamine D2 receptors by classic antipsychotic/ three areas to identify disease mechanisms and new neuroleptic agents led to the “dopamine” hypothesis, drug targets and to develop new diagnostic strata that namely that an excess of dopamine neurotransmis- map more closely onto underlying mechanisms and sion may be pathophysiologic. The close resemblance define patient subgroups for treatment studies. of ketamine psychosis to schizophrenia led to interest in the mechanisms of ketamine action, specifically its Philip Seeman, M.D., Ph.D. blockade of glutamate-NMDA receptors. This implied University of Toronto, Canada that agents stimulating such receptors, especially their 1990 Lieber Prizewinner “glycine” site, may be therapeutic. More recently, genome research has linked over a hundred genes to There are many causes of schizophrenia, including the propensity for schizophrenia. Unfortunately, each spontaneous mutations in one’s DNA, birth injuries, of these genes appears to contribute only a small por- brain accidents, prolonged isolation, and long-term mis- tion of the risk for schizophrenia, restricting the utility use of addicting drugs. Despite the different causes, the of such findings. Nonetheless, the strong association signs and symptoms of schizophrenia are similar, with of specific genes to the disease hints at specific aber- positive symptoms such as delusions and hallucinations, rations that may be pathogenic. The fact that many of and negative signs, such as social withdrawal, and an the schizophrenia-associated genes are associated with unrealistic recognition of reality. While the positive signs synaptic function bolsters the relevance of this line of

14 research. Particularly tantalizing is the possibility that a worthy and important direction to follow. These a concatenation of several predisposing genes triggers biomarkers may be genetic, neuroanatomical, neuro- psychosis. In summary, insights from drug actions are chemical, neurophysiological, or psychosocial. In the giving way to a focus on defined genetic mechanisms future they will be ascertained through genetic studies, that may tell us much about the origins, progression neurophysiology research, outcome studies and neuro- and therapy of schizophrenia. imaging, for example. As we have recently learned, one of the strongest genetic associations at a population Patrick F. Sullivan, M.D., FRANZCP level involves genes which have an immune function. University of North Carolina & Karolinska Institutet, This is based on work done on very large samples such Stockholm, Sweden as the Psychiatric Genetics Consortium which identified 2014 Lieber Prizewinner genes on chromosome 6 having a strong association with schizophrenia. Dysregulation of immune system Schizophrenia research has always been hard. This is functions has been a feature of recent work on schizo- one of the toughest and most complicated disorders phrenia etiology. By comparing the RNA from immune in all of medicine. However, it’s beginning to change. cells among clinical high risk patients vs. controls, in We finally have a minimally adequate set of scientific the future, RNA may be used as a biomarker assay for tools that we can use to ask the right questions of the psychosis risk, while immunotherapy may become a brain, the most complicated machine known to us. We viable approach for clinical treatment. Recent prospec- are beginning to get a full idea of the genetic changes tive longitudinal neuroimaging studies on prodromal that underlie schizophrenia. Due to unprecedented subjects have shown accelerated gray matter loss and international collaboration, we are working hard to third ventricle expansion around the time of onset of deliver “actionable” findings that reveal the fundamen- psychosis. Steeper gray matter loss seems to be unique tal biology, inform clinical practice, and deliver new to those Clinical High Risk (CHR) individuals with higher therapeutic targets. We think that we have identified levels of sub-psychotic pre-delusional symptoms. This the cell types that confer risk for schizophrenia. The may reflect pathophysiological processes driving emer- genetic findings agree reasonably well with known gence of psychosis. Identification and intervention of and predicted drug targets. For at least one of our this brain matter loss is a future goal for investigators. patients, we have been able to fully explain precisely Furthermore, we must stay focused on developing cop- why he became ill. Prediction of the future is always ing skills to address the everyday challenges of schizo- hazardous but, given that we finally have a min- phrenia through psychosocial research. Should we imally adequate toolkit, it is possible that we canvass recent discoveries it appears that schizo- are entering a golden age of research into the phrenia research has an exciting future as our fundamental basis of schizophrenia. technology, knowledge and methods advance. Disciplines recently thought to be nowhere near Ming T. Tsuang, M.D., Ph.D., D.Sc. the ambit of neuropsychiatry research − such as University of California, San Diego the microbiome − are now being interrogated, while 2010 Lieber Prizewinner genetics, neuroimaging and psychosocial research con- tinue to make great strides in identifying, intervening, It is imperative to the future of schizophrenia research and preventing schizophrenia. that we focus on ways in which we can identify psy- chosis before onset and intervene early − with the aim being early recovery/good outcome and/or complete prevention. The search for biomarkers which predict early psychotic symptoms at the prodromal stage is

bbrfoundation.org 15 Daniel R. Weinberger, M.D. normal and diseased brain function. The earlier circum- The Lieber Institute, Johns Hopkins University stantial and epidemiological evidence linking the origins School of Medicine of schizophrenia to prenatal life have been validated by 1993 Lieber Prizewinner molecular studies in post mortem human brain, which have shown that genes associated with schizophrenia Schizophrenia research has taken a giant leap for- risk affect early neurodevelopmental processes such as ward from the time that I was honored with the Lieber neuronal differentiation and maturation. An emergent Prize in 1993. We have learned more in the past two inference then is that early brain development mediates decades about the causes and mechanisms underlying schizophrenia genetic risk, with fundamental implica- major psychiatric disorders than in all of prior history. tions for pathogenesis. These discoveries and insights BBRF has played a major role in this sea change in provide a rich opportunity to find new treatments and general and in my scientific work in particular. When I new approaches to prevention. No treatment used in started my research career at the NIMH, the overarch- psychiatry today, whether talk or medical, was discov- ing goal was to uncover objective scientific evidence ered based on an understanding of causative mech- that the brain was the main actor responsible for anisms and pathogenesis. Having objective clues to mental illness. Refrains from an earlier era attributing causative mechanisms has to be a better approach. I psychiatric illness to family dynamics still echoed in the anticipate that within the next decade, we will see new hallways of the NIH. My early work involved applying treatments emerge based on this new research data. I neuroimaging technology to explore how structural anticipate that we will identify combinations of genetic and functional variations in the brain were associated and environmental signatures of increased risk which with schizophrenia. We showed in those studies that will be used to target high-risk individuals for preven- the brain is definitively involved. We also surmised tive monitoring and improve long term outcome. And, from associated observations that these brain changes because of these breakthroughs and the support of reflected events in brain development from much ear- organizations like BBRF, psychiatry research will emerge lier in life. But, we did not know how these changes as a top choice career for the best and the brightest of arose and how they translated into the illness. We had the next generation of research scientists. evidence of relevant biological phenomena but no information about causation. The recent discovery of genes related to risk for schizophrenia has changed the research landscape profoundly and enduringly. Genes represent causative mechanisms and they open a new era in diagnosis, treatment and prevention. We are far from achieving the full promise that information about basic mechanisms offers, but we are seeing a seismic shift in how we study schizophrenia and related conditions. It is now evident that in most cases, there are no singular causal ‘schizophrenia genes’ per se, but rather numerous, maybe up to thousands of genetic variants in the broad population that contribute small increments of risk to this complex psychiatric syndrome. Identifying genetic variants that confer schizophrenia risk and elucidating their impact on the underlying neurobiology of the disorder are critical, albeit formida- ble, tasks, given the vast unknowns and complexity of

16 The Colvin Prize for Mood Disorders Research (formerly known as the Selo, Falcone & Bipolar Mood Disorder Prize) Hagop S. Akiskal, M.D. Robert H. Belmaker, M.D. University of California, San Diego Ben-Gurion University, Israel 2001 Falcone Prizewinner 2000 Falcone Prizewinner

Mood disorders today are being investigated in spe- My area of research for over 40 years has been the cialized mood clinics where patients have thorough mechanism of action of medicines that ameliorate the evaluations with semi-structured interviews. Clinical, symptoms of bipolar disorder. For many years I was interpersonal, and biological data are gathered in a sys- convinced that unraveling the mechanism of these tematic fashion. Interpersonal and cognitive-behavioral compounds would lead to a single common mecha- therapy, as well as marital counseling, is used adjunc- nism and that the understanding of that single com- tively with other patient-friendly psychotherapies. Mod- mon mechanism would allow us to understand the ified psychodynamic psychotherapy is still alive. Many single central biochemical abnormality predisposing clinics focus on women, and this is particularly true for to bipolar mood swings. I probably would have been seasonal depressions. Subthreshold mood disorders willing to take a significant financial bet when I finished have acquired particular significance from an epidemio- psychiatric residency that I would have that answer by logical and preventive perspective. Moderate to severe the time I retired. However, after about 20 or 30 years depressions, associated with middle age and later life of research it began to seem much more likely that the are increasingly receiving stimulation-type treatments. various classes of medicines that help bipolar disorder Both psychosocial family and pharmacotherapeutic have very different mechanisms of action and their approaches are being used in children. This literature common point of convergence has not been found, is more of an art than a science. A plethora of new even though many of them have similar clinical indi- specific and non-specific pharmacological agents have cations. Moreover, my study and that of others of the entered the market. From a preventive perspective, it mechanism of action of therapies of bipolar disorder is important for primary care physicians and internists has not converged on genetic and biochemical studies to have patients screened in their offices on special- of the causes of bipolar disorder, which also seemed to ized questionnaires with special attention to identify be vary varied in many areas of the genome and with suicidality, and its prevention is a clinical art in need disparate pathophysiological relationships to areas as of becoming a science; furthermore, the boundary far flung as inflammation and cannabis abuse. Imag- between depressive, bipolar, and ADHD is in need of ing of the brain, which I once thought would never changing from art to clinical science. Suicide preven- be likely to lead to results on the molecular level that I tion both at a population level and in clinical practice believed necessary to understand bipolar disorder, now represents a new frontier, yet ECT remains a necessary has reached a level of precision that is truly inspiring. tool. The stereotype that women try and men [succeed My prediction is that the combination of neuroimaging in] kill[ing] themselves is a dangerous stereotype. The with advanced computer neuropsychological testing integration of different psychosocial approaches and under laboratory conditions of model stresses, will lead therapeutic and biological technologies, recognized by to the discovery of those circuits that function inade- NIMH and NARSAD, will delineate future vistas. The quately in those predisposed to bipolar disorder. I pre- greatest challenge in understanding human nature dict that we will thereby learn how to strengthen these resides in the genetic factors in artistic and scientific circuits not by pharmacological means or by electro- creativity. Thus, molecular genetics represents the most physiological brain stimulation, but by exercises using promising frontier. As Sir Martin Roth has said, “Psy- computer based neuropsychological programs during chiatry will remain the most human of the sciences and the well and even preventive phase of bipolar disorder. the most scientific of the humanities.”

18 Michael Berk, Ph.D., MBBCh, MMed, FF(- Wade Berrettini, M.D., Ph.D. Psych)SA, FRANCZP University of Pennsylvania, Perelman School Deakin University of Medicine 2015 Colvin Prizewinner 1996 Selo Prizewinner

Mood disorders and depression in particular are a The development of the first monoamine oxidase deceptively simple construct, as currently defined. inhibitors and tricyclic antidepressants occurred roughly However there are many paths to depression, spanning 55−60 years ago. For the next 50 years, there were no a normal adaptive physiological reaction to serious antidepressants successfully developed which did not brain disorder, driven by factors as diverse as person- act directly on one or more monoamine molecules, ality, lifestyle and genetics. This heterogeneity makes including their receptors, transporters and enzymes. algorithm based diagnosis and management complex Despite the clinical successes of these medications in and unreliable. The ability to personalize treatment, mood and anxiety disorders, primarily, many patients either by diagnostic stratification or biomarkers remains with recurrent unipolar disorders were not helped by a critical goal, although success to date has been very these useful monoamine-based agents. Remarkably, limited and has not led to widely clinically adopted in the past 5 years, a new antidepressant, not acting measures. Incorporating predisposing, precipitating directly on monoamines, has been identified, buprenor- and perpetuating factors into clinical formulation and phine. Buprenorphine is FDA-approved for the treat- hence management remains best practice. A second ment of pain and opioid addiction. Its efficacy in pain area of future development is the study of the role of and opioid addiction is due to its activity as a mu opi- non-monoaminergic pathways in pathophysiology. oid receptor partial agonist. The antidepressant activity These span inflammation, neurogenesis, apoptosis, of buprenorphine is due to its kappa opioid receptor redox signaling and mitochondrial function, and these antagonism. The antidepressant benefit may be evident are increasingly being explored via systems paradigms at 1/20 the dose used to treat opioid addiction (typi- and –omics technologies. Importantly, these have the cally 16−24 mg daily). There is evidence that buprenor- capacity to suggest novel therapeutic approaches. phine may benefit depressive patients when used Lastly, it’s worth noting that the major successes in alone or in combination with monoamine-based areas such as cancer and cardiovascular disease antidepressants. Is buprenorphine a harbinger of have been in prevention, not cure. Psychiatry successful development of alternative classes of anti- has lagged in this domain, not least because depressants? I hope so. of the complexity of the risk pathways. Nev- ertheless, known risks can be targeted, including Boris Birmaher, M.D. lifestyle factors such as diet, smoking and physical University of Pittsburgh School of Medicine activity, social factors such as community and social 2013 Colvin Prizewinner engagement as well as institutional responses to factors such as sexual and physical abuse. It’s clear that many Untreated, bipolar disorder (BP) has devastating conse- of these factors can only be realistically targeted via quences for the psychosocial development of the child. public health and policy approaches, noting that many Fortunately, new developments are shedding light on of these risks are common across non-communicable who is at risk to develop BP and the factors associ- disorders, reinforcing the necessity for cross-disciplinary ated with better longitudinal course and outcome. The public health approaches. Pittsburgh Bipolar Offspring Study (BIOS) found that youth with persistent anxiety/depression, mood lability and subclinical manic symptoms, and particularly those whose parents had early onset BP, have a 50% likeli-

bbrfoundation.org 19 hood of developing this illness. Although important, suicide. Future research will accelerate the investiga- these results apply to the group as a whole and not for tion of risk genes and genes that can protect against an individual subject. Thus, similar to the risk calcula- depression. A revolutionary technique that involves tors created to predict individualized risk of developing precise editing of genes is called CRISPR-cas13a which cancer or myocardial infarction, BIOS created a risk allows for diagnostics and disease monitoring. Finally, calculator to predict the risk of developing BP for a a 3D technology, CLARITY, will facilitate the study and specific child. This calculator will be instrumental for identification of neuropathways in the human brain. future biological studies and for the development of preventative treatments that can delay the onset of this Joseph Calabrese, M.D. illness until the child has developed the cognitive and Case Western Reserve School of Medicine, social skills to cope with the disorder. Once youths have Cleveland, Ohio developed BP it is important to be able to predict their 2004 Selo Prizewinner long−term functioning. Contrary to the common idea that BP usually is associated with poor prognosis, the As a result of good mentors and generous donors, I Course and Outcome of Bipolar Youth (COBY) study have had the good fortune of being able to contrib- showed that a substantial subgroup of youths with BP ute to the development of mood stabilizers, includ- with certain characteristics are persistently euthymic ing lithium, the atypical antipsychotics, the selective [i.e., not depressed]. These findings give hope to fam- serotonin-re-uptake inhibitors, the anticonvulsants, and ilies and youth and are informative for the long−term most recently, the D3- preferring D2/D3 partial ago- treatment of this illness. nists. Our scientific focus has always been the devel- opment of mood stabilizers for use in the treatment of William E. Bunney, Jr., M.D. bipolar disorder, and in particular, those that targeted University of California, Irvine the depressed phase of the illness – the phase where 2001 Falcone Prizewinner patients lived their symptomatic lives, and unfortu- nately, in many instances, ended their lives. I owe all of In the last decade and a half, significant progress has this to my wonderful mentors at the National Institute been made in the understanding and treatment of of Mental Health and my donors. Whereas we have mood disorders. Most current antidepressants require enjoyed the benefits of serendipity over past years, we 2−10 weeks for significant improvement while low are now entering a new generation of clinical research, doses of ketamine produce a rapid response within 24 research that thoughtfully targets pathophysiology hrs. However, some patients experience a brief epi- based upon precise science. sode of psychotomimetic symptoms. Researchers are attempting to identify ketamine-like compounds with- J. Raymond DePaulo, Jr., M.D. out these side effects. A subset of depressed patients Johns Hopkins University School of Medicine has abnormal 24−hour rhythms affecting sleep, tem- 1996 Selo Prizewinner perature, mood and hormonal secretion, which are controlled by clock genes. Depressed patients com- Mood disorders are common, costly, and disabling. pared to controls have dramatically altered clock genes Major depression and classic mania (i.e., bipolar dis- in the brain. Ketamine interacts with clock genes and order) can only be recognized clinically. Severe forms it has been hypothesized that ketamine may reset the of them can be well treated. However, patient fre- abnormal clock genes. One-third of patients who com- quently fail to get effective treatment and we don’t mit suicide visit a healthcare professional in the month know why our treatments work or fail for our patients. prior to suicide. New molecular and clinical markers We know many genes in the causal pathway to these could be used to identify individuals at high risk for conditions. We have other molecular clues from ani-

20 mal models. We have clues to treatment success from reverse the synaptic connectivity deficits caused by brain imaging, but we don’t know how the genes stress within a similar time scale and underlie the rapid and other molecular players reshape brain function antidepressant behavioral responses. Current studies to produce depression or mania, or to explain how are focused on characterization of the molecular and they produce episodic patterns of illness. We need cellular signaling pathways that mediate the rapid anti- much more research: molecular and brain imaging depressant actions of these agents and identification of surely, but we need to support large treatment and novel targets for further development of safer agents outcomes research to find predictors of outcomes, with fewer side effects. especially treatment response. We must interrogate molecules, synapses and circuits and we must develop Elliot S. Gershon, M.D. better methods to engage and follow our patients so University of Chicago that they can partner more effectively in treatment. 1996 Selo Prizewinner We need BBRF to grow and prosper; we also need the NIH budget to grow and to prioritize research in The major progress in psychiatric genetic research on mood disorders. Finally we need to support collabora- mood and other disorders has been findings of genetic tive communities (e.g., National Network of Depres- variants associated with bipolar disorder, and in the sion Centers) where academic centers working with past year with major depressive disorder. Furthermore, patients and families will conduct research to carry us there are significant overlaps of these findings, and of from discovery to recovery. the polygenic predisposition, between schizophrenia and bipolar disorder. These genetic findings, based on Ronald S. Duman, Ph.D. tens of thousands of patient and healthy volunteers, Yale University are significantly enhancing our molecular understand- 2002 Falcone Prizewinner ings of the major mood and other psychiatric disorders. However, they have not yet led to improvements in Depression is a common, devastating illness and pharmacologic or other treatments. If I have to pin- although current pharmacotherapies help some point one direction in which I expect major progress in patients, the high rates of partial- or non-response the next few years, it would be progress in molecular and a delayed therapeutic onset leave many patients bases for diagnosis, course of illness, and in develop- inadequately treated. However, new insights into the ment of pharmaceutical or other treatments targeted neurobiology of stress and human mood disorders to the individual patient’s genetic constitution. have shed light on the mechanisms underlying the vulnerability of individuals to depression and have Mark S. George, M.D. pointed to novel antidepressants. Environmental events Medical University of South Carolina such as chronic or traumatic stress, as well as other risk 2008 Falcone Prizewinner factors contribute to depression through converging molecular and cellular mechanisms that disrupt synaptic Organizations like NARSAD are successful if they can structure and neuronal activity, resulting in dysfunc- support innovative research that disrupts the cur- tion of the circuit connectivity for mood regulation and rent modes of thinking about an illness. This radical cognition. Although current antidepressants such as research then fosters innovations that lead to new serotonin reuptake inhibitors produce subtle changes understanding and hopefully new treatments. When that take effect in weeks or months, new agents such they are truly successful, a field may have a paradigm as ketamine result in rapid improvement in mood shift. NARSAD has been enormously successful in ratings within hours of dosing in patients resistant to funding high-risk mood disorders studies decades ago typical antidepressants. Moreover, these new agents that helped build a foundation for a total overthrow of

bbrfoundation.org 21 old thinking with new theories and concepts. In 2000, but keeping them remitted for years in order to rebuild depression was thought of as a chemical imbalance, their lives. We have not yet come up with a single which was largely acute (several months to a year), “cure” for depression, but we are developing multiple without lifelong sequalae. Because of the confusion different treatments, some aggressive and invasive, with normal sadness, grief and worry, depressions others relatively simple. With this expanded range were stigmatized. We now think all of these concepts of options, we are making a real difference in public are wrong. Depression is now discussed as a brain dis- health and outcomes for a set of diseases that trou- order involving disrupted circuits in the brain, much like bles mankind and creates more disease burden than Parkinson’s Disease. Many acute episodes recur, and any other illness. Within the next decade, this NARSAD substantial numbers of patients have lifelong illnesses inspired revolution realistically may enable “cures” for akin to diabetes. Stigma drops as people adopt this most patients. All it takes is a bit more research. new line of thinking. There is a focus on early aggres- sive treatment with long-term follow-up and lifelong Robert M. A. Hirschfeld, M.D. management. My own work proposing noninvasive Weill Cornell Medical College brain stimulation as a treatment arose out of brain 2003 Falcone Prizewinner imaging studies of depression and sadness, and began to define these dysfunctional circuits. Because I was Many years ago Stan Kenton, the great band leader operating out of a different paradigm, my ideas and and jazz legend in the mid-20th century, was asked those of the other brain stimulation depression pio- by a reporter where jazz was going. Without hesitat- neers were not well received, particularly by a con- ing, he replied, “we are going to Cleveland on Friday.” servative NIH. Luckily, early NARSAD grants helped My response to where the future of mood disorder me continue my science. There is now tremendous research is going is similar—I know where I am going excitement as the new paradigm emerges. Now, we this weekend, but don’t have a clue about the future have five different transcranial magnetic stimulation of mood disorder research. That said, I fervently hope (TMS) companies with FDA approval, and univer- that personally targeted more effective treatments sal insurance approval of TMS for depression. with benign side effect profiles will be developed. We can use sophisticated brain imaging to I spend considerable time as a clinician trying to see which circuits are not acting correctly in ameliorate the naturally occurring mood swings depression, and then document their return and managing the distressing side effects of the to more normal activity after a successful treatments I prescribe. course of TMS. We have even now shown that a ther- apeutic course of TMS over 4-6 weeks actually regrows Kay Redfield Jamison, Ph.D. the brain in some of the mood regulating regions that The Johns Hopkins University were not working. Some researchers are proposing 2000 Falcone Prizewinner individualized medicine approaches where psychia- trists position TMS directly over the brain region, for I think the field is going full-ahead in directions that that person, that is not working. We now understand have great promise, and raise a few concerns. Mostly, how talking therapies like cognitive behavioral therapy great promise. The most generative fields, almost (CBT) work on changing circuits, and are combining certainly, remain genetic and neuroimaging research, external brain stimulation with devices like TMS with which will lead to earlier and more accurate diagno- sophisticated behavioral “exercises,” rapidly changing sis of mood disorders, help sort out the important circuits and enabling patients to have self-learned skills relationship between mania (far too little studied) and for the next problem that life throws at them. And the recurrent depression, and generate more specific and focus now is not just on getting patients undepressed, less problematic treatments. We will better understand

22 the enormously important relationship between patho- However, using agents that target these neuroactive logical and normal mood states, as well as the relation- cytokines, astute researchers found preliminary evi- ship between temperament, cognitive styles (includ- dence that cytokines play a fundamental role in mood ing those associated with imaginative thought), and disorders. Formal clinical trials are under way. Much of moods. We will gain a much deeper understanding of the disability caused by mood disorders is due to the ourselves in comparison with other species in terms of fact that they are highly recurrent. Thus, an ability to mood, energy, behavior, and cognition. As a result of attempt to intercept disease progression, and to move increased knowledge and a more sophisticated ability away from a “diagnose & treat” model to a “predict to manipulate the human genome, we will be con- & preempt” would undoubtedly have great benefit. fronted with profound ethical issues in clinical practice In this regard, although mood disorders are not classic and social policy. neurodegenerative disorders, in many patients, these disorders are associated with regional atrophic brain Husseini K. Manji, M.D. changes. Studies have shown that lithium exerts neuro- George Washington University trophic/neuroprotective effects which may underlie its 1999 Falcone Prizewinner ability to attenuate recurrences. Thus, there is consid- erable excitement about the ability to develop novel It is a pleasure to comment here on the progress treatments to recapitulate many of lithium’s beneficial and future of studying and treating mood disorders. effects with fewer side-effects. Finally, our ubiquitous Although considerably more research is undoubt- mobile devices, equipped with small, unobtrusive edly needed, I believe that the tremendous research sensors, make it possible to capture streaming data on advances made in recent years — only a handful of aspects of patients’ physiology, behavior, and symp- which are reviewed below — hold considerable prom- toms in real time (i.e., rather than only at clinic visits). ise for making a real difference in the lives of individ- Although issues of validation, privacy, etc., need to uals suffering from these devastating disorders. From be fully addressed, this may lead to “early warning the standpoint of novel therapeutics, one of the most signals” of changes in clinical state (e.g., worsening exciting areas of research is the concept of synap- depression, suicidality, switch into mania), and hope- tic plasticity, loosely defined as the processes that fully preempting severe exacerbations. As the evidence regulate the strength of a signal transmitted through reviewed above suggests, many reasons exist to be a synapse. We now know that a major mechanism optimistic that science and technology will continue to underlying synaptic plasticity is the trafficking of NMDA grow our understanding of the pathogenesis of mood and AMPA receptor subunits. Taken together with disorders and help us create improved treatments. clinical findings that low-dose ketamine (an NMDA antagonist) has considerable antidepressant efficacy Helen S. Mayberg, M.D. and acts within hours or days, the evidence suggests Emory University that it may indeed be possible to treat severe treat- 2007 Falcone Prizewinner ment-resistant depression rapidly. This breakthrough concept goes against accepted therapeutic “dogma” We no longer debate if depression is a brain disor- in our field. Another exciting area of research suggests der—that is a given. But the evolution, viewed over the that neuroimmune cascades may play a role in mood last 30 years, gives one pause: from mind to chemistry disorders. Extensive data have shown that proinflam- to brain circuits to complex dynamical system, now matory cytokines are elevated in mood disorders, but explored with mind-boggling new tools and all emerg- for many years they were thought to be linked only ing over a relatively short period of time. In addition to to the medical comorbidities associated with mood the ongoing technical advances that will take neuro- disorders (e.g., cardiovascular disease, type 2 diabetes). science in important and unimaginable new directions,

bbrfoundation.org 23 is the need to leverage available strategies to develop In the future, we must move toward studies that real world solutions that offer precision approaches to elucidate the real causes of mood disorders. Once treatment of individual patients now, while also provid- we understand causes, we will be in a much stronger ing an adaptable platform to integrate the innovations position to seek treatments and cures. of the future. We are seeing the emergence of the first precision medicine approaches to the treatment David J. Miklowitz, Ph.D. of depression, building on the experience and insights UCLA School of Medicine of the cancer and infectious disease communities to 2011 Colvin Prizewinner develop biomarkers that match individual patients to the treatment that will get them well, while avoiding The study of bipolar disorder is, in my opinion, becom- those that are unlikely to provide benefit. Whether it is ing more balanced. Most investigators recognize that the choice of psychotherapy, medication or brain stim- genetic, behavioral, and psychological or environmen- ulation, understanding the complexity of brain circuits tal factors (e.g., childhood adversity) all have a role in and the influence of genes, developmental insults and illness onset and prognosis. We are increasingly rec- ongoing life stress and experience will be required to ognizing that optimal treatment regimens include tar- make fundamental progress on understanding depres- geted psychotherapy as well as medications. The role sion risk, pathogenesis and treatment mechanisms, and of the immune system in bipolar disorder is becoming to have clinically meaningful impact on patients and more evident. The unique changes in neural circuitry their families by further preventing relapse and facilitat- associated with bipolar disorder are beginning to ing resilience. emerge from meta-analyses. Progress has been made in the search for genes as well: studies of multi-gen- Francis J. McMahon, M.D. erational families with bipolar disorder have identified National Institute of Mental Health Intramural “neuroimaging phenotypes” that are genetically-trans- Research Program mitted candidate traits for the illness. The pharma- 2016 Colvin Prizewinner cological options for bipolar disorder are becoming broader; we are no longer relying only on lithium, Mood disorder research has made great progress in valproate or antidepressants. We have clinical deci- recent years. Studies once focused on descriptions sion-making algorithms that include mood stabilizers, of the illnesses and their correlates have grown into antipsychotics, antidepressants and anxiolytics, given in studies that are beginning to define the causes of different combinations at different illness phases; and mood disorders and the neurobiological pathways more experimental treatments such as ketamine, tran- through which these causes act. Through genetic scranial magnetic stimulation, or deep brain stimula- studies, we can now, for the first time, begin to tion. A big area of progress has been the identification understand why mood disorders are inherited, how of childhood behavioral antecedents. Although there inherited risk acts over the lifetime of an individual, are still debates about what is and is not a child with and how we might intervene to improve outcomes. bipolar disorder, we agree that many people have their

24 first onset in childhood or adolescence, even though who in the population is at risk for these devastating the diagnosis may not be clear until much later. Having disorders. We have been less successful in developing a parent with bipolar disorder is a key risk factor. In the novel treatments for those who do not respond to near future we may have enough evidence to choose conventional treatments such as antidepressants, mood medications for specific patients in part on the basis stabilizers or electroconvulsive therapy. Clearly we are of their familial responses to these agents. Finally, our on the verge of realizing true personalized medicine in lab and other labs continue to test psychosocial inter- psychiatry being able to match individual patients with ventions that may alter the course of bipolar disorder the most optimal treatment for them. This is truly the in children or adults. Psychoeducation – acquainting Holy Grail for practitioners. patients and families with what we know about the illness and its self-management – is now considered to Andrew A. Nierenberg, M.D. be a key element of good clinical care. Specific therapy Harvard Medical School approaches (e.g., interpersonal or cognitive-behav- 2013 Colvin Prizewinner ioral therapy, family-focused therapy, structured group treatment) are being studied from the perspective of The future of therapeutics for mood disorders holds the transportability into community care settings. A major promise to integrate precision with personalized medi- objective within the next decade is to develop much cine. Precision medicine will arise from pluripotent cells clearer guidelines for what forms of therapy works best derived from individuals with mood disorders, along for what types of patients. with neuroimaging and other clinically informative bio- markers. Pluripotent cells will provide a transcriptome Charles B. Nemeroff, M.D., Ph.D. (after exposure to medications or to-be-developed University of Miami reagents) which will allow for a molecular diagnosis 1997 Selo Prizewinner (similar to a tumor biopsy). Neuroimaging will provide a circuit-based phenotype of dysregulations in functional It hardly seems possible that 20 years have passed since networks. Other to-be-defined biomarkers will include NARSAD awarded me the Selo Prize for Outstand- smart phone-based dynamic real time assessments, ing Achievement in Mood Disorders Research. Of the genetics, and potential blood-based biomarkers. These many professional organizations I have been fortunate multi-dimensional assessments will be combined using to be associated with, NARSAD, now BBRF, is one of a causal dynamic network computational model which my absolute favorites. This is not only because of the will guide short and long term treatment as well as kind recognition they have provided to my research in therapeutics for prevention and early intervention. Cli- the form of the award noted above, a Distinguished nicians will use the information from precision medi- Investigator award, and an appointment to the Scien- cine innovations to determine personalized treatment tific Council, but the extraordinary and unique role it of mood disorders by collaborating with people with plays in the development of young investigators in our mood disorders and their families. They will share field. Our small and medium sized grants are virtually a decision making about benefits and risks and mea- prerequisite to obtain NIH funding in this very compet- sure outcomes together iteratively. The outcomes data itive era. In terms of mood disorders research, we have from precision and personalized treatment of mood made some remarkable strides in further elucidating disorders will be collected and available for everyone the neurobiological underpinnings of depression and through open source, including patients and their fam- bipolar disorder with increasing evidence for a preem- ilies. Crowdsourcing analyses will lead to new innova- inent role of inflammation, gene-environment inter- tions which can be fed back into the system to even actions and epigenetics, to name a few of the recent further improve outcomes. findings. This has led to clear progress in understanding

bbrfoundation.org 25 A. John Rush, M.D. recent studies suggest that inflammatory processes can National University of Singapore & Duke be measured in the blood and may suggest the prefer- Medical School ential selection or avoidance of particular antidepres- 2000 Falcone Prizewinner sant medications. Finally, the widespread evaluation of multiple indicators of brain function — including Depressive disorders affect a large proportion of functional imaging, metabolomics, proteomics, genet- patients and account for substantial disability. Recent ics, and tests of brain function — are shedding light on research, however, has made some substantial not only etiologically distinct subtypes of depression, advances that fall into four main domains: the types of but they are also helping to inform treatment selection treatments we offer; how we deliver those treatments; decisions and to provide important prognostic infor- to whom we offer specific treatments, and our under- mation so that care delivery can be better tailored to standing of the basic neurobiology underpinning these different individuals with depression. depressions. There have been remarkable advances in our ability to use brain stimulation methods – especially Harold A. Sackeim, Ph.D. those that do not entail anesthesia or the induction Columbia University of seizures to help patients recover from depressive 2004 Falcone Prizewinner episodes and prevent them from slipping into new episodes. These brain stimulation interventions are Brain stimulation is a rapidly emerging field of medi- becoming widely used to help those for whom medi- cine, offering a fundamental alternative to pharmacol- cations or therapy have not been sufficiently effective. ogy in the development of neurotherapeutics. Brain The rapid reversal of severe depression, and suicidal stimulation technologies also offer unparalleled oppor- ideation, has launched efforts to develop acutely tunities to advance understanding of basic neural active medications that could reverse depression mechanisms and the pathophysiology of disease within a day. The psychotherapies have also states. The application of these technologies advanced with evidence of efficacy in mind- to the treatment of mood disorders has been fulness-based treatments and the devel- especially fruitful. Electroconvulsive therapy opment of specific treatments to combat (ECT), the “grandfather” of neuromodulation suicidal ideation and risk. We have also learned technologies, has undergone dramatic improvement how to better deliver the treatments that we have, that have shed it of also most all its adverse cognitive using simple clinically available scales, upon which side effects, while retaining its profound therapeutic advances and biomarkers will be placed in the future. properties and placing it on a firm scientific basis. Tran- The adoption of so-called measurement-based care to scranial Magnetic Stimulation (TMS) and Vagus Nerve tailor the delivery of treatment to individuals – whether Stimulation (VNS) have already made important contri- medications, psychotherapies, or brain simulation butions to therapeutics of treatment-resistant depres- methods – has been shown to increase the effective- sion (TRD). Similarly, there is marked interest in the use ness of medications without increasing their side of deep brain stimulation (DBS) and various forms of effect burden. In addition these simple clinical mea- noninvasive transcranial electrical stimulation (tES) in sures increase the detection of individuals earlier in the treatment-resistant depression. I expect the explosive course of illness and more effectively engage patients growth of the field of brain stimulation to continue, as participants in their care. A third major advance is and one can expect new technologies to expand our our developing ability to select individual patients for capacity to stimulate neural tissue focally and thus a particular treatment; this should be strongly encour- directly alter circuit and network function. For exam- aged or avoided depending on clinical, biological, neu- ple, I believe we will soon have the capacity to release ro-functional, genetic and other studies. To illustrate, or activate specific molecules on a local basis in the

26 human brain by making them sensitive to brain stim- is also subject to abuse. To mitigate the risk of abuse, ulation interventions. I expect that these advances in one company is developing a combination of buprenor- biotechnology will result in improved therapeutics for a phine with samidorphan (a mu antagonist) to lessen variety of neuropsychiatric conditions. However, mood the risk of tolerance and dependence. The combination disorders have been especially responsive to this class has been shown to be effective at low doses of both of interventions, and we anticipate substantial progress molecules in two refractory depression studies. Last, in coming years as we learn how to best apply existing the hallucinogen psilocybin has been reported to have technologies and explore novel, emerging technologies. potent and enduring antidepressant properties in dou- ble-blind studies of cancer patients with pronounced Alan F. Schatzberg, M.D. depression and anxiety. Development of these various Stanford University agents will raise questions regarding the risk-benefit 2005 Falcone Prizewinner ratio of the specific compound for the patient as well as for our society writ large. The development in the late 1980s of widely effec- tive antidepressants such as the selective serotonin Thomas G. Schulze, M. D. reuptake inhibitors (SSRIs) had a major impact on the Medical Center of the University of Munich treatment of patients with major depression. These 2016 Colvin Prizewinner agents are broadly effective and generally well toler- ated; however, many patients do not respond, leav- When I started my career two decades ago, mood ing an ever-growing number of refractory patients. disorder genetics was characterized by studies in small Unfortunately, the numerous, failed investigational samples producing disparate and very often non-repli- antidepressant trials have resulted in several large cable results, leading to widespread frustration within pharmaceutical companied discontinuing their antide- the scientific community. The advent of genomics in pressant development programs. Still, a few interesting the first decade of the new millennium and the fact antidepressant strategies have begun to yield promis- that researchers all over the world have embraced the ing results. However, several of them do raise potential idea of large-scale collaborative efforts, however, have social issues because they involve agents of potential propelled powerful genome-wide association studies abuse. For example, ketamine given intermittently has (GWAS). Ever increasing sample sizes, now totaling been demonstrated to have transient antidepressant several tens or hundreds of thousands individuals have effects and is being developed as an intranasal formu- yielded a large number of vulnerability loci for bipolar lation. The drug can be abused and there are many and unipolar depression. Taking into account ongoing ketamine abusers in this country and in China. A mu studies, we can expect to see close to 100 confirmed partial agonist, buprenorphine, that is used to treat GWAS hits for mood disorders within shortly, thus opiate addiction, has recently been reported at low narrowing the gap to recent successes in schizophrenia. oral doses to have anti-suicidal properties. This drug These GWAS are being complemented by exome or

bbrfoundation.org 27 whole-genome sequencing studies. All these findings conceptualized today, is too late, and that most of the will help develop a better understanding of pathways morbidity of this condition needs to be addressed long and mechanisms underlying mood disorder. They will before illness onset. Working through large consortia help spur developments of novel pharmacological and looking into the analysis of big data and machine targets and lead to innovative drug repurposing trials. learning for genetics, proteomics, transcriptomics and Planning for the next two decades, we should not be metabolomics, as well as the connectome, may only be complacent, though. We need to leave the comfort fruitful if it goes in hand with accurate, deep pheno- zone of studying diagnostic entities. We have to study typing, beyond the boundaries of traditional classifica- the biology of (disease) course, as well as outcome and tions. Innovative mechanisms of action, new treat- recovery. We have to dramatically increase samples ment targets, and novel methods (including chemical, sizes for pharmacogenetics studies. We have to put physical and psychotherapeutic interventions) need the other “omics” into the equation. And, we have to be developed over the next two decades, and only to extend our research to include populations from all great amounts of private and public funding and indus- around the world to get a global picture of genetic try-government collaborations can make it possible. liability factors. Above all, these endeavors have to adhere to the idea of friendly data sharing, creating a Karen Dineen Wagner, M.D., Ph.D. long-lasting bond between clinicians and basic scien- University of Texas Medical Branch tists that will eventually deliver on our promise of offer- 2012 Colvin Prizewinner ing hope and cure to millions. There have been significant advances in the treatment Eduard Vieta, M.D., Ph.D. of mood disorders in youth during the past decade. My University of Barcelona, Spain area of research interest focuses on identification of 2012 Colvin Prizewinner effective pharmacological treatments for depression and bipolar disorder in children and adolescents. If we want to reach the cure for bipolar disor- The next step in treatment research for youth is der, I deeply believe that the way to go is to to identify which treatment is effective for a spe- focus on the understanding of how emo- cific child or adolescent. Neurobiological and tions, mood and energy are regulated in the psychosocial factors which may contribute to brain. Research on bipolar disorder needs to treatment response require further study. Since go in two main directions: one, integrating there is a familial component to mood disorders, the advances in the physiology and pathophysiology it is important to determine whether a child with a of brain processes, and two, addressing the unmet mood disorder will have symptom improvement with needs of people with this condition through strate- the same medication that was effective for treating a gies of early detection and intervention. I am increas- parent with a mood disorder. ingly convinced that even “early intervention,” as it is

28 Myrna M. Weissman, Ph.D. ising clinical and biological markers of antidepressant New York State Psychiatric Institute treatment outcome, will be ready soon. To maximize 1994 Selo Prizewinner genetic understanding of a complex disorder such as depression, scientists worldwide have joined their I was invited to comment on mood disorders because data in a Genome Wide Association (GWA) analysis. of winning the Brain and Behavior Selo Award in Promising new genetic findings from the GWA should 1994 for “outstanding achievement in Mood Disor- be released this year. Computational science and der Research.” The award included my late husband biomedical engineering are promising new partners Gerald Klerman, M.D. who had died in 1992. The for understanding brain processing and translating Award in 1994 covered our clinical and epidemiology findings into office-based diagnostic tests or for mon- research showing that depression was a disorder that itoring clinical outcome and detection of early signs first begins in youth but reoccurs through the lifes- of relapses. Evidence-based psychotherapy develop- pan. We showed that it was more common in women; ments have not been static. IPT now has nearly 100 that rates had increased in cohorts born since World clinical trials and a simpler version for health workers War II; that it was highly familial in biological relatives; for worldwide distribution was launched by the World and that it bred true. The award also included our Health Organization in 2016. There is now a solid base development of Interpersonal Psychotherapy (IPT) for of psychotherapies with evidence from controlled clin- depression. In 1994 there were about 8 clinical trials. ical trials. Cognitive Behavioral Therapy (CBT) has had Our findings, if presented today for the Selo Award, the most clinical trials and even wider dissemination, would not win the prize. That is good news. The find- and recent studies to test the biological mechanism of ings have been replicated, mostly accepted, and the change. CBT investigators had led efforts to develop field has now moved onto extending and deepening and test electronic versions to reduce cost and increase the direction. In 2017 studies of families at high risk availability. Science builds on strong past discoveries for depression are now incorporating neuroimaging, and may deepen or even refute them. NARSAD has electrophysiology and genetics to unravel the bio- been the scaffold for many young scientists who have logical mechanisms underlying depression. Machine contributed to these discoveries. A review of the NAR- learning coupled with Magnetic Resonance Imaging SAD Young Investigator 2017 winners will give you a (MRI) has begun to find dimensions of depression that preview of what discoveries to expect in the future. cut across and underneath our conventional diagnostic The NARSAD scaffold of research support is a critical group. This search for precision in medicine is leading piece early in their work. to diagnostic classification based on biomarkers, neu- ral circuits and cognitive processing. The results from a clinical trial, Establishing Moderators and Bio-sig- natures of Antidepressant Response in Clinical care (EMBARC), designed to systematically explore prom-

bbrfoundation.org 29 The Ruane Prize for Childhood & Adolescent Psychiatric Research David Brent, M.D. BJ Casey, Ph.D. University of Pittsburgh School of Medicine Yale University 2006 Ruane Prizewinner 2015 Ruane Prizewinner

The suicide rate in the United States has increased dra- A fundamental issue in psychiatric medicine is the matically in the past decade. Four new developments need for empirical evidence indicating when, during hold promise for improving our ability to predict and development, a treatment, or intervention will be most prevent suicide. First, data mining of electronic health effective for a patient. Dramatic behavioral and brain records using machine learning and natural language changes occur across development, especially during processing can be used to identify individuals at risk adolescence, when there is a peak in diagnosis of many for suicide, and notify primary care and emergency psychiatric disorders. The most common disorders department clinicians of their patients’ suicidal risk. during this time are anxiety, stress and mood disorders. Second, digital phenotyping using passive cell phone Current research findings suggest the importance of data, speech quality, and facial expressions can assess treating the biological state of the developing versus suicidal risk, monitor clinical status, and provide feed- developed brain by optimizing treatments that match back to both patients and clinicians. Third, smartphone the developmental readiness of the brain. applications, triggered by digital phenotyping, can be used to provide timely interventions for suicidal F. Xavier Castellanos. M.D. patients. Finally, brief, computerized adaptive tests, NYU Langone Medical Center, Department which personalize risk assessment by selecting of Child and Adolescent Psychiatry questions from a larger item bank based on 2015 Ruane Prizewinner patients’ answers to initial screening questions, (Comment pertains to image on page 32) can identify individuals at imminent risk for suicide in primary care, emergency department, or hospital Science is a profoundly social process, and so is science settings. These four approaches can be used to combat advocacy. Confronted with irrefutable evidence that the staggering increase in the national suicide rate by autism spectrum disorder is vastly more common than extending the reach of evidence-based approaches and formerly believed, advocates have focused on increas- getting the right assessments and right interventions to ing the priority of autism research for funders as well the right people at the right time. as investigators. This word cloud illustrates the most commonly encountered terms in the more than 600 grants currently funded by NIH which include both ‘autism’ and ‘child’ as keywords. It encapsulates cur- rent research directions, including the awareness that many children with autism also have Attention-Deficit/

bbrfoundation.org 31 Word cloud provided by F. Xavier Castellanos. M.D.

Hyperactivity Disorder (ADHD); the conviction that brain ing of the specialty with adult psychiatry. As we have imaging remains an important means of discovering learned more about the brain, we appreciate the conti- mechanisms; the importance of focusing on outcomes nuity of growth and development, from conception to and risk factors, including environmental exposures. adulthood and in some cases (e.g., the development of Also highlighted are constructs such as cognitive “wisdom”) well into middle and old age. Second, treat- control, and of course, genomics. While much more ment methods, whether psychopharmacologic or psy- research into neurodevelopmental disorders such as chotherapeutic, have no clear age-based cut-off points. autism and ADHD is still needed, the pace of discovery Third, the more we have learned about the genetics is unquestionably accelerating. and epigenetics of mental illness, the greater the importance of avoidable trauma in the development E. Jane Costello, Ph.D. of mental disorders. Fourth, longitudinal, developmen- Duke University Medical Center tal studies are revealing that psychiatric disorders are 2009 Ruane Prizewinner common: about 80% of youth experience one or more by age 18, and share the equifinality – the same effect The most important progress made in child and adoles- or result – from many risk exposures. The same factors, cent psychiatry in the past decade is the gradual meld- such as poverty, inequality, and poor parental education

32 resulting in malnutrition and obesity, have comorbid fosters better outcomes in schizophrenia, whose onset adult outcomes with psychiatric disorders, such as is usually in mid to late adolescence. Such scientific diabetes and cardiovascular disease. These advances efforts require the collaboration of multiple disciplines, have, however, been held up by unexpected problems involving clinicians, neurobiologists, molecular biolo- in some areas where a decade ago great progress was gists, and others. The promise of neurodevelopmental predicted, most notably in genomics. Rather than the research for child psychiatry is too important to miss “Decade of the Brain,” we are learning more about the opportunity to pursue it. how the environment, from the microbiome to the climate, affects human development. Future progress Terrie E. Moffitt, Ph. D. & will require us to develop new ways to explore this Avshalom Caspi, Ph.D. interface, and to prevent the accumulation of danger- Duke University ous exposures over the life span. 2010 Ruane Prizewinners

Rachel G. Klein, Ph.D. In both child and adult psychiatry, evidence is building New York University that a person’s tendency toward mental disorder can 2004 Ruane Prizewinner be assessed along a single dimension. A high score on this dimension indicates younger onset of disorder, Historically, child psychiatry has been a stepchild of longer persistence of disorder over time, more comor- psychiatry. For decades, research focused on adults, bid disorders during a lifetime, and greater severity with little attention paid to childhood antecedents. of symptoms. This single dimension is termed “p”, This neglect has been dramatically reversed in the past because it resembles a dimension already familiar to decade, because research has shown conclusively that behavioral scientists and clinicians: the g factor of most serious psychiatric disorders have their origins in general intelligence. Just as the g dimension reflects childhood. We have come to understand that the study low-to-high intellectual ability, the p dimension rep- of all aspects of development, especially brain develop- resents low-to-high psychopathology severity, with ment, will be essential to further our understanding of thought disorder at the extreme. The dimension of mental disorders. Such efforts, though relatively recent, “p” influences present/absent status on hundreds of have already dismissed the popular notion that child- psychiatric symptoms, which our diagnostic systems hood mental disorders are arbitrary labels. The validity typically aggregate into dozens of diagnoses, which in of childhood psychiatric disorders has been established turn make up the two domains of externalizing versus by research demonstrating their continuity into adult- internalizing disorder, which finally aggregate into one hood, and especially by showing brain abnormalities dimension from low to high: “p”. Studies show that in some childhood disorders. Moreover, studies have the higher a person scores on p, the worse that person established genetic influences in multiple childhood fares on measures of their family history of psychiatric conditions. Although progress has been significant, illness, brain function, childhood developmental history, much remains unknown. As an example, in spite of temperament and personality, polygenic risk scores establishing genetic transmission, specific mechanisms from genome wide association studies, and life impair- of gene expression are not yet understood. The future ment. This single p dimension may help to account for of child psychiatry rests on efforts to study brain devel- psychiatry’s lack of specificity: multiple different diag- opment to enable the identification of early dysfunc- noses share the same risk factors, and often respond to tion. This knowledge will inform early treatment and, the same therapies. Research is needed to test if “p” ultimately, prevention of the disorders as well as their can predict treatment resistance. progression into adulthood. Indeed, we now know, based on systematic research, that early intervention

bbrfoundation.org 33 Daniel S. Pine, M.D. John L. R. Rubenstein, M.D., Ph.D. National Institute of Mental Health University of California, San Francisco 2011 Ruane Prizewinner 2016 Ruane Prizewinner

In many ways, the progress in child psychiatry over t Progress in identifying genes that contribute risk for he past 20 years has been profound, and this progress Autism Spectrum Disorder (ASD) has opened the door outlines the future in research in this area. In particu- to a deep understanding of mechanisms that can cause lar, most mental health conditions are now recognized severe childhood psychiatric disorders. These genetic as disorders of brain development. This recognition studies have indicated that ASD can be caused by dis- reflects progress that has been made through studies in ruption of several biological processes (gene regulation, child psychiatry. Moreover, tremendous advances also synapse development/function, and neural excitabil- have occurred in treatment, where many medications ity). Fundamental research in these areas will provide and psychotherapies have been shown to substantially insights into how disruption of development and impact pediatric mental illnesses. Finally, cascades of function of the brain contributes to disease risk. Fur- risk factors have been identified. These include genetic thermore, these basic studies will facilitate translational and environmental risks, which have been shown investigations into rational therapeutic approaches. to shape brain development and associated risks for Because a clear pathway for discovery is now open, mental illnesses. In light of these advances, hope for I am optimistic that progress will be made on more future discoveries is amazingly high. On the other hand, precise diagnosis and treatment for ASD. Furthermore, the more that we learn about mental illness and brain because there is evidence that ASD may share similar development, the more complex we have understood genetic mechanisms with other psychiatric disorders, the problems to be in child psychiatry. As a result, prog- such as schizophrenia, I am hopeful that insights gained ress over the next decade is likely to accrue gradually, as from understanding ASD will help researchers and clini- the individual pieces of a complex puzzle are identified cians make progress to more broadly advance under- and slowly assembled. standing psychiatric disorders.

Judith L. Rapoport, M.D. Matthew W. State M.D., Ph.D. National Institute of Mental Health Yale University 2002 Ruane Prizewinner 2012 Ruane Prizewinner

Our clinical studies of childhood onset schizophrenia, a There has been a recent explosion of progress in the rare and severe form of the disorder defined as onset genetics of autism spectrum disorder. These advances before age 13, indicate that these children have high have been marked by the discovery of around 70 rates of several biological risk factors. 80% have a vari- specific risk genes subject to rare, large effect de novo ety previous neurodevelopmental disorders suggesting (new, spontaneous) mutations that disrupt protein syn- an overall “brain vulnerability.” Also, 14% of our child- thesis or function. This differentiates ASD from other hood onset patients have various chromosomal duplica- psychiatric disorders, such as schizophrenia or bipolar tions or deletions called Copy Number Variants (CNVs) disorder, where the lion’s share of recent progress has – higher than the 2−3% rate in later onset disorders. been via the identification of common, small-effect These abnormalities are nonspecific, as they increase alleles in the non-protein-coding segments of the the risk for autism, developmental delay as well as genome. These findings have led to some distinctive schizophrenia. Going forward the actual mechanism opportunities in ASD and other neurodevelopmental of these variants will be important in understanding disorders showing similar results. Because the muta- schizophrenia and other neurodevelopmental disorders. tions fall directly within genes and carry many-fold

34 increases in risk, there is a relatively direct path to all have advanced to the level of characterizing individ- neurobiological studies. And these have quickly begun ual cases. Diagnosis can then become more precise and to identify key biological pathways and spatio-temporal describe the individual’s profile of dysfunctions rather aspects of ASD risk, with multiple laboratories identi- than a heterogeneous syndrome. Treatment and the fying excitatory neurons in mid-fetal prefrontal human monitoring of treatment will become more personal, cortex as one of likely many--important anatomical useful at an earlier stage of disorder, and correspond- regions and developmental epochs. Over the next sev- ingly more effective. In another 50 years we could be eral years, reliable gene discovery will surely continue, looking back at another revolution. as there is strong evidence of many more risk genes in the genome. Routine sequencing of the entire human Anita Thapar, M.D., Ph.D. genome (whole genome sequencing) will help with Cardiff University School of Medicine these efforts and provide additional biological insights. 2014 Ruane Prizewinner Finally, developmental, systems and compu- tational neurobiological studies are destined Research findings have been so important for ADHD – to offer new and important insights into both a disorder that can be misunderstood by some. Huge the genetic and environmental contributors international efforts mean we now know there is a to ASD, leveraging a growing set of definitive strong genetic contribution; specific genes that are molecular clues provided at last by successful involved are also being identified. It now is clear that genomic studies. there is strong biological and clinical overlap with other brain disorders that first show in childhood, such as Eric Andrew Taylor, M.D. autistic spectrum disorder, communication and learn- King’s College London Institute of Psychiatry, ing difficulties. This group is now called the childhood Psychology and Neuroscience neurodevelopmental disorders. Future research and 2008 Ruane Prizewinner clinics in some countries are beginning to investigate and assess these conditions together. Research also In the 50 years that I’ve been involved with the science has highlighted the plight of adults; for many, ADHD and practice of mental health there have been revolu- remains a problem beyond childhood. As a result, new tionary changes for the better. The large, old, depriving methods of assessment and diagnoses that are more institutions have mostly gone. Effective medicines and age appropriate are beginning to emerge. Investiga- psychotherapies have arrived. We have realized that tions of the entire population are also proving exciting. most severe mental illnesses start young and are rooted These are telling us that ADHD behaves like a spectrum. in brain dysfunctions of various kinds. There is much Sophisticated new methods are being used to identify still to do, and the future should bring translation of environmental as well as genetic causes. Future discov- hard-won scientific knowledge into better clinical tools. eries will be crucial for informing prevention and early Longitudinal studies will have identified the factors intervention programs. making for better or worse outcomes. Neuroimaging, neuropsychology and machine learning applications will

bbrfoundation.org 35 The Goldman- Rakic Prize for Outstanding Achievement in Cognitive Neuroscience Amy F. T. Arnsten Karl Deisseroth, Ph.D. Yale University Stanford University 2015 Goldman-Rakic Prizewinner 2015 Goldman-Rakic Prizewinner

A major goal for understanding the neurobiology of The development between 2004 and 2009 of opto- mental illness will be the bridging of cognitive neu- genetics (controlling specific neural elements during roscience (including findings from neuropathological behavior using microbial opsin genes, fiberoptics, and and neuroimaging studies in patients) and cellular and cell targeting tools) was supported in its early stages by molecular neuroscience, so that we can understand my NARSAD Young Investigator Award, and has helped how a wide variety of genetic insults can lead to a thousands of investigators around the world advance shared phenotype. As many mental disorders target our shared understanding the circuit underpinnings newly evolved brain circuits, we must respect that these of adaptive and maladaptive behavior. In one exam- neurons are often uniquely regulated at the molecular ple (depression), specific cellular connections – span- level. We have been making progress in many arenas, ning the entire adult mammalian brain – have been for example, seeing how atrophy of the deep layer identified that are causally involved in precise control III microcircuits in dorsolateral prefrontal cortex leads of anhedonia- and hopelessness-related behaviors. to symptoms of thought disorder, and how molec- More broadly, exploration is now possible of a virtu- ular insults to these circuits render them vulnerable ally limitless range of ideas and hypotheses regarding to dendritic spine loss. It is hoped that insights from the causal and global circuit dynamics of both normal neuropathological studies in patients can provide “top- behavior and psychiatric disease mechanisms, includ- down” guidance for basic research, and that basic ing also states related to anxiety, addiction, and altered research can in turn illuminate how genetic insults social behavior. Though my first steps that led to these lead to circuit dysfunction. In this way we can keep on advances were supported by NARSAD, these were not course to better learn how to protect brain networks, part of a traditional disease-related research program. and develop treatments to prevent or slow the course Rather, interdisciplinary basic-science collaboration has of mental disorders. been the hallmark of these efforts, characterized by joint efforts among physicians, biologists, physicists, materials scientists, biochemists, chemists, and chem- ical engineers. We and others have discussed how to balance funding of early versus late-stage research, and we have suggested that scientists must commu- nicate to the broader public that any specific goal of a research portfolio – be it disease treatment or national

bbrfoundation.org 37 interest – is best served with a major basic research Michael E. Goldberg, M.D. component where direct links between research and Columbia University goal are not known, or even knowable. Looking to 2011 Goldman Rakic Prizewinner the future, this approach (which NARSAD/BBRF has pioneered and exemplified) will continue to deepen our We know little about the mechanisms underlying understanding of psychiatric disease symptoms and, human behavior. Modern cognitive neuroscience views more broadly, the sensations, cognitions, emotions, the brain as a network for turning perception into memories, and actions that contribute to the common action, to facilitate earning reward. Some of the great- experience of humanity. est insight into this process comes from studying the activity of individual brain cells while monkeys perform Joaquin M. Fuster, M.D., Ph.D. difficult cognitive tasks. For example we know a lot University of California, Los Angeles about the cortical and subcortical networks involved 2006 Goldman-Rakic Prizewinner in visual attention, and the generation of the eye movements that humans make to facilitate attention. Cognitive neuroscience is the neuroscience of the We are beginning to understand how the brain labels human mind. It is the science that explores the brain things in the environment that will cause pleasure and mechanisms of the five basic cognitive functions: atten- things that will cause pain. What we do not under- tion, perception, memory, language, and intelligence. stand are the mechanisms that drive human choice These functions work with the cognitive networks of and motivation. Why do people make bad choices, the cerebral cortex (“cognits”) and their relations with such as an addict who has gone through rehabilitation subcortical centers of the brain. The essential elements who chooses to become addicted again? What are of those networks or cognits consist of widely distrib- the derangements of brain networks that cause the uted neurons and the fiber connections within and anhedonia of severe depression so that nothing gives between them. The points of contact of those con- pleasure? What are the genetic and neurochemical fac- nections are called synapses, which are little switches tors that cause humans to act in self-destructive ways? that by chemical and electrical changes make cognitive What is the network change that causes cognitive dis- functions and their networks work or shut off – as in tortion? The promise of cognitive neuroscience is that sleep or inattention. Synapses are modifiable (plastic) understanding the processing in the normal brain by learning and memory. They grow and their power of will enable us to understand what goes transmission is enhanced by education and life experi- wrong in the psychologically damaged ence. In aging and degenerative diseases of the brain, brain, and help us to heal it. like Alzheimer and Parkinson, they deteriorate, along with the neurons and nerve fibers that connect them. Robert C. Malenka, M.D., Ph.D. With a large variety of methods (neuroimaging, neuro- Stanford University chemistry, neuropharmacology, neurophysiology, nutri- 2010 Goldman-Rakic Prizewinner tion science and genetics), modern cognitive neurosci- ence investigates the basic and translational aspects of Major advances in methodologies that allow scientists cognitive function. The principal objectives are two: (a) and physicians to interrogate and manipulate neural to promote healthy development of the brain; and (b) circuit activity in awake behaving animals and humans to prevent and heal the ravages of aging, psychosis and hold the promise to revolutionize our understanding of dementia. Progress in their pursuit is costly in money the pathological brain mechanisms that mediate many and human resources. of the most prominent symptoms of major mental ill- nesses. Leveraging advances from human genetics, we are now able to generate animal models with the same

38 genetics as human patients and using these models, threatening, as well as the behavioral and physiolog- define and even repair the circuit dysfunctions medi- ical responses to the stressor. The adult and develop- ating the pathological behaviors at the core of many ing brain possess remarkable structural and functional mental illnesses. The new insights generated by this plasticity in response to stress, including neuronal basic research will guide human brain imaging studies, replacement, dendritic remodeling, and synapse turn- the results of which will be used to stratify patients over. Neurotransmitters, neuromodulators, neuroen- based on a combination of their symptoms and brain docrine, autonomic, immune and metabolic mediators activity fingerprints to ensure that they receive the opti- are essential for epigenetic regulation of brain and mal treatments for their specific condition. These new body adaptation via the active process of allostasis. insights will also guide efforts using novel platforms However, chronic stress causes an imbalance of neural to develop new medications that improve symptoms circuitry subserving cognition, decision-making, anxiety via currently unknown, novel mechanisms of action as and mood that can alter expression of those behaviors well as guide direct brain interventions to modify dys- and behavioral states. This imbalance, in turn, affects functional circuits using non-invasive techniques such systemic physiology via the same mediators and leads as transmagentic stimulation or targeted ultrasound to increased allostatic load and overload. Thus, in the stimulation. With the amazing advances that have short term, as for increased fearful vigilance and anxiety occurred over the last decade and with many more on in a threatening environment, these changes may be the horizon, I am confident that we are on the cusp adaptive. But, if the danger passes and the behavioral of a revolution in how we diagnose and treat mental state “gets stuck” along with the changes in neural cir- illness. Within 20 years we will have vastly improved cuitry, such maladaptation may need intervention with diagnostic capabilities and completely novel treatments a combination of pharmacological and behavioral ther- that we can administer clinically in much more effec- apies, as is the case for chronic anxiety and depression. tive and sophisticated ways. Although challenging, the The entire brain also has receptors for sex hormones future is bright for those of us who care about reducing that influence many functions, along with developmen- and treating brain and behavior illnesses. tally programmed sex differences, and there are, as a result, important sex differences in brain function that Bruce S. McEwen, Ph.D. are now being explored. Moreover, the life course has The Rockefeller University taken on new meaning as a determinant of trajectories 2005 Goldman-Rakic Prizewinner of life-long health; and adverse early-life experiences, interacting with genotype, produce lasting epigenetic Our discovery in 1968 of cortisol receptors in the effects on brain and body over the lifespan, among hippocampus provided a gateway into later discov- which included increased risk for depression, diabetes, eries, throughout the brain, of receptors and actions substance abuse and other disorders. While prevention of stress, sex as well as metabolic hormones upon is most important, the plasticity of the brain gives hope cognitive function, self regulatory behavior, mood and for therapies that take into consideration brain–body many other aspects of brain function. This has not only interactions. broadened the definition of “neuroendocrinology” to include the continuous, reciprocal communication Earl K. Miller, Ph.D. between the brain and the body via hormonal and Massachusetts Institute of Technology neural pathways but it has also contributed transla- 2016 Goldman-Rakic Prizewinner tionally to neurological and psychiatric investigations showing plasticity and vulnerability of the human brain. I see cognitive neuroscience becoming increasingly inte- The brain is the central organ of stress and adaptation grative both within and across levels of inquiry. When I to stress because it perceives and determines what is began my career, the focus was on the brain’s individ-

bbrfoundation.org 39 ual parts (individual neurons, brain areas, etc.). It was ments for these conditions. Work in my laboratory, as if the brain was a clock and if we could figure out and in many others, over the past couple of decades each “gear,” we would figure out the whole. But we has identified numerous molecular and cellular adapta- have seen increasing awareness that any understand- tions induced in brain in response to chronic exposure ing of brain function is going to depend on a network to a drug of abuse or stress, with an increasing num- understanding, i.e., how the parts work together. For ber being related causally to behavioral symptoms in one thing, it is becoming clear that the brain’s individ- animal models. A major goal of current research is to ual neurons and areas do not have single functions, move beyond studies of single adaptations to under- that their signals only make sense in the context of stand how a myriad of molecular changes summate what other neurons and areas are doing. This has to underlie specific changes in neural and synaptic necessitated the rise of computational approaches and function in a given brain region. Likewise, it will be theory needed to describe and understand network important in turn to understand how these neural and interactions. Finally, we are seeing innovation of tech- synaptic changes summate to alter the functioning niques and approaches that cut across different levels. of the brain’s circuitry to mediate specific behavioral Molecular tools are providing greater insight into net- abnormalities that define an addicted or depressed works’ properties by allowing us to perturb networks state. This delineation of molecular, cellular, and circuit in precise ways. In short, I see different strands of mechanisms of addiction and depression will require neuroscience that have traditionally been separate increased attention to the specific cell types beginning to weave together. This is what hap- (both neuronal and non-neuronal) where pens when any field of science matures. the drug- and stress-induced adaptations occur and to the specific microcircuits within Eric J. Nestler, M.D., Ph.D. brain pathways affected by those adaptations. Mount Sinai School of Medicine Finally, we must do a far better job of translating our 2008 Goldman-Rakic Prizewinner increasing knowledge of the neurobiological basis of drug addiction and depression to the clinic. We It was a tremendous honor for me to receive the have arguably not made appreciable improvements Patricia S. Goldman-Rakic Award from BBRF. It was in addiction and depression treatments over the past particularly meaningful since Dr. Goldman-Rakic was several decades. This is due mostly to the unique com- a close colleague of mine at Yale for many years. The plexity of the brain—which goes far beyond that of key goals of my laboratory’s research are to under- all other organ systems. However, it also is due to the stand how drugs of abuse or stress change the brain field’s dramatically reduced ability to readily study the in lasting ways to induce addiction- or depression-re- effects of drugs with novel mechanisms in humans. lated behavioral abnormalities in animal models and The hope is that the transformational advances in our to use that information to develop improved treat- ability to study molecular, cellular, and circuit mech-

40 anisms in the brain, together with a renewed invest- Larry R. Squire, Ph.D. ment in experimental human pharmacology, will lead University of California, San Diego to the fundamental improvements in therapeutics that 2012 Goldman-Rakic Prizewinner are so sorely needed. This is a great time for cognitive neuroscience and Michael Posner particularly for study of those features of cognition University of Oregon that are relevant to mental illness: attention, memory, 2004 Goldman-Rakic Prizewinner planning, decision making, and the organization of action. We are learning about these functions – how During the past decade research in cognitive neurosci- they operate and sometimes fail – in ever-increasing ence has provided an important foundation for future detail. Studies in humans help identify the compo- advances in understanding and treating mental illness. nents of these functions and the underlying brain The development of resting state MRI and of connecto- systems. Studying in monkeys can illuminate how mics has allowed the possibility of tracing the develop- these functions operate. And these problems are now ment of human brain networks from birth through the being brought to rats and mice with increasing success, life span. This provides a foundation for understanding where it has become possible using extraordinary new atypical development in childhood, the risk taking and techniques to study the cellular and molecular events, disorders of adolescents, and the loss of function in old and the circuitry, that support many cognitive functions. age within a single framework of brain development. Basic science will play a vital role in the development of This research is fostering new methods of treatment better diagnosis, prevention, and treatment of mental while at the same time improving our understanding of illness. It is sometimes said that we want to fix the car existing treatments. Distinguishing between changes in but we need to know how the car works. the depressed brain arising from drug treatments and those resulting from cognitive behavioral therapy marks an important advance in our ability to choose among or combine treatment modalities. Understanding the mechanisms of self-regulation may allow treatments for substance abuse that do not rely on the intention of the addicted person. An increase in our knowledge of how genetic and epigenetic mechanisms relate to brain networks paves the way for possible individual- ized therapies. These dramatic basic research findings have already influenced patient care and the future should see a dramatic increase in these efforts.

bbrfoundation.org 41 The Maltz Prize for Innovative and Promising Schizophrenia Research (formerly known as the Baer Prize) Stephen J. Glatt, Ph.D. Jeremy Hall, M.D., Ph.D. State University of New York, Professor of Psychiatry and Neuroscience Upstate Medical University Director, Neuroscience and Mental Health 2010 Baer Prizewinner Research Institute 2007 Baer Prizewinner We have long known that the risk for mental illness runs in families and, at least in part, is attributable Success in genomic discovery is now transforming our to genes. With support from the Brain and Behavior understanding of the causes of severe psychiatric disor- Research Foundation, we have made in the last decade ders such as schizophrenia. Advances in neuroscience undeniable progress in identifying some of the risk and stem cell biology are also increasingly providing genes for schizophrenia, bipolar disorder, major depres- the tools to translate these genetic discoveries into sive disorder, and other major mental disorders. Contin- mechanistic and therapeutic insights. The challenge ued collaborative science is key to assembling samples we face now is to use these approaches in an inte- large enough to have confidence in the identification grated and recursive fashion to translate genetic dis- of additional genes, but eventually this effort will “max covery into meaningful impacts on the treatment and out.” Once the majority of genetic risk factors have lives of patients. This will require the development of been identified, we will be in a unique position to programs of research that our focussed on delivering identify and study resilience factors, as many individuals clinical outputs and integrating with drug discovery who carry a large number of mental illness risk genes and the pharmaceutical industry. Our own work at do not develop any disorder. These individuals should the Cardiff Neuroscience and Mental Health Research be studied in depth so we can identify the protective Institute focusses on key pathways of risk for schizo- genes and environments from which they have bene- phrenia identified from genetic studies (e.g., synaptic fitted, and to determine ways in which the biological proteins; neuro-immune targets) and on developing a pathways that promote resilience can be fostered in translational platform linking genetic, cellular, animal at-risk individuals, and in the population at large. and human studies against which to prosecute future drug screening and development. Overall we aim contribute to the global efforts at develop genuinely new therapeutic approaches for this disabling disorder.

bbrfoundation.org 43 William P. Horan, Ph.D. including psychiatric conditions. We must intercept University of California, Los Angeles adverse brain development very early- during gesta- 2016 Maltz Prizewinner tion-to prevent a number of conditions including some mental illnesses. Our research team has an ongoing I am optimistic that new treatments that help people double-blind randomized trial assessing the impact with psychosis achieve more productive and personally of maternal choline supplementation (in the form of meaningful lives in the community will be available in phosphatidylcholine) during pregnancy on early child the next decade. We already have a good understand- neurodevelopment. Based on our pilot data, we antic- ing of some of the key factors that hold people back ipate improved child outcomes including behavior, from achieving their goals in areas such as relation- attention, and social interaction in the children whose ships, independent living, and work/school. Social mothers received choline while they were developing cognition has emerged as one of the most important in the womb versus children whose mothers received factors. Social cognition refers to the diverse men- a placebo. These are early markers of schizophrenia. If tal operations underling social interactions such as this supplement, which is safe during pregnancy and perceiving, interpreting, and managing responses to easy to take, is preventive, we can significantly reduce the behaviors of other people. Findings from many the human suffering related to schizophrenia and other research groups in the United States and abroad severe mental illnesses. strongly support targeted psychosocial interventions as a way to improve social cognitive skills. Further, there is Amanda J. Law, Ph.D. emerging evidence that these interventions can impact University of Colorado School of Medicine the brain systems involved in social cognition. A new 2011 Baer Prizewinner wave of studies is now evaluating creative approaches to enhance skill acquisition in these interventions, 2017 marks the 30th anniversary of the neurodevel- such as combining them with complementary phar- opmental hypothesis of schizophrenia. The original macological treatments and new technologies. These theory, offered independently in the papers of Wein- studies are also developing new ways to translate berger (1987) and Murray and Lewis (1987), proposed newly acquired social cognitive skills into meaningful that a prenatal/early developmental event could disrupt improvements in daily life functioning. Social cognitive normal growth and maturation of the brain, leading treatments will likely be important new tools to help to manifestation of schizophrenia in later life. Remark- people with psychosis maximize their functional recov- ably, even 30 years ago, it was recognized that genetic ery and personal fulfillment. and in-utero environmental factors (such as prenatal infection and obstetric complications) may contribute M. Camille Hoffman, M.D. to later risk. Despite the wealth of epidemiological University of Colorado evidence to support the hypothesis, still, little is known 2015 Baer Prizewinner about the mechanistic basis of how these factors impact early brain development. Today, we are in an As an obstetrician and maternal-fetal medicine sub- unprecedented era of psychiatric genetics research and specialist, I am hopeful that the field of schizophrenia the knowledge generated is expected to transform research is moving towards prevention. A hypothesis our biological understanding of the disorder. Although called the developmental origins of health and disease, most efforts to date have focused on identifying genes or DoHaD, has a robust body of data to support the associated with risk, a critical next step is translating impact of genetics, epigenetics, and environmental these findings into molecular and neurobiological influences on fetal life with respect to the down- mechanisms and understanding how they interact with stream development of chronic diseases of adulthood, early developmental adversity. For more than a decade,

44 our research has focused on understanding the neuro- pathophysiology, reduce disability, and improve out- biological role of genes associated with schizophrenia, comes for people with mental illness. incorporating developmental studies in humans and mice. Looking forward, we propose that the next gen- Barnaby Nelson, Ph.D. eration of animal studies in schizophrenia will integrate Orygen & University of Melbourne gene models with in-utero models of environmental 2015 Baer Prizewinner risk. Such studies have the potential to provide novel insight into the early neurodevelopmental origins of Although progress has certainly been made in symptom schizophrenia, the in-utero mechanisms involved, and management in schizophrenia, the underlying causes allow for the identification of prevention or interven- of the disorder remain elusive. In my view, progress on tion strategies. this front requires a resuscitation of detailed study of psychopathology, a return to understanding core phe- Amanda McCleery nomenological features of the disorder (i.e., character- University of California, Los Angeles istic disturbances of subjective experience in schizo- 2016 Maltz Prizewinner phrenia beyond “symptom counting”) and improved integration of the different domains of research (e.g., Over the last two decades there has been a dramatic the phenomenological, neurocognitive, neurobiological shift in the conceptualization of schizophrenia. There is domains). Apart from the obvious benefit of improved now a growing recognition that cognitive impairments understanding of the disorder, these efforts will guide are a core feature of the illness. Cognition, research into pathogenetic mechanisms, lead to which includes domains such as attention, increased ability to identify patients at highest risk learning, and memory, is highly predic- of the disorder, and improve early intervention and tive of community functioning in schizo- targeted therapies. phrenia, and hence, it is a prime target for intervention. The overarching aim of my research has Stephen Ripke, M.D. been to identify and understand cognitive predictors Psychiatric Genomics Consortium of community functioning in schizophrenia and related 2014 Baer Prizewinner conditions. My work is informed by developmental psychopathology, and I aim to gain a nuanced under- To date, genome-wide association studies (GWAS) have standing of the trajectory of cognition over the course identified more than 100 schizophrenia-associated loci of illness in order to identify critical periods, key targets in the genome and have led to novel insights into the for intervention, and mechanisms of change. With the biology of this common psychiatric disorder. Many of support of funding from the Brain & Behavior Research the identified genes fall into functional categories of Foundation, I have expanded my research program to synaptic function and plasticity, glutamatergic neuro- include novel electrophysiological methods to probe transmission, neuronal calcium signaling, neurodevel- the processes that underlie impaired cognition in opment and immune processes. Since the early days of schizophrenia, including neuroplasticity. Through this my medical training I have had an interest in pursu- line of research, I aim to increase our understanding ing computational methods in genetic research. The of the bases of cognitive impairment in schizophrenia, combination of strong computational and statistical and to guide development of treatment strategies to background with medical/clinical training allows me to remediate impaired cognition. I am grateful for the execute all necessary steps from receiving raw geno- continued support of the Brain & Behavior Research typic data up to drawing medical/clinical conclusions Foundation. The Foundation provides critical funding from the results. Having lead many analyses of the for pioneering research that aims to elucidate disease Psychiatric Genomics Consortium in recent years – the

bbrfoundation.org 45 largest collaborative experiment in psychiatric genetics Daniel Wolf, M.D., Ph.D. to date – I have developed a strong understanding of University of Pennsylvania what successful studies in the future would look like. 2009 Baer Prizewinner With larger sample sizes and novel methodological approaches, we are well positioned to continue our Biological research in psychiatry and in schizophrenia in strong record of discovery. particular is benefiting from a new focus on unpacking the heterogeneity within diagnostic categories by relat- Lorna W. Role, Ph.D. ing specific symptom dimensions to particular cogni- Stony Brook University tive-emotional processes and their underlying brain cir- 2009 Baer Prizewinner cuitry. My own work, supported by BBRF and the Baer Award, along with work by many others in I was lucky enough to be brought into the NAR- the field, has helped identify reduced function SAD/BBRF “family” by one of the Foundation’s early in brain reward circuitry as a neural correlate of forays into trying to attract people into the field motivation deficits in schizophrenia. These moti- who were not working on schizophrenia or other vation deficits, along with other “negative symp- neuropsychiatric diseases. It has been a transforma- toms,” cause much of the disability in schizophrenia, tive experience for me, taking my research from (very) and unfortunately remain resistant to current treat- basic science studies of mechanisms of synaptic trans- ments. However, hope lies ahead. The identification mission to (now 12 years) of effort that is much more of specific brain circuit abnormalities is providing new translationally directed. This has been a tremendously biomarkers and targets for treatment development, positive expansion of our research efforts and interests, and together with our rapidly expanding understand- setting new goals to our studies of how genes impli- ing of basic neuroscience and human genetics, will lead cated as susceptibility factors in schizophrenia might to transformative new therapies. As the field moves influence circuit excitability. As such, I think an import- increasingly toward understanding the earliest stages in ant direction for innovation in the field is to continue the development of schizophrenia, where dysfunction to encourage radically new perspectives and fusion of in brain motivation circuitry may provide one early sig- different disciplines. Collaborative interactions optimize nal of risk, we will ultimately achieve the ability to pre- the power of diversity in thinking and approaches. In vent schizophrenia and other illnesses from arising in my view, neuropsychiatric therapies of the future can the first place. In the meantime, there is an enormous only benefit from the convergence of perspectives as amount of work that needs to be done to get there. apparently disparate as computational neuroscience, genetics and biomedical engineering.

46 Overcoming Mental Illness with Science

• For the past 30 years the Brain & Behavior Research Foundation has fostered new research pathways and transformative breakthroughs.

• Our 60,000 donors have joined together in the great challenge of modern medical science–overcoming mental illness.

• Our 168 member volunteer Scientific Council has selected the best research strategies and scientists to pioneer in ending the suffering from brain and behavior disorders.

• Our 4,000 research grantees have dedicated their outstanding talents and training to develop improved treatments and methods of prevention for mental illness.

Join us in finding cures for mental illness. Make a gift today. Learn more at bbrfoundation.org

bbrfoundation.org 47 The Brain & Behavior Research Foundation is committed to alleviating the suffering of mental illness by awarding grants that will lead to advances and breakthroughs in scientific research. The Foundation funds the most innova- tive ideas in neuroscience and psychiatry to better understand the causes and develop new ways to treat brain and behavior disorders.

Since 1987, the Foundation has awarded more than $365 million to fund more than 4,000 leading scientists around the world. This has led to over $3.5 billion in additional funding for these scientists. 100% of donor contributions for research are invested in our grants leading to advances and breakthroughs in brain and behavior research. This is made possible by the generous support of two family foundations which cover our Foundation’s operating expenses.

646.681.4888 | bbrfoundation.org | [email protected] Sign up for eNews: bbrfoundation.org/signup. Find BBRFoundation on:

JULY 2017