Biological Psychiatry

Harold A. Sackeim, Ph.D., Chief of Psychiatric Research
Jeremy Coplan, M.D., Psychiatrist (Research) II
D. P. Devanand, M.D., Psychiatrist (Research) II
Sarah H. Lisanby, M.D., Psychiatrist (Research) II
James R. Moeller, Ph.D., Research Scientist V
Mitchell S. Nobler, M.D., Psychiatrist (Research) II
Gregory Pelton, M.D., Psychiatrist (Research) II
Joan Prudic, M.D., Psychiatrist (Research) II
Yaakov Stern, Ph.D., Research Scientist VI
Rikki Waterhouse, Ph.D., Research Scientist V

OVERVIEW
The Department of Biological Psychiatry (DBP) traces its origin to the founding of NYSPI in 1896, and was the first of the differentiated research divisions to emerge a few decades later. Under the leadership of Paul Hoch and subsequent Chiefs, the department made groundbreaking contributions to therapeutics. These included the introduction of electroconvulsive therapy (ECT) to the US by Lothar Kalinowsky, and the conduct of some of the first trials in the US of antidepressant, anxiolytic, and antipsychotic medications., Today the department has grown to approximately 70 FTEs, and is widely considered the premiere group in the study and clinical use of therapeutic brain stimulation in psychiatric disorders. However, current clinical research in the DBP has expanded to include large-scale studies of the pathophysiology and/or treatment of mood disorders, anxiety disorders, Alzheimer’s disease and other dementias, and schizophrenia. DBP has two primate research programs, a large brain imaging group, new capabilities in receptor imaging, laboratories for transcranial magnetic stimulation (TMS) and electrophysiology, and unique strengths in neuropsychology and interventional cognitive neuroscience. Basic research is strongly represented, and several of the faculty focus their research efforts on the interface between basic neuroscience and applications to clinical populations. For example, in the last few years, work with nonhuman primates laid the foundation for the introduction of 3 new therapies (magnetic seizure therapy [MST], ultrabrief ECT, and focal electrically-administered seizure therapy [FEAST]) for the treatment of severe psychiatric illness. Thus, much of the work in DBP is truly translational.

Clinical Research Facilities
During the 1980’s, strong collaborative ties with Neurology, especially with Dr. Richard Mayeux, led to opening the Memory Disorders Clinic at NYSPI - the major outpatient research center at CUMC for patients with Alzheimer’s disease. This facility, now in its 18th year, is directed by Drs. Mayeux and Devanand, with Dr. Stern serving as Director of Neuropsychology. The success of this collaboration, fundamental to the Alzheimer’s Disease Research Center at Columbia University’s Medical School, led the DBP to open the Huntington’s Disease Center of Excellence, directed by Dr. Steven Marder. In the early 1990’s, Dr. Sackeim invited Dr. Steven Roose to join him in establishing the outpatient facility focusing on the pathophysiology and treatment of Late-Life Depression, which has become one of the most active clinical research facilities at NYSPI. Similarly, in the late 1990’s, with the pioneering work being done at NYSPI in developing new somatic treatments for depression, and the need for a clinical structure in which patients could be followed longitudinally, the DEP opened a fourth outpatient facility, the Brain-Behavior Clinic, co-directed by Drs. Lisanby and Seidman. These four clinics, Memory Disorders, Huntington’s Disease, Late-Life Depression, and Brain-Behavior, comprise the Neuropsychiatry Clinics at NYSPI. This organizational structure has fostered innovative research across the usual disciplinary boundaries. It has contributed to Dr. Devanand’s seminal work on the treatment of behavioral disturbance and psychosis in patient’s with Alzheimer’s disease, his work on the relationship of mood disturbance to the onset of dementia, and the research by Dr. Pelton on the treatment of elderly depressed patients with cognitive impairment, the topic of his recently received K-Award. Indeed, patients in Drs. Devanand’s and Pelton’s protocols are recruited at the Late-Life Depression or the Memory Disorders Clinic. Alternatively, Dr. Stern, through interactions with Dr. Moeller and Sackeim, adopted their techniques for parametric variation of task difficulty and for identifying topographic covariance patterns in imaging data. This led to a series of funded studies using PET in normal aging and in patients with Alzheimer’s disease to identify compensatory mechanisms in the context of cognitive decline. Similarly, strengths in the areas of brain imaging, cognitive neuroscience, and brain stimulation, led the DARPA of the Department of Defence, to renew a grant focusing on the effects of sleep deprivation on decision processes. This $5M award to Drs. Stern, Lisanby and Sackeim is one of the only human research projects supported by this federal DOD initiative.

The availability of research beds at PI has made possible the well recognized research programs in ECT, magnetic seizure therapy (MST) and, most recently, focal electrically administered seizure therapy (FEAST) as well as the program jn brain stimulation and experimental therapeutics. Patients participating in these research studies are amongst the most severely ill, and these new forms of therapeutics for their conditions, if found to be efficacious, hold great potential.

Dr. Sackeim also directs the ECT program at CUMC (Presbyterian Hospital) and the Payne Whitney Clinic and Westchester Divisions of New York Hospital. This leadership role for these four clinical facilities is a unique example of how the merger of the two hospitals can lead to improvement in services and new research opportunities.

Basic Research
The DBP has two primate facilities at NYSPI and Downstate. The major focus of the NYSPI facility is the evaluation of the safety and physiological effects of new and established forms of brain stimulation, especially ECT, MST, and FEAST. Directed by Dr. Lisanby, and with the collaboration of Drs. Arango, Dwork, and Underwood from the Department of Neuroscience at NYSPI and Dr. Terrace from the Department of Psychology, the impact of these interventions on primate models of amnesia, neurogenesis, apoptosis, and other cellular mechanisms is under active investigation. It was this work that led to the refinement of MST and its initial evaluation in clinical trials in major depression.

Dr. Jeremy Coplan recently joined DBP on a part-time basis. Dr. Coplan’s clinical research interests are in the field of anxiety disorders. He is the co-director of the non-human primate facility at Downstate, studying bonnet monkeys. Bonnet monkeys are especially social animals and keenly sensitive to environmental manipulations. Dr. Coplan’s development of the variable foraging paradigm as a model for the intergenerational transmission of a mood/anxiety disorder is likely the only model in psychiatry of parent-child transmission of psychopathology where aspects of the dyadic interaction have primary causal status. This work has shown that even when adults the offspring show structural and neurochemical abnormalities.

The Downstate program is also the site for intensive research on the effects of antidepressant treatments on neurogenesis. Dr. Tarique Perera has just received a K-Award and a NARSAD award for his work in this area. He is validating a new paradigm for induction of “depression” in primates, investigating new methods to block the development of neurogenesis (use of the Gamma knife at Columbia), and determining whether neurogenesis is necessary and/or sufficient for antidepressant effects. This research was the first to show increased cellular proliferation in non-human primates following ECT and antidepressant medications, and specifically an increase in new neurons and endothelial cells. This work has also revealed dramatic changes in factors modulating the viability of new cells (eg, bcl-2).

Currently, DBP is the second most active group at CUMC in the use of PET, and has been for several years. The brain imaging program has several components. First, a series of a series of clinical research protocols using structural MRI, fMRI, MRS, and PET concentrate on the pathophysiology and treatment response in a variety of disorders. The imaging portion of major national study of Lyme Disease (Dr. Fallon: PI) has been conducted by the DBP, and has revealed marked abnormalities of CBF and metabolism in persistent disorder, partially reversible with extended intravenous antibiotic treatment. Work in late-onse4t major depression (Dr. Sackeim: PI) has isolated a network whose modulation accounts for about 80% of the variance in clinical improvement following treatment with a SSRI. These striking findings are in full agreement with the metabolic pathways altered by successful treatment with ECT. Dr. Nobler recently received a R01 to study the pathophysiology of amnesia induced by ECT. This modality is the only context in which people can be examined before, during and after the resolution of amnesia. Thus, this model has unique advantages in improving our basic understanding of memory mechanisms and of the dysregulation that results in amnesia.

Recently, Dr. Rikki Waterhouse transferred to the DBP. Much of her work concentrates on tracer development for use with PET. She has already succeeded in bringing a sigma receptor ligand to the human, and has made distinct progress in other domains. Due to the numerous interactions of sigma receptors with other neurochemical systems, and especially dopamine, there is widespread interest internationally in using the new ligand in studies of a host of neurological and psychiatric disorders. With the treatment development in DBP producing new forms of focal brain stimulation, Dr. Waterhouse will have the opportunity to use interventional stimulation techniques with receptor mapping technology to determine whether neurochemical systems can modulated in a focal manner.

Dr. Moeller has been a key contributor the DBP’s imaging efforts since the late 1980’s. He is the originator of the Scaled Subprofile Model and other techniques to isolate independent sets of topography in imaging data and to score individuals for their manifestation of each topography. With Dr. A. Eidelberg, a long-term DBP collaborator, this method has shown remarkable success in predicting the degree of symptomatic change in Parkinson’s disease with a variety of interventions. His methods are at the core of the imaging work in Lyme Disease, major depression, and cognitive alterations with normal aging. He has recently extended his analytic method to a voxel-based approach and for use with fMRI. Dr. Mensh’s primary work is also at the methodological level. He has developed a library of routines for the analysis of PET-MRI data. Indeed, he is completing work now on a novel method of using a library of parcellated brains to automatically parcellate (determine regions of interest) a new brain.

Collaborations
Collaborations with scientists outside the institution are extensive. Dr. Sackeim is the PI or Co-PI of 5 national, multi-center studies, examining ECT, rTMS (2), citalopram, VNS, and MST. He is the Science Advisor for the NIMH contract, STAR*D. The work on neurogenesis at both primate facilities involves virtually all the leaders in this field, including those skeptical and enthusiastic about the phenomenon. The work involving the safety of MST and ECS (sham-controlled) has stereology performed by the group in Denmark that invented the methodology. Currently, Drs. Eidelberg at North Shore, Manji at NIMH, and Herbert Terrace at the downtown campus have adjunct academic appointment in DBP. There are more than 30 outside mentors on the K-Awards held by junior faculty in the department.

Future Directions
The work of the DBP is the only organized effort at NYSPI to address issues in geriatric psychiatry. Drs. Roose, Devanand and Sackeim direct a Geriatric Neuropsychiatry research fellowship which has strong involvement from Neurology. The development of a more complete geriatric program is a goal, incorporating greater clinical exposure.

The work of the DBP is responsible for many of the advances in brain stimulation in psychiatry. For almost 25 years, the DBP has received the vast bulk of the funding related to ECT. With its preclinical work with primates, and the new techniques of rTMS, MST, FEAT, VNS, and DBS, this group is uniquely positioned to establish a center for the study of brain stimulation in psychiatry. This idea has been enthusiastically received at NIMH, and the first Intervention Center with a strong translational research component will be submitted in the fall of 2004. The vision is to further develop within the DBP expertise in (1) the relevant animal models, especially in primates, (2) the physics and neurobiology of brain stimulation, (3) the phenomenology and treatment of mood disorders, and (4) advanced neuroimaging to identify targets for therapeutic change and to investigate mechanisms of illness and recovery.

BIBLIOGRAPHY
Devanand, D.P., Adorno, E., Cheng, J., Burt, T., Pelton, G.H., Roose, S.P., and Sackeim, H.A.: Late onset dysthymic disorder and major depression differ from early onset dysthymic disorder and major depression in elderly outpatients. Journal of Affective Disorders, 2004, 78:259-267.
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