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Home , Psychiatric genetics

Celebrating the legacy of the Institute of Psychiatric Research (IPR), and moving brain research forward

In 2013-2015, the Institute of Psychiatric Research building (IPR) on the IUPUI campus was demolished and a new Research Building was constructed as part of the

Neuroscience Center of Excellence on West 16th Street. The city lost the address that housed the

IPR as Eskenazi Hospital expanded to fill that space. The IPR building was a testament to the

scientific prowess and creativity found among those who studied mental disorders at Indiana

University. It was a center for outstanding research and teaching in the service of improved

patient care for persons suffering with brain disorders. We review brain research done at the IPR

and highlight its future at Indiana University Medical Center.

The Institute of Psychiatric Research was a free-standing center developed by the State of

Indiana in 1957 to investigate the causes of mental illness. Everything reflects its time and place.

Sixty three years ago, the US was led by President Dwight Eisenhower, Elvis Presley emerged as

the world's major musical star, and the discovery of the DNA double helical structure was just

three years old. Governor George Craig and Commissioner Margaret Morgan saw

a need for research on the underlying physical causes of psychiatric disorders, such as

, mood and anxiety disorders, , dementia, and addiction. At the time, many

believed that these were individual spiritual problems or moral failings, although newer theories

assigned blame to poor parenting and childhood mistreatment. Indeed, the medical paradigm,

including commonly used current psychiatric drugs was just coming into clinical use during the

1950’s (Table 1). With a far-sighted approach, the State of Indiana and the IU School of Medicine embraced the fledgling field of biological , instead. While not neglecting

interpersonal and social causes, the emphasis of is on understanding brain

function and on firmly embedding psychiatry within the realm of medicine.

The vision of the Governor, the State Legislature, and the Mental Health Commissioner to put a

major focus on neuropsychiatric research was bold and forward-looking. With the exception of

the New York State Psychiatric Institute and the Institute of Living (Hartford), there were few

free-standing centers for biological studies of psychiatric disorders (though there were a number of psychoanalytically-oriented institutions). At that time, specific psychiatric disorders were not

substantially represented in the scientific literature. For example, during 1950-1955, articles

published globally in autism and Alzheimer's disease came to no more than 19 and 74 articles,

respectively (Table 2). The following fifty years witnessed increasing research activity, and

during 2000-2005 articles published in autism and Alzheimer's disease rose to 3,270 and 18,800,

respectively (Table 2).

Over the past sixty years, biological psychiatry has received support from three sets of data: 1)

the undeniable response of severely ill patients to treatment with psychotropic medications, 2)

imaging studies revealing abnormal brain function associated with many psychiatric disorders,

and 3) the burgeoning knowledge of human genetics and its role in all of the major brain

disorders.

The Institute of Psychiatric Research (IPR) at the Indiana University School of Medicine was

built by the state in 1956 and opened in 1957 with a nationally known Board of Directors. IPR was to combine the best and brightest in the fields of not only psychiatry and psychology, but

also biochemistry, , , classical genetics, and the new field of

.

IPR took the lead in several vital threads of neurological and psychiatric research over the

ensuing decades. In the 1960s, IPR researchers discovered that glycine was a neurotransmitter.

They also established general principles for the confirmation of neurotransmitters. Since that

time, glycine (initially known as an inhibitory transmitter) has been identified as a key modulator

of excitatory pathways in the human brain. In the 1970s, IPR faculty contributed to our

understanding of the brain chemical serotonin, and the ways in which serotonin affects behavior.

We now know that serotonin contributes to the action of most commonly used antidepressant

drugs.

In the late 1980s, groundwork was laid at IPR for the study of psychiatric genetics, or the

understanding of brain biological differences that lead to vulnerability to depression or addiction.

Recently this work has expanded to consider the genetic basis of drug response, which have led

to the modern realization that drug effects are not “one-size-fits-all”. Different people have

different responses to the same dose of the same drug, and these differences can come from

genetic variations. In addition, during this decade, evidence that has helped demonstrate the fundamentally biological nature of “mental” disorders such as schizophrenia was found in

magnetic resonance imaging scans of the brain by a group at IPR.

In the 1990s Indiana University scientists led groundbreaking research demonstrating that

addiction is biologically tied to some of the same pathways (serotonin and dopamine) that are

used to treat depression and other psychiatric disorders. The genetic regulation of Alzheimer’s

disease and the molecular basis of the drugs used to treat Alzheimer’s (primarily drug effects on

the messenger chemical acetylcholine) have also been successfully explored at the IPR.

The first decade and a half of the 21st century saw additional expansion at IPR. In addition to

strictly biological studies, the interaction of environment with health history, genes, and drug treatments became a matter of important study. A whole-system approach has become important at IPR, where more traditional “single-focus” studies are now expanded and complemented by models that explicitly incorporate environmental and genetic risk factors for a disorder, such as the “Latent Early-life Associated Regulation” (LEARn) model, which proposes specific mechanisms by which environment and genetics interact within a person to produce effects that appear years to decades after an initial exposure to a toxin. The concept of early-life exposure having effects in later stages of life may have relevance for social problems such as crime and poverty as well as specific brain disorders such as and attention deficit disorder.

Another recent pioneering study being conducted by IPR investigators relates to the development of novel and specific protein biomarkers, which may be useful in understanding and diagnosing autism, bipolar disorder, and Alzheimer’s disease.

In each decade, IPR has changed its focus and has remained fundamentally useful. Our faculty and staff are now experiencing a significant development. IPR is no longer a stand-alone physical institution. Science now progresses as a team effort, especially in complex fields like

neuroscience and psychiatry. The faculty and research staff of IPR have moved to new facilities

that are intermingled with faculty from , , and other Departments of the

Indiana University School of Medicine and IU Health.

Throughout its history, IPR contributed heavily to training neuroscientists and in the Hoosier state and beyond, and to other scholarly activities. It became the home of Editors of internationally-respected journals, such as Current Alzheimer Research (Bentham) and

Psychiatric Genetics (Wolters Kluwers). In addition, IPR served as a magnet for many highly

competitive federal and corporate grants, providing jobs and economic stimulus to the state.

Over $20.7 million in grants (primarily from the National Institutes of Health) were awarded to

IPR investigators during 2009-2014. This reminds us that public and private investments in scientific research always pay off to the society in large as evident from the IPR’s significant contributions in research, teaching and training. Notably, IPR initiated the first graduate program in Medical Neurobiology at IUSM, and had been the home of this successful program until 2000.

The Institute’s mission continues vigorously in its new home in the Neuroscience Center of

Excellence at 16th and Senate near the IU Health Methodist campus, by the NIH-funded researchers in the area of alcohol, addiction, Alzheimer’s disease, bipolar disorder, schizophrenia, suicide and panic disorders. Other scholarly activities, such as grand rounds and group meetings, enrich the mission.

Indianapolis has made a significant imprint on neuropsychiatry. Eli Lilly developed the antidepressants Aventyl in the 1960s and Prozac in the 1980s and has continued with agents such as Zyprexa and Strattera and Cymbalta in recent years. The city of Indianapolis has also supported scientific/industrial advances from the Dow, Beckman, and Alison companies.

The building development on the IUPUI campus, even for those working there, has been a continual surprise over the last several decades. With the full demolition of the IPR building and the surrounding area as well as the construction of the massive Eskenazi hospital, geography of that area has changed forever. Neither the Union building, Wishard drive, nor “791 Union

Drive”, the address that made in numerous pages of so many international journals, exist anymore. Demolition of the IPR building, nevertheless, did not dampen psychiatric research at all. The landscape of psychiatric research continues to expand at the level of biochemistry, genetics, neurobiology, neuropharamacology and to find biomarker tools for early- diagnosis, genetic markers for a drug’s reaction, and of course novel drugs for various psychiatric diseases. Therefore, it is befitting that IPR gets a new home where multiple disciplines merge, intersect and cross-fertilize to novel ideas. The initial IPR founders and subsequent IPR directors always thought of psychiatric research as a dynamic journey to understand the biological mechanism of mental illnesses, and 791 Union Drive was just the beginning.

In short, the pioneering work started at the Institute of Psychiatric Research transferred to our new home with a continuing determination to understand and treat brain disorders. The task we face is the understanding of the basic processes of the brain, and then the translation of basic science discoveries to new strategies for prevention and treatment of these devastating disorders.

Debomoy K. Lahiri and John I. Nurnberger

Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of

Medicine, Neuroscience Research Building, 320 West 15th Street, NB 200C, Indianapolis, IN

46202-2266, USA

Table 1: Research activity (global) in major classes of psychiatric drugs within 50 years apart, as measured by the number of publication hits in PubMed. Searched items 1950/01/01 to 2000/01/01 to 1955/01/01 2005/01/01 SSRI 0 8,226 SNRI 0 1,040 Tricyclics 4 3,224 Antipsychotics 582 13,023 Other important activity Drug biomarker 0 22,420 Drug development 145 89,620 Source: PubMed search was carried out with the ‘Data Publication’ field and the indicated search years. All other fields were unselected, including languages. Only restriction place was the five years search period separated by 50 years, as mentioned above.

Table 2: Research activity (global) in major psychiatric disorders within 50 years apart, as measured by the number of publication hits in PubMed within the indicated years. Searched items 1950/01/01 to 2000/01/01 to Fold increase 1955/01/01 2005/01/01 Autism 19 3,273 172 Alzheimer’s disease 74 18,800 254 Bipolar disorder 218 5,213 24 Suicide 245 9,365 38 Dementia 280 25,540 91 Addiction 317 7,000 22 1,074 7,700 7 Schizophrenia 1,366 14,960 11 Footnote: PubMed search was carried out with the ‘Data Publication’ field and the indicated search years. All other fields were unselected, including languages. Only restriction place was the five years search period separated by 50 years, as mentioned above.

Table 3: Highlights of IPR History

1] John I. Nurnberger, MD, 1st Institute Director (1956 – 1973) Initial faculty: Drs. Aprison, Armus, Drew, Ferster, Grosz, McCaman, Persky, Zuckerman (1950s & 60s) 2] Early brainstorming session with Director and faculty initiated an era of multidisciplinary research in psychiatry; Institute used the shop-made operant chamber & control system (1950s – 1960s) 3] M.H. Aprison, PhD, original faculty (late 1950s) and Institute Director (1973 – 1978). Instrumental in developing criteria for identifying neurotransmitters. Discovered glycine as a neurotransmitter (with R. Werman). Instrumental in developing an animal model of depression (with J.N. Hingtgen, PhD). 4] Marion K. DeMyer, MD, pioneering researcher in autism and schizophrenia (1960s - 1980s). Helped define autism as a neurodevelopmental disorder. Conducted MRI scans of the brains of schizophrenics that demonstrated abnormal brain structure 5] Hugh C. Hendrie, MB, ChB, Institute Director (1978 – 1986). Chairman, Department of Psychiatry & Institute Executive Director 1986-2000. Conducted a pioneering longitudinal study on the incidence, prevalence and risk factors for Alzheimer’s disease in African Americans in Indianapolis and Africans in Ibadan, Nigeria (with K. Hall). 6] W.J. McBride, PhD. Led team that established the 1st animal model of alcoholism (1980s – 1990s). Led research program that determined brain sites where alcohol was rewarding 7] J.N. Hingtgen, PhD, Director of the 1st graduate program in Medical Neurobiology (1980s) 8] John I. Nurnberger, Jr, MD, PhD, Director Institute of Psychiatric Research (1986 – 2014) Leader in the development of psychiatric genetics as an international discipline. Led multi- institutional research programs on molecular genetics of bipolar disorder, alcoholism and disorder. 9] Anantha Shekhar, MD, PhD, pioneered in developing an animal model of panic disorder (1990s). Led team that identified neuronal dysfunctions underlying panic attacks and anxieties 10] Debomoy K. Lahiri, PhD, established Laboratory of in IPR (1990s). Pioneered cellular models to study molecular causes of psychiatric disorders: Alzheimer’s disease and Bipolar disorder. Developed novel genomic DNA techniques being used worldwide. Led research on amyloid plaque biogenesis in Alzheimer’s disease, and testing neuroprotective molecules for age-related disorders

Table 4: Additional Institute Faculty 1960s – 1990s

. John Paul Brady . Lew Graham . Robert Werman . Judy Richter . Marilyn McCaman . Alan Freeman . Claude Marmasse . Jay Simon . Arturo DeHoyos . Sandy Morzorati . Eugene Levitt . James Murphy . Joseph Zimmerman . Phil Shea . Donald Doehring . Sean O’Connor . James Norton . Aimee Mayeda . Harry Brittain . Al Sattin . Frank Walker . Steve Dunlop . James Trofatter

Current listing of Department of Psychiatric Research: https://medicine.iu.edu/departments/psychiatry/research/ Major Themes of Figures and Slides:

Fig. 1: Rise (& renovation) of the IPR building

Fig. 2: Changing faces of researchers at the IPR

Fig. 3: Diverse research tools from , mouse brain slices to chemistry

Fig. 4: Landscape of research models- from large animal to tissue culture studies

Fig. 5: Adapting neurochemistry with molecular and genetic studies at IPR

Fig. 6: Research data analysis and discussion of the results--then and later

Fig. 7: Passing the torch- Trainees learning the craft- PhD student to MD/PhD student

Fig. 8: Major pillar of IPR activity-clinical research: Interaction of research coordinators with psychiatrists

Fig. 9: IPR - the center for multidisciplinary research from Alcoholism, depression and suicide

Fig. 10: Demolition of the IPR building