Stanley Center for the Innovative Treatment of Bipolar Disorder

SECOND INTERNATIONAL CONFERENCE 
ON BIPOLAR DISORDER


Introduction

Poster Sessions

Audio Recordings

Bipolar Conferences Home

June 19-21, 1997
Sheraton Hotel at Station Square
Pittsburgh, Pennsylvania

Introduction to the Conference

For more than a decade after the introduction of lithium pharmacotherapy, manic-depressive illness was thought of as a problem solved. Recently, however, both naturalistic studies and controlled trials have indicated that we still have much to learn about this puzzling and destructive disorder.

In June 1994, the University of Pittsburgh Medical Center's Western Psychiatric Institute and Clinic sponsored the First International Conference on Bipolar Disorder, which attracted more than 400 participants. The conference provided an opportunity for researchers and clinicians to meet and share new information on the neurobiology and pathophysiology of bipolar illness, psychobiology and psychosocial vulnerability factors, and recent findings on epidemiology and clinical course.

The Second International Conference on Bipolar Disorder, planned for June 1997, will continue the work begun at the first conference. the second conference will present an update on etiologic factors and treatment methods, including current information on the genetics of bipolar disorder as well as both biological and psychotherapeutic modalities for the acute and maintenance treatment of bipolar disorder. An increasing array of treatment options is becoming available for this disorder, and the roles and significance of these new therapies will be discussed. Top scientists and clinicians from around the world will be available to entertain questions from the audience following presentations and in panels. The conference will also feature " Ask the Experts" question-and answer sessions on June 19 and 20, 1997.

Table of Contents

Course Directors

Maintenance Pharmacotherapy

Ask the Experts

Child and Adolescent Bipolarity

Psychosocial Aspects

Ask the Experts

Recent Genetic Findings

New Pharmacotherapies

Stanley Foundation

Course Directors

Ellen Frank, Ph.D.
Professor of Psychiatry and Psychology
University of Pittsburgh School of Medicine

Biography

Dr. Ellen Frank is Professor of Psychiatry and Psychology at the University of Pittsburgh School of Medicine. She graduated from Vassar College in 1966 and received a master’s degree in English from Carnegie Mellon University in 1967. Her doctoral work in psychology was done at the University of Pittsburgh and completed in 1979.

Under a grant from the National Institute of Mental Health, Dr. Frank is currently studying the efficacy of Interpersonal and Social Rhythm Therapy, a treatment she developed for manic-depressive illness, which focuses on helping patients to increase the regularity of their daily routines and improve their day-to-day relations with others.

She is also conducting a major NIMH-sponsored study of women with recurrent depression in which she hopes to sort out how biology, life stress, and different "doses" of psychotherapy, interact in increasing or decreasing vulnerability to new episodes of depression.

An expert in mood disorders and their treatment, Dr. Frank was a member of the American Psychiatric Association’s Task Force on DSM-IV and was Chair of the Food and Drug Administration’s Psychopharmacologic Drugs Advisory Panel. Dr. Frank is currently a member of the MacArthur Foundation Research Network on Psychopathology and Development and is Chair of the American College of Neuropsychopharmacology’s (ACNP) Task Force on Continuing Education.

Dr. Frank is an Honorary Fellow of the American Psychiatric Association.

Samuel Gershon, M.D.
Professor of Psychiatry
University of Pittsburgh School of Medicine

Biography

Samuel Gershon, M.D. joined the faculty at the University of Pittsburgh in April, 1988, and at that time assumed the titles of Associate Vice President for Research in the Health Sciences, Vice President for Research at the University of Pittsburgh Medical Center, and Associate Research Director for Neurosciences in the Department of Psychiatry. He is also Professor of Psychiatry at the School of Medicine. Prior to his tenure with the University of Pittsburgh, Dr. Gershon held the positions of Professor and Chairperson at the Department of Psychiatry at Wayne State University, and was also Director of the Lafayette Clinic. Dr. Gershon’s career as a psychiatrist and researcher spans more that 30 years. During this time, he has published more than 600 writings and has won several prestigious awards including, among others, the Pfizer Scholarship for Medical Research Overseas and the American Psychiatric Association’s Rush Gold Medal Award.

David J. Kupfer, M.D.
Thomas Detre Professor and Chairman
Department of Psychiatry
Professor of Neuroscience
University of Pittsburgh School of Medicine

Biography

David J. Kupfer, M.D., Thomas Detre Professor and Chairman of the Department of Psychiatry and Professor of Neuroscience at the University of Pittsburgh School of Medicine, received his bachelor (magna cum laude) and M.D. degrees from Yale University. Dr. Kupfer continued his postgraduate clinical and research training at the Yale New Haven Hospital and at the National Institute of Mental Health (NIMH). In 1970, he was appointed an assistant professor of psychiatry at Yale University School of Medicine. Dr. Kupfer joined the faculty at the University of Pittsburgh in 1973 as Associate Professor of Psychiatry and Director of Research and Research Training at Western Psychiatric Institute and Clinic. He was promoted to Professor of Psychiatry in 1975 and became chairman of the department in 1983. In 1994 he was named the Thomas Detre Chair in Psychiatry. For more than twenty years, Dr. Kupfer’s research has focused primarily on the conceptualization, diagnosis, and treatment of mood disorders. He has written more than 600 articles, books, and book chapters that address diagnosis and treatment of recurrent mood disorders, and the relationship between biological rhythms, sleep and depression. In recognition of his contributions to the field, Dr. Kupfer has been the recipient of numerous awards and honors, including the A.E. Bennett Research Award in Clinical Science (1975), the Anna-Monika Foundation Prize (1977), the Daniel H. Efron Award (1979), the Twenty-Sixth Annual Award of the Institute of Pennsylvania Hospital in Memory of Edward A. Strecker, M.D. (1989), the William R. McAlpin, Jr. Research Achievement Award (1990), the 1993 American Psychiatric Association Award for Research in Psychiatry, the First Isaac Ray Decade of Excellence Award (1994), and the Twelfth Annual Edward J. Sachar Award (1996). He was elected to the Institute of Medicine of the National Academy of Sciences in 1990.

Alan G. Mallinger, M.D.
Associate Professor of Psychiatry and Pharmacology
University of Pittsburgh School of Medicine

Biography

Dr. Mallinger has pursued parallel interests in clinical psychiatry and basic psychopharmacology research during his career. His areas of research include laboratory studies on the mechanisms of lithium action, biological investigations of bipolar disorder, therapeutic options for treatment-resistant mania, and pharmacokinetic studies of MAO inhibitors. He is currently Director of the Psychopharmacology of Mania and Depression basic research program at Western Psychiatric Institute and Clinic, as well as Medical Director of the Maintenance Therapies in Bipolar Disorder study, and the Stanley Center for the Innovative Treatment of Bipolar Disorder. Dr. Mallinger has authored or coauthored 50 scientific articles and book chapters. He also serves on the Merit Review Committee for Mental Health and Behavioral Sciences of the Department of Veterans Affairs.

Michael E. Thase, M.D.
Professor of Psychiatry
University of Pittsburgh School of Medicine

Biography

Michael E. Thase, M.D. is Professor of Psychiatry at the University of Pittsburgh School of Medicine and the Western Psychiatric Institute and Clinic. His research interests pertain to the assessment and treatment of mood disorders, including the short-term and prophylactic efficacy of pharmacotherapy and cognitive therapy in relationship to the psychobiological correlates of depression. A 1979 graduate of the Ohio State University College of Medicine, Dr. Thase has directed the Depression Treatment and Research Center at the University of Pittsburgh since its inception in 1987. In 1988, he became Director, Division of Mood, Anxiety, and Related Disorders, and Associate Director of the Mental Health Clinical Research Center at Western Psychiatric Institute and Clinic. Dr. Thase has authored or coauthored over 200 scientific articles and book chapters. He is coeditor of the books entitled Handbook of Outpatient Treatment, published in 1990 by Plenum Press, and Cognitive Therapy with Inpatients: Developing a Cognitive Milieu, which was published in 1992 by Guilford Press.

Overview of Findings of Longitudinal Clinical Studies
Jan Fawcett, M.D.
Stanley G. Harris, Sr. Professor and Chairman
Department of Psychiatry
Rush-Presbyterian-St. Luke’s Medical Center

Abstract

The NIMH Collaborative Depression Study followed the outcome of 954 patients with major affective disorders from 1978 until the present. This study collected outcome and family data on Bipolar I, Bipolar II, and Schizoaffective patients. Treatment was uncontrolled and its intensity and type were recorded at six- month intervals. The study yields data on the naturalistic outcome of patients relative to their affective subtype over ten years of follow-up. Data relating to naturalistic clinical outcome from this and other studies such as the Iowa at Western Psychiatric Institute and Clinic 500 will be considered in this presentation.

References:

Coryell W, Keller M, Endicott J, Andreasen N, Clayton P, Hirschfeld R. " Bipolar II illness: Course and outcome over a five-year period." Psychol Med 19:129-141, 1989.

Coryell W, Endicott J, Maser JD, Keller MB, Leon AC, Akiskal HS. " Long-term stability of polarity distinctions in the affective disorders." Am J Psychiatry 152(3):385-390, 1995.

Coryell W, Endicott J, Maser JD, Mueller T, Lavori P, Keller M. "The likelihood of recurrence in bipolar affective disorder: The importance of episode recency." J Aff Dis 33(3):201-206, 1995.

Winokur G, Coryell W, Akiskal HS, Endicott J, Keller M, Mueller T. "Manic-depressive (bipolar) disorder: The course in light of a prospective ten-year follow-up of 131 patients." Acta Psychiatrica Scand 89:102-110, 1994.

Winokur G, Coryell W, Keller M, Endicott J, Akiskal H." A prospective follow-up of patients with bipolar and primary unipolar affective disorder." Arch Gen Psychiatry 50:457-465, 1993.

Winokur G, Tsuang (eds). The Natural History of Mania, Depression and Schizophrenia. Washington, DC, American Psychiatric Press, 1996.


Biography

Jan Fawcett, M.D., Chairman of the Department of Psychiatry at Rush-Presbyterian-St. Luke’s Medical Center is a graduate of Yale University School of Medicine. He received his psychiatric training at Langley Porter Neuropsychiatric Institute and at the University of Rochester Medical Center. Dr. Fawcett’s career in research began at the Clinical Center of the National Institute of Mental Health (NIMH) in Bethesda, Maryland where he became involved with research concerning the biomedical aspects of depression and suicide. He came to Chicago in 1966 to establish a Depression Research Unit at the Illinois State Psychiatric Institute to study the pharmacology and biochemistry of depression as well as the prediction and prevention of suicide.

Dr. Fawcett became the Stanley G. Harris, Sr. Professor of Psychiatry at Rush-Presbyterian-St. Luke’s Medical Center in 1972. In June, 1992, Dr. Fawcett was appointed the Grainger Director of the Rush Institute for Mental Well-Being at Rush-Presbyterian-St. Luke’s Medical Center. He has continued his research in the area of depression as a principal investigator of the NIMH Psychobiology of Depression Collaborative Study, a nineteen-year study of the diagnosis and outcome of depressive illness. In addition, he is pursuing studies in the areas of depression, suicide and alcoholism. A frequent contributor to scientific journals, Dr. Fawcett is also active in professional organizations such as the American College of Neuropsychopharmacology, the National Depressive and Manic-Depressive Association (NDMDA), and the Psychiatric Research Society. In 1989, he was the recipient of the Dr. Jan Fawcett Humanitarian Award for the NDMDA, named in his honor, received the Dublin Research Award from the American Association of Suicidology in 1991, and received the 1993 American Suicide Foundation Research Award. He is presently the Editor of Psychiatric Annals, past president of the Psychiatric Research Society (1993-1994) and past president of the American Suicide Foundation (1991-1994).

Lithium Maintenance Therapy: Efficacy-Dose Relationships
Alan J. Gelenberg, M.D
Professor and Head, Department of Psychiatry
University of Arizona

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Abstract

Although it has been almost half a century since Cade described lithium’s effects in manic-depressive patients, we still do not understand completely the relationship between lithium dose and efficacy. Most recent reports suggest that maintaining a lithium level between 0.6 to 0.8 mEq/L will provide adequate protection for many patients against relapse and cause few side effects. However, some studies show no correlation between lithium levels and rates of relapse, and others indicate that some patients would do well on lower levels. Levels below 0.4 mEq/L appear generally inadequate to protect against relapse, but no one has systematically compared 0.4 to 0.6 mEq/l with 0.6 to 0.8 mEq/L to see if a slightly lower range may be just as efficacious. As with lithium dose-efficacy relationships, the relationship between lithium dose and adverse effects is also uncertain, although generally assumed to be positive and linear. The largest and best controlled blood lithium level study reported a 2.6-times increase in relapses in patients maintained in the range of 0.4 to 0.6 mEq/L versus those maintained between 0.8 and 1.0 mq/L. Questions remain about special populations.

Biography

Alan J. Gelenberg, M.D. is Professor and Head of the Department of Psychiatry at the University of Arizona, Editor-In-Chief of the Journal of Clinical Psychiatry, and founding author of the monthly newsletter Biological Therapies in Psychiatry, now in its 20th year. Before coming to Tucson in 1989, Dr. Gelenberg spent over 19 years in Boston, where he was on the faculty of Harvard Medical School and Massachusetts General Hospital.

Dr. Gelenberg has conducted clinical psychopharmacology research for twenty-four years. He has been principal investigator on grants from the federal government, industry, and private foundations. His 1976 Lancet paper, "The Catatonic Syndrome", has been cited in over 100 other publications, and he was first author on a report on lithium that appeared in 1989 as a lead article in the New England Journal of Medicine. He is currently studying treatments for mood disorders and Schizophrenia and has authored about 200 scientific articles, editorials, and book chapters. Dr. Gelenberg is Vice President of the board of his medical school’s faculty practice plan and has helped redesign public mental health services in his region.

Dr. Gelenberg serves on editorial boards and reviews for about ten medical journals. He has been Senior Editor of The Practitioner’s Guide to Psychoactive Drugs, third and fourth editions. Often a guest lecturer and visiting professor, Dr. Gelenberg has served on grant review and advisory committees for the National Institutes of Mental Health and Drug Abuse, the Pfizer Visiting Professorship Program in Psychiatry, and the Psychiatric Advisory Panel to the United States Pharmacopeial Convention. He is a fellow of the American Psychiatry Association’s Committee on Research on the Psychiatric Treatments, is Vice President of the Board of Directors of COPE Behavioral Services, Inc., on the board of the American Society of Clinical Psychopharmacology, the Professional Advisory Council of the Neuroleptic Malignant Syndrome Information Service, consults to Merck-Medco Managed Care, and is listed in The Best Doctors In America.

A native of Philadelphia, Alan Gelenberg received an A.B. from Columbia University and an M.D. from the University of Pennsylvania. After a year’s internship in internal medicine, he was a resident in psychiatry at Massachusetts General Hospital.

The Role of Antidepressant Treatments in Rapid Cycling
Athanasio Koukopoulos, M.D.
Director of the Centro Lucio Bini
Chief, Medical Staff
Clinica Belvedere Montello
Italy

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Abstract

All the patients suffering from mood disorders examined at the Centro Lucio Bini during the years 1990-1996 were classified according to the DMS-IV criteria. The entire group consisted of 1257 patients; 737 women and 520 men. One hundred-forty-one of the 87 women and 54 men had a rapid cycling course. This number of RC patients represents the 11.2% of the total group of 1257 and the 17% of the 812 bipolar patients. The large majority of the RC patients belonged to the BP II diagnostic group (n 93) followed by the BP I group (n 42). Only 6 were unipolar depressives. The age-at-onset of rapid cyclicity was 41 years for women and 43 for men.

The average number of episodes per year during rapid cyclicity was 7.20, while in the previous course it was 0.89 per year. Twenty patients were spontaneous RC, while in 121 patients the rapid cycling coincided with antidepressant drug treatments. In a few cases, lithium, ECT, corticosteroids, cannabis, cocaine, and caffeine were involved, and in one case rapid cyclicity started during psychotherapy, concomitantly with an intense transfert. A dopaminergic hypothesis is discussed.

Of the 141 RC, 22% of the women and 15% of the men suffered from hypothyroidism. All were receiving lithium. Three factors were found to favour the induction of rapid cycling:

1) The high previous cyclicity;

2) The cycle with the sequence Depression-Hypomania (Mania), the same that makes a patient resistant to prophylactic lithium (a). The same cycle pattern of the switch process

3) Premorbid temperaments marked out by high energy and intense motionability like the Hyperthymic and the Cyclothymic Temperament.

BP II patients best represent these three factors, and indeed 28% of them become RC and 66% of all RC are BP II.

(a) A. Koukopoulos, Reginaldi, P. Laddomada, G. Floris, G. Serra, L. Tondo: "Course of the Manic Depressive Cycle and Changes Caused by Treatments." Pharmacopsychiat, 13(1980) 156-167.

Biography

Dr. Koukopoulos is Director of the Centro Lucio Bini, a center for the treatment and the study of psychiatric conditions and especially of affective disorders, which he and some of his colleagues founded in 1976, and Chief of the medical staff of the Clinica Belvedere Montello, a private psychiatric inpatient facility in Rome, which he established with some of his colleagues in 1963.

His main activity is the examination and treatment of psychiatric patients with a particular interest in affective disorders. In addition to his clinical activity, he has been performing clinical research into the course of manic-depressive illness and the pattern of manic-depressive cycle.

He is also conducting studies on manic-depressive temperament and its importance in the genesis of affective disorders and their course.

Related to the above issues have been other lines of research, such as the response to prophylactic lithium treatment and the increase of bipolarity and frequency of recurrences following antidepressant drug treatments. The temperament, the previous course, and the concomitant factors of rapid cyclicity, have been an important part of his work for more than twenty years.

Update on Antiepilectic Drugs (AEDs) in Bipolar Disorder
Susan L. McElroy, M.D.
Associate Professor of Psychiatry and Psychopharmacology
University of Cincinnati School of Medicine

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Abstract

An increasing number of studies performed over the past several decades have shown that a variety of antiepileptic drugs (AEDs) are effective in the acute and prophylactic treatment of some patients with bipolar disorder, including those inadequately responsive to or intolerant of treatment with lithium. These agents include a number of standard AEDs (e.g., carbamazepine and valproate) and the investigational AED oxcarbazepine. Indeed, carbamazepine and valproate are considered by many authorities to be first-line mood-stabilizing agents, along with lithium, in the treatment of bipolar disorder. Although it is presently unknown whether the mechanisms of action underlying the antiepileptic properties of these drugs are responsible for their mood-stabilizing effects, it has been suggested that newer AEDs, including gabapentin, lamotrigine, and topiramate, should be screened for putative thymoleptic properties. In this talk, new data on the efficacy of VPA and CBZ in bipolar disorder will be reviewed. Also, preliminary experience with gabapentin, lamotrigine, and topiramate in the treatment of bipolar disorder will be discussed.

Biography

Susan L. McElroy received her M.D. from Cornell University Medical School. Following her residency in internal medicine at Columbia Presbyterian Hospital, New York, she completed a residency in psychiatry at McLean Hospital in Belmont, Massachusetts, where she was a Clinical Fellow in Psychiatry at Harvard Medical School. Dr. McElroy served as Director of the Psycho-pharmacologic Services, Adult Outpatient Clinic at McLean Hospital from 1988-1191 and was an assistant professor of psychiatry at Harvard Medical School.

In 1991, Dr. McElroy became Associate Professor of Psychiatry and Pharmacology at the University of Cincinnati College of Medicine, where she is Director of the Biological Psychiatry Center and Codirector of the Biological Psychiatry Program.

Dr. McElroy has published 90 original articles, 1 book, 44 reviews and book chapters, 10 letters, and 71 original abstracts, most regarding the treatment of bipolar disorder. She lectures extensively on the subject, both nationally and internationally.

Dr. McElroy’s research interests include: Bipolar Disorder, Depression, Paraphilia, Obsessive Compulsive Disorder, and the various Impulse Control Disorders (e.g., Compulsive Shopping, Binge Eating Disorder, Kleptomania, Intermittent Explosive Disorder)

Steven E. Hyman, M.D.
Director
National Institute of Mental Health

Biography

Steven E. Hyman, M.D., is Director of the National Institute of Mental Health (NIMH), a component of the National Institutes of Health. Prior to his NIMH appointment in April 1996, Dr. Hyman was Associate Professor of Psychiatry and Neuroscience at Harvard Medical School and Director of Psychiatry Research at Massachusetts General Hospital. Dr. Hyman also served as director of Harvard University’s Interfaculty Initiative on Mind, Brain, and Behavior. This program brought together faculty from Harvard’s diverse schools to focus on clinical and policy issues in the light of modern brain research.

Dr. Hyman received his BA from Yale in 1974 (summa cum laude); his MA from the University of Cambridge in 1976, where, as a Mellon Fellow, he studied the history and philosophy of science; and his MD from Harvard Medical School (cum laude) in 1980. He was a medical intern at Massachusetts General Hospital (MGH), a psychiatric resident at McLean Hospital, and a clinical fellow in neurology at Massachusetts General Hospital. His postdoctoral training in molecular biology was in the Laboratory of Howard M. Goodman, also at Massachusetts General Hospital.

Dr. Hyman’s laboratory focuses on how the neurotransmitters dopamine and glutamate produce long-term changes in brain function by activating or suppressing the expression of genes within nerve cells. In recent years, his main focus has been on alterations in gene expression in the striatum and nucleus accumbens, brain regions involved in the control of motivated behavior, and implicated in the action of both antipsychotic medications and drugs of abuse. As NIMH Director, Dr. Hyman continues to direct an active research program located on the NIH campus in Bethesda, Maryland.

In addition to his scientific writing, Dr. Hyman has authored and edited several clinical textbooks. He serves on the editorial board of the Archives of General Psychiatry.

Bipolar II and III: Interface of Temperament and soft Bipolarity
Hagop S. Akiskal, M.D.
Professor of Psychiatry
Director of International Mood Center
University of California at San Diego

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Biography

Prior to his present post, Dr. Akiskal served as Senior Science Advisor to the Director of the National Institute of Mental Health (1990-94). Earlier he was at the University of Tennessee, Memphis, where he established Mood Clinics which have had worldwide appeal because of their philosophy of conducting clinical training and research while delivering high quality care. Dr. Akiskal’s studies examine the relationship of subclinical temperament traits and various affective disorders, with special focus on the soft bipolar spectrum. He has contributed over 300 papers to the scientific literature and authored or edited ten books, the latest of which is Dysthymia and the Spectrum of Chronic Depressions (Guilford Press, 1997). Dr. Akiskal has won numerous national and international awards, including the Gold Medal for "Pioneer Work" from the Society of Biological Psychiatry (1995).

Assesment and Management of Suicide Risk in Bipolar Patients
Jan Fawcett, M.D.

Abstract

This session will focus on questions concerning the risk of suicide in bipolar patients, its assessment and management. Are certain types of bipolar patients higher risks? Is the risk acute or chronic? How is acute risk determined? How is chronic risk assessed? Finally, what are the management strategies for both acute risk and chronic risk bipolar patients? These and other clinical issues raised by the participants will be considered.

References:

Fawcett J, Scheftner W, Clark D, Hedeker D, Gibbons R, Coryell W. "Clinical predictors of suicide in patients with major affective disorders: A controlled prospective study." Am J Psychiatry. 1987, 144(1):35-40.

Fawcett J, Scheftner WA, Fogg L, Clark DC, Young MA, Hedeker D, Gibbons R. "Time-related predictors of suicide in major affective disorder." Am J Psychiatry, 1990, 147(9):1189-1194.

Winokur G, Tsuang MT. The Natural History of Mania, Depression and Schizophrenia. Washington DC, American Psychiatric Press, 1996.

David J. Miklowitz, PH.D.
Associate Professor of Psychology
University of Colorado at Boulder

Biography

Dr. Miklowitz received his doctorate from the University of California, Los Angeles, in 1985, and has been on the clinical psychology faculty at University of Colorado, Boulder, since 1989. He has been conducting research on psychosocial factors relevant to bipolar disorder since the early 1980's. He has demonstrated in two separate studies that family stress factors are important predictors of the course of bipolar disorder. With his colleague Michael Goldstein, he developed a new psychosocial treatment - family-focused psychoeducational treatment - used in combination with medication for recently episodic bipolar patients. He is currently testing the efficacy of this treatment in an experimental trial. Dr. Miklowitz has published 60 papers and book chapters, come of which have appeared in the Archives of General Psychiatry, the British Journal of Psychiatry, the Journal of Abnormal Psychology, and the Journal of Nervous and Mental Disease. He has an in-press book with Michael Goldstein, Bipolar Disorder: A Family-Focused Treatment Approach, by Guilford Press. He has received Young Investigator research awards from the International

Michael Strober, Ph.D.
Professor of Child and Adolescent Psychiatry
University of California, Los Angeles, School of Medicine

Biography

Dr. Strober is Director of the Adolescent Mood Disorders Program, Department of Psychiatry, University ofCalifornia Center for the Health Sciences at Los Angeles. He has been involved in research on pediatric bipolar disease since 1976, with particular emphasis on its genetic epidemiology and naturalistic course. In addition, he has been conducting clinical trials investigating the effectiveness of various pharmacological treatment strategies in this age group, and is collaborating on studies of brain imaging in early-onset bipolar disease. Dr. Strober’s research appears in various peer-review publications, and he serves as ad hoc reviewer for some fifteen psychiatric research journals. Dr. Strober has served as a grant reviewer for NIMH, and was a consultant for the American Academy of Child and Adolescent Psychiatry Practice Guidelines for the treatment of pediatric bipolar illness. In addition to these academic activities, he is a clinical administrator for the UCLA Neuropsychiatric Hospital adolescent inpatient service.

Mania in Preschoolers and Prepubertal Children
Elizabeth B. Weller, M.D.
Professor of Psychiatry and Pediatrics
University of Pennsylvania

Abstract

Mania in children had been rarely diagnosed until recently. In Kraeplin’s series of adult manics, the occurrence of mania before the age of 10 was 0.5% with a surge of new cases with the onset of puberty. DSM-III-R added to the confusion of overidentifying mania in children by removing the length of an episode of one week. As a result, children with behavioral disorders, such as ADHD and conduct disorder, with symptoms of mania, such as overactivity, irritability and reckless behavior, were diagnosed to have mania. In this presentation, a review of clinical presentation of mania will be contrasted with that of ADHD and conduct disorder. An emphasis on how to tell the disorders from each other by using proper diagnostic evaluation, structured and semi-structured interviews, and rating scales will be presented. The questions of comorbidity with ADHD and conduct disorder will be discussed in the context of mixed manic states.

Biography

Elizabeth Weller, M.D., Professor of Psychiatry and Pediatrics at the University of Pennsylvania, Frederick H. Allen Chair, Department of Psychiatry at Children’s Hospital of Philadelphia, was born and raised in Lebanon, in an American family. She received her undergraduate degree with Alpha Omega Alpha honors after a pediatric internship in 1975 from the American University of Beirut. She did her psychiatry residency at Washington University in St. Louis where she met and married her spouse. They moved to Kansas City, where she completed her training in child and adolescent psychiatry at the University of Kansas Medical Center. Upon completing her training, she joined the faculty as Assistant Professor of Psychiatry and Pediatrics. She established the children’s unit there and served as Director of Child and Adolescent Psychiatry Residency Training and Acting Head of Child and Adolescent Psychiatry. She was promoted to Associate Professor of Psychiatry and Pediatrics.

In 1985, she joined the faculty at Ohio State University as Professor of Psychiatry and Pediatrics and later as Professor of Neuroscience. She was the Director of Child and Adolescent Psychiatry, lead the Pediatric Consultation/Liaison, established a clinical research unit for prepubertal children, and was Director of Training of Child and Adolescent Psychiatry residents. She was named Associate Chair in Psychiatry and was Chair of the Credentialing Committee at the Ohio State University Hospital.

On the national level, she has been active as President of the Society of Biological Psychiatry, and as a member of the Executive Council of the American Association of Directors of Residency Training. She has also served as a council member of the American Association of Clinical Psychiatrists, Program Director, American Academy of Child and Adolescent Psychiatry, council member, the American Board of Psychiatry and Neurology, Chair of Written Exam Committee, Treasurer of the Board, President of Child and Adolescent Psychiatry Board, Representative of the AACAP to the Commission of Recertification, and just recently, was elected as a director of the American Board of Psychiatry and Neurology. Dr. Weller had done mood disorder research with her spouse Dr. Ronald Weller since residency training. They have had National Institute of Mental Health funding to study the treatment of deressed children, as well as funding from the pharmaceutical industry to test University of Pennsylvania new pharmacological agents. Since 1983 they have been studying bereavement in children and adolescents and their surviving parents. They have received federal funding to study prepubertal children and adolescents and have received renewed funding to follow-up these subjects five years post-loss. Dr. Weller has studied and published extensively in mood disorders and bereavement in children and adolescents. She has lectured nationally and internationally and has been invited for major named lectureships across the country and internationally.

Dr. Weller has received numerous awards since her undergraduate studies. She has received awards as teacher, mentor and a researcher. She has been named as one of the best doctors in America. She has reviewed for and been on editorial boards of major psychiatric journals such as The Journal of the American Academy of Child and Adolescent Psychiatry, The Journal of American Psychiatric Association, Journal of Biological Psychiatry, Annals of Clinical Psychiatry, Journal of Child and Adolescent Psychopharmacology, The Journal of Depression, as well as Journal Watch for Psychiatry. She was recently named the Frederick Allen Chair of Psychiatry at the Children’s Hospital of Philadelphia, Vice Chairman in the Department of Psychiatry at the University of Pennsylvania and the Medical Director of the Child Guidance Center in Philadelphia.

Juvenile Mania and ADHD: Two of One Disorders?
Joseph Biederman, M.D.
Professor of Psychiatry
Harvard University

Abstract

A bi-directional association between ADHD and bipolar disorder has been identified in the literature. Whether children with both conditions suffer from ADHD, bipolar disorder, or both is a subject of great clinical and scientific concern. Several analytical efforts will be presented to evaluate this issue, including the clinical correlates of children with mania, the clinical correlates of children with ADHD and bipolar disorder, family genetic studies of children with ADHD and mania and children with mania and ADHD, and symptom overlap analysis. Taken together, these findings present a compelling argument for the syndromatic independence and etiological association of ADHD and mania

Biography

Dr. Biederman is Chief of the Joint Program in Pediatric Psychopharmacology at the Massachusetts General and McLean Hospitals in Boston, MA and Professor of Psychiatry at Harvard Medical School. Dr. Biederman’s clinical program treats more than 1,500 children, adolescents and adults, and evaluates more than 300 new patients every year. Dr. Biederman’s research focus is on ADHD, juvenile mood and anxiety disorders, and studies of children at risk. Dr. Biederman’s program has a wide range of pediatric psychopharmacologic activities, including pharmacokinetic studies and Phase I, II, and III clinical trials. Currently two clinical trials in juvenile mania are being conducted.

Dr. Biederman has been the recipient of the American Psychiatric Association Blanche Ittelson Award for Excellence in Child Psychiatric Research and the American Academy of Child and Adolescent Psychiatry Charlotte Norbert Rieger Award for Scientific Achievement. He has been inducted into the CHADD "Hall of Fame". Dr. Biederman has also been selected every year since its inception into The Best Doctors in America a compilation of the best physicians in the country. Dr. Biederman is mentor to more than 10 junior investigators in the field. He is on the editorial board of multiple journals, a reviewer for most of the psychiatric journals, and has served as a grant reviewer on the Child Psychopathology and Treatment Review Committee of the NIMH.

Controlled Study of Phenomenology and Course of Pediatric Bipolarity
Barbara Geller, M.D.
Professor of Psychiatry
Washington University School of Medicine

Abstract

Data on methodology and midpoint baseline assessment from the ongoing NIMH grant "Phenomenology and Course of Pediatric Bipolarity" will be presented. This study comprises 270 subjects aged 7-16 years old: 90 with BP (with or without ADHD); 90 with ADHD (without MDD or BP); and 90 community controls aggregately matched to the BP group. Consecutive case ascertainment from clinical sites in the St. Louis metropolitan area was used to obtain BP and ADHD subjects. Community controls were obtained by a random-digit dialing survey conducted by RTI. Assessments were multi-domain (psychopathology, psychosocial, educational, physical); multi informant (parent, child, school); and multi-modal (semi-structured interview, self-report). BP subjects were reassessed at six-month intervals to investigate naturalistic course. ADHD and community controls were reassessed at two-year intervals for comparison with the two-year time point of assessment of BP group. Hypotheses concluded that children and young adolescents would have a chronic, rapid cycling, mixed course, in contrast to the episodic course with discrete onsets and clear offsets commonly observed in older adolescents and adults. It was also hypothesized that mania criteria would be similar across age groups but would present with age specific manifestations in children and younger adolescents. Data presented will include demographic, diagnostic, comorbidity and course characteristics, and will include age-specific manifestations of elated mood, grandiosity, delusions, and hypersexuality.

Biography

Barbara Geller, M.D. is Professor of Psychiatry at Washington University School of Medicine in St. Louis, Missouri. She is an established NIMH-supported investigator in the areas of phenomenology, psychopharmacology, and naturalistic course of manic-depressive (bipolar) disorders in children and adolescents. Dr. Geller has served on and chaired numerous federal committees; received the Cummings Foundation Special Research Award from the American Academy of Child and Adolescent Psychiatry; served on multiple editorial boards; and authored over 65 publications.

 

The Naturalistic Prospective Course of Juvenile Bipolar Illness
Michael Strober, Ph.D.

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Abstract

It is estimated that upwards of 15% of individuals with bipolar illness experience their first full-blown episode of either mania or depression prior to age 20. Given the substantial morbidity and economic burdens associated with severe affective disease, and the possible long-term deleterious effects of delaying potentially effective treatments, research on juvenile forms of bipolar illness will be crucial to further informing our knowledge of genetic, neurobiological, clinical, and therapeutic aspects of the affliction. This presentation will summarize results from a number of recently completed studies on the longitudinal, prospective course of bipolar illness in adolescents hospitalized at UCLA Neuropsychiatric Institute, as well a the pharmacological response profiles in this age group during acute and maintenance therapy. Data presented will describe the time course of recovery from index episodes of illness, and of relapse into new episodes of illness, as well as clinical predictors of these course trajectories. In addition, data from several case controlled treatment trials will be presented and discussed.

Life Events and Bipolar Disorder
Constance Hammen, Ph.D.
Professor of Psychology and Psychiatry and Biobehavioral Sciences
University of California, Los Angeles

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Abstract

Psychosocial variables affect the course of bipolar disorder, and may contribute to the tremendous variability in outcomes among bipolar patients. Further understanding of the nature and mechanisms of psychosocial factors could potentially aid in the therapeutic management of the disorder. Moreover, further understanding might help shed light on important conceptual questions about the mechanisms of the illness. Our previous work has focussed largely on the role of stressful life events and chronic stressors. We have demonstrated that episodes may be precipitated by stress, and that the lives of typical bipolar patients are indeed marked by elevated levels of episodic and chronic stress, potentially contributing to recurring symptoms and disability.

The presentation will review data from a two-year longitudinal study of fifty-two bipolar I patients, addressing two questions: expansion of the question of stress as a precipitant of episodes, and whether there is a "sensitization" effect as often hypothesized in clinical lore, suggesting that patients in later stages of illness (with more prior episodes) have episodes less influenced by stressors than do those in the beginning or early stages of illness. Findings indicate that both presence of severe stressors and total elevations of stress were associated with greater likelihood of relapse/recurrence. Also, the "sensitization" hypothesis was not confirmed, and to the contrary, those with histories of more prior episodes were more likely to relapse following stressors that those with fewer episodes. Further, several personality characteristics are relatively associated with stress reactivity.

Biography

Dr. Hammen is head of the Clinical Psychology Graduate Program at the University of California, Los Angeles, and Research Director of the Affective Disorders Clinic. Her research program on unipolar and bipolar disorders includes studies of stress, family, interpersonal, and cognitive factors in mood disorders - in samples including adults, children, and youth. Current projects include longitudinal studies of young women at risk for depression in the transition from high school to adulthood, and a fifteen-year follow-up study of children of depressed women in a community sample. Dr. Hammen has written numerous research articles and several books, including Depression Runs in Families: The Psychosocial Context of Risk and Resilience in Children of Depressed Women (1991); Psychological Aspects of Depression (1992, with Ian Gotlib); and Depression, a textbook to be published in 1997. She is editorial consultant for various journals in psychiatry and psychology. She is presently on the editorial board of Development and Psychology. Dr. Hammen is past president of the Society for Research in Psychopathology (1995-6) and currently serves of and NIMH grant review panel.

Cognitive Therapy in Dipolar Disease
Russell T. Joffe, M.D.
Professor and Chairman
Department of Psychiatry
McMaster University

Abstract

Bipolar disorder is characterized by a chronic recurrent course of illness. Pharmacotherapy is generally only partially effective in the long-term treatment of this disorder. Therefore, alternative treatment strategies need to be carefully considered.

Psychotherapy, such as interpersonal and cognitive behavioural therapy, have been shown to be effective in the acute and prophylactic maintenance treatment of unipolar depressive illness. There is both empirical and theoretical justification for their application in bipolar disease. Preliminary evidence suggests that cognitive behavioural treatments may be efficacious in the treatment of bipolar disease. The literature examining this issue will be critically reviewed and evaluated. Preliminary data from a study of cognitive behavioural treatment over six months in a cohort of patients with bipolar affective disorder will be presented. To date, 30 subjects have completed the treatment protocol.

Biography

Dr. Joffe received his undergraduate medical education in Johannesburg, South Africa, and then specialized training in psychiatry at McMaster University. Following completion of his residency he did a two-year fellowship in biological psychiatry and psychopharmacology in the Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD, under the supervision of Dr. Robert M. Post. From 1985 until 1994, he was on staff in the Department of Psychiatry, University of Toronto, where he developed a clinical research program for the mood disorders, both depressive and manic-depressive illness.

Dr. Joffe’s main clinical and research interests have been in the area of the psychopharmacology of refractory mood disorders. His main research area has been on the role of thyroid hormones in the regulation of mood and the biology of mood disorders. His clinical work has focused on the use of thyroid hormones to treat refractory depression. This has led to the development of novel hypotheses about the role of thyroid hormones in the regulation of mood and the potential different effects of the two thyroid hormones, triiodothyrone (T3) and thyoxine (T4) in treating depression. He has been actively involved in preclinical and basic studies, in collaboration with various investigators, understanding how the mature brain regulates thyroid hormone and how the two thyroid hormones (T3 and T4) affect brain thyroid hormone levels.

Together with Dr. A.J. Levitt, Dr. Joffe has recently developed an innovative service: DIRECT (Depression Information and Resource Education Centre - Toll Free), a toll-free telephone line with 200 recorded messages about clinical depression and manic depressive illness, which will give detailed expert information on treatment to both doctors and patients.

Dr. Joffe has given almost 200 invited lectures; has published over 170 peer-reviewed scientific articles; approximately 125 published abstracts, and 25 book chapters. In addition, he has edited four scientific books with Dr. A.J. Levitt, entitled The Thyroid Axis and Psychiatric Illness, published by American Psychiatric Press, Washington, DC 1993; with Dr. Joseph R. Calabrese, entitled Anticonvulsants in the Mood Disorders, published by Marcel Dekker, New York, 1994; with Dr. L. Trevor Young, entitled Bipolar Disorder: Neurobiology and Clinical Applications, to be published by Marcel Dekker; and a second book with Dr. A.J. Levitt, entitled Conquering Depression, to be published by Empowering Press.

Dr. Joffe is a reviewer for some 20 scientific journals, sits on the editorial advisory board for the Journal of Psychiatry and Neuroscience as well as on the editorial board of the Canadian Review of Affective Disorders, and has also sat on numerous scientific advisory boards, including the Medical Research Council of Canada, Behavioural Sciences Committee, and the grants committee of the Ontario Mental Health Foundation.

Interpersonal and Social Rhythm Therapy for the Treatment of Bipolar Disorder
Ellen Frank, Ph.D.
Professor of Psychiatry and Psychology
University of Pittsburgh School of Medicine

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Abstract

For decades after the advent of lithium carbonate for the treatment of manic-depressive illness, the idea that psychotherapy might have a role in the treatment of this disorder was in serious disfavor. More recently, clinicians and researchers alike have come to recognize that even with appropriate pharmacotherapy, the risk of recurrence following remission of an acute episode approaches 50% over a two- to three-year period. This has led several groups of investigators to develop "adjunctive" family, marital and individual psycho-therapeutic interventions for bipolar patients. Our research group has focused on an individual intervention, Interpersonal and Social Rhythm Therapy (IPSRT) that includes both interpersonal and behavioral components. The behavioral components focus on stabilizing social routines in an effort to enhance the circadian integrity presumed to be critical to maintenance of the well state. We are testing this intervention as both an acute and maintenance treatment in a randomized controlled trial. This presentation will focus on a description of the intervention, as well as information on the impact of IPSRT on time to remission following initiation of acute treatment, and on the impact of time to recurrence following the achievement of stable remission.

Biography

Dr. Ellen Frank is Professor of Psychiatry and Psychology at the University of Pittsburgh School of Medicine. She graduated from Vassar College in 1966 and received a master’s degree in English from Carnegie Mellon University in 1967. Her doctoral work in psychology was done at the University of Pittsburgh and completed in 1979.

Under a grant from the National Institute of Mental Health, Dr. Frank is currently studying the efficacy of Interpersonal and Social Rhythm Therapy, a treatment she developed for manic-depressive illness, which focuses on helping patients to increase the regularity of their daily routines and improve their day-to-day relations with others.

She is also conducting a major NIMH-sponsored study of women with recurrent depression in which she hopes to sort out how biology, life stress, and different "doses" of psychotherapy, interact in increasing or decreasing vulnerability to new episodes of depression.

An expert in mood disorders and their treatment, Dr. Frank was a member of the American Psychiatric Association’s Task Force on DSM-IV and was Chair of the Food and Drug Administration’s Psychopharmacologic Drugs Advisory Panel. Dr. Frank is currently a member of the MacArthur Foundation Research Network on Psychopathology and Development and is Chair of the American College of Neuropsychopharmacology’s (ACNP) Task Force on Continuing Education.

Dr. Frank is an Honorary Fellow of the American Psychiatric Association.

Psychoeducational Family Management
David J. Miklowitz, Ph.D.
Associate Professor of Psychology
University of Colorado at Boulder

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Abstract

There is renewed interest in psychosocial treatments for bipolar disorder, delivered on an outpatient basis in combination with medications. We developed one such program - family-focused psychoeducation treatment (FFT) - for recently ill bipolar patients with parental or spousal relatives. A study is described examining whether FFT is effective (in combination with medications) in ameliorating the course of bipolar disorder over one- and two-year periods of follow-up. Bipolar patients, all of whom had been ill with mania or mixed episodes over the 3 months prior to study entry, were randomly assigned to FFT with medications or a comparison condition, crisis management with medications. FFT consisted of three phases delivered over 9 months: psychoeducation, communication enhancement training, and problem-solving skills training. When compared to crisis management, FFT was more successful in reducing levels of bipolar symptoms over one year. Examining mechanisms of change, we determined that FFT led to greater increases in the frequency of positive communication behaviors among patients and family members than was seen in the comparison crisis management condition. Thus, family psychoeducational treatment provides one means of addressing the psychosocial factors associated with bipolar disorder during the post-episode phases of the illness.

Biography

Dr. Miklowitz received his doctorate from the University of California, Los Angeles, in 1985, and has been on the clinical psychology faculty at University of Colorado, Boulder, since 1989. He has been conducting research on psychosocial factors relevant to bipolar disorder since the early 1980's. He has demonstrated in two separate studies that family stress factors are important predictors of the course of bipolar disorder. With his colleague Michael Goldstein, he developed a new psychosocial treatment - family-focused psychoeducational treatment - used in combination with medication for recently episodic bipolar patients. He is currently testing the efficacy of this treatment in an experimental trial. Dr. Miklowitz has published 60 papers and book chapters, come of which have appeared in the Archives of General Psychiatry, the British Journal of Psychiatry, the Journal of Abnormal Psychology, and the Journal of Nervous and Mental Disease. He has an in-press book with Michael Goldstein, Bipolar Disorder: A Family-Focused Treatment Approach, by Guilford Press. He has received Young Investigator research awards from the International Congress on Schizophrenia Research and the National Alliance for Research on Schizophrenia and Depression.

Paula J. Clayton, M.D.
Professor and Head
Department of Psychiatry
University of Minnesota Medical School

Biography

Dr. Paula Clayton attended the University of Michigan where she received a Bachelor of Science degree in 1956. She graduated AOA from Washington University School of Medicine In St. Louis, Missouri in 1960. After an internship, she took her psychiatry residency at Washington University. She became an instructor and chief resident in 1965/66. Thereafter, she joined the faculty and progressed from an assistant professor to associate to full professor in 1976. In July of 1981, she moved to Minnesota to become Professor and Head of the Department of Psychiatry, University of Minnesota Medical School. In 1969, she published, with Drs. Winokur and Reich, the first textbook on mania, entitled Manic Depressive Illness. She has published three additional books, 150 papers in reference journals, and 20 book chapters. Her area of expertise and research is mood disorders, particularly bipolar and unipolar disorders, and bereavement.

Dr. Clayton is Professor and Head of the Department of Psychiatry at the University of Minnesota Medical School in Minneapolis, Minnesota. She is a Fellow in the American Psychiatric Association, a member of the American Psychopathological Association, American College of Neuropsychopharma-cology, and Society of Biological Psychiatry. She was on the DSM-III Task Force for Nomenclature and Statistics and was on the Membership Committee for the APA. She has been president of the American Psychopathological Association, Psychiatric Research Society, and Society of Biological Psychiatry. She is on five editorial boards, has been a panel member for AAMC, for the Institute of Medicine, and for the VA Medical Centers. She was a member of the National Board of Medical Examiners Psychiatry Test Committee and a member of the FDA. In 1985, she received the Athena Award from the University of Michigan for being the outstanding woman alumna of the year. She also received a distinguished alumnae award in 1985 from Washington University, and in 1993, the First Aphrodite Jannopaulo Hofsommer Award from Washington University. At the University of Minnesota, she has been on numerous search committees, served as Chief of Chiefs for the medical school, and been a member of the University Senate. She has held numerous NIMH grants, both as a coinvestigator and principal investigator, and has servedstudy sections for NIMH and NIAAA.

Treatment of Depressed Phase of Bipolar Disorder
Jonathan M. Himmelhoch, M.D.
Professor of Psychiatry
University of Pittsburgh School of Medicine

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Biography

Jonathan M. Himmelhoch, M.D. is Professor of Psychiatry, University of Pittsburgh School of Medicine and Director of the Research Affective Disorders Clinic. He founded the Affective Disorder Clinic and the Lithium Clinic at Yale Unviersity in 1968. Since that time, he has developed an international reputation as an expert in bipolar disorders. He introduced the first modern controlled research in mixed mania in 1976. He has since investigated the treatment of those states with antikindling anticonvulsants and has examined their relationship to epilepsy. Along with Michael E. Thase, M.D., and Alan G. Mallinger, M.D., he has demonstrated the superiority of the monoamine oxidase inhibitor tranylcypromine for bipolar depression.

Marital Approaches: Psychoeducational Marital Intervention
Daniel Carpenter, Ph.D.
Clinical Instructor of Psychology in Psychiatry
Department of Psychiatry
Cornell University Medical College

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Biography

Daniel Carpenter, Ph.D. is the Director of Clinical Data Service for Merit Behavioral Care Corporation and Clinical Instructor of Psychology in Psychiatry at the Cornell University Medical College, Department of Psychiatry. He is currently involved in several business and academic projects focused on utilization of information technology to study and close the gap between the efficacy and effectiveness of psychiatric care. He is a member of the Expert Consensus Consortium, the group of investigators which has published a series of Practice Guidelines in Psychiatry, including guidelines for bipolar disorder, schizophrenia, and obsessive-compulsive disorder. For the past several years, he has also been involved in several studies involving patients with bipolar disorder and their families. He served as Project Manager for the NIMH-funded study, "Marital Treatment for Bipolar Disorder Patients" (John F. Clarkin, Ph.D., Principal Investigator). In addition to his clinical and research training, he is a computer programmer with expertise in database management.

Marital Approaches
Gabor I. Keitner, M.D.
Professor of Psychiatry
Brown University School of Medicine

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Biography

Dr. Keitner is Associate Psychiatrist-in-Chief and Director of Adult Psychiatry and The Mood Disorders Program at Rhode Island Hospital. He has been conducting research into the role of the family on the course and outcome of depression and bipolar disorder. With other members of The Mood Disorders Program (I. Miller, C. Ryan, N. Epstein, D. Bishop), he has developed models of family assessment (The McMaster Model of Family Functioning) and family therapy (The Problem Centered Systems Therapy of the Family). A major focus on investigation in the Mood Disorders Program is the usefulness of combining psychopharmacology, psychotherapy and family therapy in the treatment of mood disorders. He is also conducting clinical trials to evaluate new antidepressants. In addition to his research, Dr. Keitner directs the inpatient program at Rhode Island Hospital specializing in the treatment of the acute phase of severe mood disorders.

Robert M.A. Hirschfeld, M.D.
Titus H. Harris Distinguished Professor and Chairman
Department of Psychiatry and Behavioral Sciences
University of Texas Medical Branch

Biography

Dr. Hirschfeld is the Titus H. Harris Distinguished Professor and Chair of the Department of Psychiatry and Behavioral Sciences at The University of Texas Medical Branch (UTMB) at Galveston. Dr. Hirschfeld is internationally known for his research on the diagnosis and treatment of depression and anxiety. He is listed in the book, The Best Doctors in America, a directory of the top one percent of physicians in the United States as rated by their peers. He was also listed as one of the nation’s 327 Best Mental Health Experts in Good Housekeeping. He served as Chair of the Scientific Advisory Board of the National Depressive and Manic Depressive Association, is on the Board of Directors of the American Suicide Foundation and the Anxiety Disorders Association of America, and is Vice President of the American Suicide Foundation.

The author of numerous scientific papers which have been published in leading psychiatric and medical journals, Dr. Hirschfeld is the author of the book, When the Blues Won’t Go Away: New Approaches to Dysthymic Disorder and Other Forms of Chronic Depression, which was published in June 1991. Dr. Hirschfeld has also written chapters on mood disorders in four major psychiatric textbooks and has contributed chapters in nearly two dozen other books on psychiatry. He most recently served as Workgroup Chair in the development of the American Psychiatric Association’s Practice Guidelines for Treatment of Patients with Bipolar Disorder.

Prior to joining UTMB in July 1990, Dr. Hirschfeld spent 18 years at the National Institute of Mental Health, where he was Chief of the Mood, Anxiety, and Personality Disorders Research Branch, and was the Clinical Director of NIMH’s Depression/Awareness, Recognition, and Treatment (D/ART) Program. Dr. Hirschfeld has received the Administrator’s Award of Meritorious Achievement and the Outstanding Service Medal from the Alcohol, Drug Abuse and Mental Health Administration, the World Psychiatric Association Gerald L. Klerman Award for Panic Disorder, and most recently, the Jan Fawcett Humanitarian Award from the National Depressive and Manic-Depressive Association. He received his Bachelor of Science degree from Massachusetts Institute of Technology in 1964 and earned his M.D. from the University of Michigan in 1968. Dr. Hirschfeld received his M.S. from Stanford University Medical Center in the same year. He was board certified in 1975 by the American Board of Psychiatry and Neurology.

Marguerite Donoghue, R.N., M.S.N.
Vice President, Research and Regulatory Affairs
Capitol Associates, Inc.

Biography

Prior to entering a public policy career, Marguerite Donoghue worked as an oncology clinical nurse specialist in Pittsburgh, Pennsylvania, and was integrally involved in establishing the South Hills Family Hospice. At the National Institutes of Health, Ms. Donoghue assisted in developing clinical research programs in cancer and AIDS, and served as the Assistant to the NIH AIDS Research Director responsible for liaison and coordination of AIDS research activities with the Public Health Service agencies and Congress.

Ms. Donoghue joined Capitol Associates, Inc., a government relations firm, over 10 years ago. Marguerite works with national research groups, major coalitions, nonprofit organizations, universities, biotechnology and pharmaceutical companies and professional societies to develop, guide, evaluate and implement in the Congress and the Administration, advocacy strategies to meet their legislative, regulatory, and policy objectives. She is also responsible for policy issues related to the NIH and regulatory issues for the Food and Drug Administration. Ms. Donoghue serves as a board member of the Ad Hoc Group for medical research, CoDirector of the FDA Council, and Executive Director of the National Coalition for Cancer Research. She serves on the advisory board of the Office of Cancer Communication, National Cancer Institute.

Overview of Studies: The State of the Search for Bipolar Genes
J. Raymond DePaulo, Jr., M.D.
Professor of Psychiatry
Johns Hopkins University School of Medicine

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Abstract

Efforts to understand the genetics of bipolar disorder have been hindered by the complexity of the phenotype and by apparently nonmendelian modes of transmission. Difficulties in replication of the early reports of linkage to chromosomal loci have spurred the development of novel methods for analyzing complex phenotypes. Phenotypic variations within and between families have provided clues for locating genes and, if successful, may speed the study of how such genes work. Recent studies confirming original reports of linkage of manic depressive illness to loci on chromosome 18 and to chromosome 21 also are encouraging. However, the tasks of narrowing the critical regions to facilitate sequencing and positional cloning, and testing candidate mutations once they are identified, may prove to be as difficult as finding and replicating linkage in bipolar families. The recent success and the next hurdles for the field will be discussed.

Ms. Donoghue is the author of several nursing textbooks and has written over 40 articles and chapters for peer-reviewed journals, and textbooks on professional and clinical nursing subjects, as well as policy issues, such as medical research and how Congress works.

Biography

Dr. J. Raymond DePaulo, Jr., is Professor of Psychiatry and Director of the Affective Disorders Clinic, Johns Hopkins University School of Medicine. Dr. DePaulo is active in patient care, research and education. His major clinical and research efforts have focused on the genetic causes of and medical treatments for depression and manic-depressive illness. He is currently the principal investigator on several NIH and other grants, all of which seek to find genes which underlie bipolar affective disorder. Dr. DePaulo has won several awards for research and teaching. The most recent award received was the 1996 SELO Prize for outstanding achievement in depression research given by the National Association for Research on Schizophrenia and Depression (NARSAD). Dr. DePaulo has also actively promoted the development of the Depression and Related Affective Disorders Association (DRADA), a group that has united the efforts of patients, family members, mental health professionals and others to organize programs of education, mutual support groups and research dissemination related to depressive disorders. With Keith Ablow, Dr. DePaulo has written a book on affective disorders for the general public on How to Cope with Depression (published by Fawcett Books).

Latest Findings on Human Chromosome 18 in Bipolar Illness
Wade Berrettini, M.D. Ph.D.
Professor of Psychiatry and Pharmacology
Thomas Jefferson University

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Abstract

A linkage study of 22 bipolar (BP) families has been performed (Berrettini et al, Arch Gen Psych 54: in press, 1997; PNAS, 91:5918, 1994). These BP families include nearly 400 persons, 173 whom have PBI, schizoaffective (SA), BPII with major depression or recurrent unipolar (UP) diagnoses. Affected-sibling-pair (ASP) and affected-pedigree-member (APM) analyses were done on peri-centromeric chromosome 18 microsatellite markers (D18S53, S37, S40, S45), yielding statistically significant evidence (p<.0001) for a BP susceptibility gene in this region. This BP linkage has been confirmed independently by Stine et al (Am J Hum Genet 57:1485, 1995), who observed that the linked kindreds were those in which paternal transmission of illness was present. We confirmed (Gershon et al, Neuropsych Genet 67:202, 1996) that evidence for linkage to this region was derived entirely from only those kindreds in which fathers transmitted illness to their offspring. This chromosome 18 susceptibility locus has also been observed by Gilliam et al, who described a lod score of 2.68 at D18S53 in a recessive analysis of 5 paternal BP kindreds (61st Symposium on Quantitative Biology, Cold Spring Harbor Laboratory Press, in press). Nothen et al (Biol Psych 39:615, 1996) reported a lod score of 2.48 for D18S453 among 61 German BP kindreds using a recessive disease model analysis. Analysis by the sex of the transmitting parent revealed that the positive statistics derived mostly from paternal kindreds. Wiedenauer et al (Psych Genet 6:152, 1996) reported a lod score of 3.2 at D18S53 in an ASP analysis for ? 60 multiplex schizophrenia kindreds, in which only two BP cases were described. Thus, there are multiple confirmations of our report of BP linkage to 18p microsatellite markers.

Intronic variants of the Golf gene, an 18p11 alpha subunit of G-protein (a candidate gene for this linkage) have been discovered. A single base pair change (G to A) has been observed in intron 3, and these will be discussed as possible disease-associated variants.

Biography

Wade Berrettini was born in Wilkes Barre, PA, in 1951 and graduated with honors in chemistry from Dickinson College in 1973. Dr. Berrettini graduated from Jefferson Medical College in 1977, and earned his doctoral degree in Pharmacology two years later from the Thomas Jefferson University School of Graduate Studies. For nearly a decade, he studied genetics of behavioral disorders at the National Institute of Mental Health (NIMH) in Bethesda, MD, as a member of the Clinical Neurogenetics Branch. Since 1991, Dr. Berrettini has been a professor in the departments of psychiatry and human behavior and pharmacology at Thomas Jefferson University. In 1992, Dr. Berrettini received the Established Investigator Award from the National Alliance for Research on Schizophrenia and Depression (NARSAD) for a linkage study of bipolar disease. He has continued to explore this area of research, along with other projects, which include a genetic study of anorexia nervosa and animal model studies of both alcoholism and seizures. These projects reflect Dr. Berrettini’s interest in the molecular genetics of human psychopathology and in animal models of behavioral disorders. In April, 1996, Dr. Berrettini received a Pfizer Visiting Professorship Award from the University of Washington Department of Psychiatry. Later that year, Dr. Berettini received the Selo Prize for his outstanding achievement in affective disorders research. Dr. Berrettini has authored over 100 scientific publications and currently is on the editorial boards of Neuropsychopharmacology, Psychiatric Genetics, Addiction Biology, Molecular Psychiatry and the American Journal of Drug Abuse and Alcohol Abuse.

Genetics of Affective Disorder: A Genome Scan
Melvin G. McInnis, M.D., MRCPsych
Assistant Professor of Psychiatry
Johns Hopkins University School of Medicine

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Multiplex bipolar families were ascertained through a treated bipolar I proband with 2 affected first-degree relatives. Diagnoses were made according to RDC, with a trained psychiatrist using the SADS-L instrument. An initial genome screen was completed on 28 families, with several regions of genetic interest identified. A subsequent screen of the second set of 23 families has been completed. Model-based parametric analyses and model-free nonparametric analyses were used. Follow-up on the regions identified in the initial screen of the 28 families suggests regions on chromosomes 4, 5, 7, and 18 are likely to contain susceptibility genes for bipolar disorder.

Biography

Dr. McInnis is a Canadian citizen, an Icelandic medical doctor, an English psychiatrist and an American geneticist. He qualified in medicine at the Unversity of Iceland in 1983, completing his internship there as well. His interest in genetics begain in 1984, when he began collecting Icelandic bipolar families in collaboration with Hugh Gurling, then at the Institute of Psychiatry, London.

He completed his residency training at the Maudsley Hospital in London in 1989, after which he came to the Johns Hopkins University and began a fellowship in medical genetics under the preceptorship of Victor A. McKusick and Stylianos Antonarakis. In 1993, he became Director of the George Browne Psychiatric Genetics Laboratory, which focuses on the genetics of bipolar disorder.

Alternatives to Linkage Methods in Bipolar Disorder
Peter McGuffin, M.D., PH.D., FRCP, FRCPsych
Professor and Chairman of the Division of Psychological Medicine
University of Wales College of Medicine
Wales

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Abstract

Linkage studies of complex diseases such as Bipolar Disorder require the assumption that at least some cases are explained by the segregation of genes of large effect. It is also assumed that the mode of transmission can be inferred, at least approximately, and that, within multiply-affected families, there is etiologic homogeneity. Such assumptions have been shown to work in at least some disorders, such as early onset Alzheimer's disease and breast cancer. Unfortunately they have so far appeared to let us down in trying to locate and identify the genes for Bipolar Disorder. This is probably because major gene forms are rare or nonexistent and nearly all cases are oligogenic (resulting from the combined action of several genes each of small effect). Oligogenes can, however, be detected, using 'model free' methods such as affected sib pair studies or allelic association studies, which have an advantage of being able to find genes of very small effect. Such approaches have already proved successful in other common diseases and are also being applied in Bipolar Disorder, where their uses and prospects for success will be reviewed with a particular emphasis on allelic association.

Biography

Peter McGuffin graduated from medical school at the University of Leeds, England, where he also received his postgraduate training in internal medicine. He completed his training as a psychiatrist at the Maudsley Hospital, London and was awarded a Medical Research Council Fellowship to study genetics at London University and at Washington University, St Louis, Missouri. He subsequently became an MRC Senior Clinical Fellow at the Maudsley and the Institute of Psychiatry until taking up his present post in 1987. He has published a number of books and many papers, mainly on the genetics of normal and abnormal behavior.

Kay Redfield Jamison, Ph.D.
Professor of Psychiatry
Johns Hopkins University

Biography

Kay Redfield Jamison is Professor of Psychiatry at the Johns Hopkins University School of Medicine. She is the author of Touched with Fire: Manic-Depressive Illness and the Artistic Temperament, and coauthor of the standard medical text on manic-depressive illness. The latter was chosen in 1990 as the Most Outstanding Book in Biomedical Sciences by the American Association of Publishers. She is the author or coauthor of four books and approximately 100 scientific publications about mood disorders, suicide, psychotherapy, and lithium. Dr. Jamison, formerly the director of the UCLA Affective Disorders Clinic, was selected as UCLA Woman of Science and is listed in Best Doctors in America. She is a recipient of the American Suicide Foundation Research Award, the UCLA Distinguished Alumnus award, the Fawcett Humanitarian Award from the National Depressive and Manic-Depressive Association, the Steven V. Logan Award for Research into Brain Disorders from the National Alliance for the Mentally Ill, and the William Styron Award from the National Mental Health Association.

She was a member of the first National Advisory Council for Human Genome Research, and is now the clinical director for the Dana Consortium on the Genetic Basis of Manic-Depressive Illness. She is on the National Committee for Basic Sciences at UCLA. She is also the executive producer and writer for a series of award-winning public television specials about manic-depressive illness and the arts. Her most recent book, An Unquiet Mind, received the 1995-96 Critics’ Choice Award, and was selected by The Boston Globe, Entertainment Weekly, and the Seattle Post Intelligencer, as one of the best books of 1995. An Unquiet Mind was on The New York Times Bestseller List for more than five months.

Dr. Jamison is Honorary Professor of English Studies at the University of St. Andrews, Scotland, and a member of the Pulitzer Prize Jury.

William Z. Potter, M.D., Ph.D.
Executive Director and Lilly Clinical Research Fellow of
Nervous Systems Disorders, Clinical Research
Lilly Research Laboratories

Biography

William Z. Potter, M.D., Ph.D. has been Executive Director and Lilly Clinical Research Fellow of Nervous System Disorders, Clinical Research at Lilly Research Laboratories, since January, 1996. He developed a Lilly/IU fellowship early in 1996 and was named Professor of Psychiatry in IUMC. Before being associated with Lilly Research Laboratories, he held the position of Chief, Section on Clinical Pharmacology, Intramural Research Program at the National Institute of Mental Health in Bethesda, Maryland. He has been with the Public Health Service and the National Institutes of Health since 1971. Born in Charleston, South Carolina, he attended Western Reserve Academy in Hudson, Ohio, and Eastbourne College, in Eastbourne, Sussex, England. He received his B.A. (Philosophy) from Indiana University in 1968, and received his M.D. and Ph.D. at Indiana University in 1970 and 1972, respectively. He was board certified in psychiatry in 1978 and in clinical pharmacology in 1979.

Dr. Potter belongs to many societies in which he has served in numerous capacities as an officer, board member or scientific program committee member, including the American Society for Clinical Pharmacology and Therapeutics, American College of Neuropsychopharmacology, Society of Biological Psychiatry, American Psychiatric Association, American Society of Clinical Psychopharmacology, Inc. and Collegium Internationale Neuropsychopharma-colgium.

He also serves on various editorial boards, including that of the Archives of General Psychiatry, Clinical Pharmacology and Therapeutics, Depression, Journal of Psychopharmacology, Psychopharmacology Bulletin, as well as serving as U.S. Consulting Editor to Therapeutic Drugs and reviewer for the major pharmacological and clinical research journals.

He has authored more than 200 publications in the field of preclinical and clinical pharmacology, mostly focused on drugs used in affective illnesses. He is considered to be a "World Opinion Leader" in manic-depressive illness. He has received many honors during his career, such as 1975-1977 Falk Fellow, American Psychiatric Association, 1986 Meritorious Service Medal, United States Public Health Service and in 1990, St. Elizabeth’s Residency Program Alumnus of the Year Award.

Potential Role of Novel GABA Modulators
John F. Tallman, Ph.D.

Abstract

GABA is the major amino acid inhibitory transmitter in the brain. It mediates this inhibitory activity through the use of two families of receptors called the GABAa, and GABAb receptors. GABAa receptors are part of the ligand-gated channel super family, while GABAb receptors are linked to G-proteins. GABAa receptorsmediate fast neurotransmission, while GABAb receptors are more modulatory in nature.

GABAa receptors are composed of five subunits arranged combinatorally in the membrane. These subunits are composed of separate gene products grouped into four or five separate clusters based upon their amino acid sequence. Thus, alpha , beta , delta, gamma , and epsilon clusters exist and one prototypical GABAa receptor may have the composition alpha 1,beta 2, gamma 2 where more than one of each alpha and beta is found. Details of the structures of other subtypes and their formations will be discussed.

The GABAa receptors are important from a pharmacological perspective because about 20 years ago they were discovered to be the site of action of an important class of drugs, the benzodiazapines. These drugs have been used in millions of patients to treat anxiety, sleep disorders, seizures and alcohol withdrawal. The original generation of drugs were discovered through their in vitro properties and it is now known that they strongly interact with most of the GABAa receptor subtypes in a relatively nonspecific fashion. Along with their therapeutic potential, they may cause dependence and withdrawal on discontinuation.

Newer marketed drugs interact with the GABAa receptors and to some extent distinguish subtypes of these receptors, but have rather full activities at these subtypes. Examples of each will be presented. The current trend in the industry is to reduce the side effect profile by increasing subtype specificity and limiting the pharmacological activity (called partial agonists) of these drugs. Experimental drugs of this profile are in development and represent the next generation of anxiolytics, devoid of sedations and abuse liability.

Biography

John F. Tallman, Ph.D., has been Executive Vice President, Scientific Director, Chairman of the Scientific Advisory Board and a Director of Neurogen since July 1988. Dr. Tallman has served as Secretary of the company since August 1994. Prior to joining Neurogen, Dr. Tallman was Associate Professor of Psychiatry and Pharmacology at Yale University and currently serves as an Adjunct Professor in such departments. Dr. Tallman had previously served in research director positions at the National Institute of Mental Health in Bethesda, Maryland. He has conducted research in the area of molecular pharmacology with an emphasis on psychopharmacology for over 20 years. Dr. Tallman received his Ph.D. in Biochemistry from Georgetown University.

Leads From Studies of Mood Stabilizers
Husseini K. Manji, M.D., FRCPC
Associate Professor of Psychiatry and Pharmacology
Director, Molecular Pathophysiology Program
Wayne State University School of Medicine

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Abstract

Bipolar affective disorder (BD, manic-depressive illness) is a common (lifetime prevalence of 1.2%), severe, chronic, and life-threatening illness. Despite much research, however, there is a dearth of knowledge concerning the etiology of this disorder. The discovery of lithium’s efficacy as a mood-stabilizing agent revolutionized the treatment of patients, with BD; however, despite its role as one of psychiatry’s most important treatments the biochemical basis for lithium’s antimanic and mood-stabilizing actions remains to be fully elucidated. Furthermore, increasing evidence suggests that a significant number of patients respond poorly to lithium therapy, while many others are helped, but continue to suffer significant morbidity. The recognition of the significant morbidity and mortality of the severe mood disorders, as well as the growing appreciation that a significant percentage of patients respond poorly to existing treatments, has made the task of discovering new therapeutic agents that enhance compliance, work quickly, potently, specifically, and with few side effects, increasingly more important. Considerable recent evidence has shown the anticonvulsants, carbamazepine and, in particular valproic acid (VPA), to be efficacious in the treatment of BD. In addition, these structurally very dissimilar compounds offer the potential not only for the elucidation of the targets both common to and unique among the different agents, but may also help to identify the biochemical substrates predisposing individuals to BD.

In recent years, it has become increasingly clear that rather than any single neurotransmitter system being responsible for depression or mania, multiple interacting and overlapping systems are involved in regulating mood, and that most effective drugs may exert their therapeutic efficacy by affecting the functional balance between interacting systems. In this context, signal transduction pathways are in a pivotal position in the CNS, and represent attractive targets to explain the efficacy of these mood-stabilizing agents in treating multiple aspects of the illness. We have therefore conducted an integrated series of clinical and preclinical studies in order to determine if signal transduction pathways represent therapeutically-relevant targets for mood- stabilizing agents. We have found that in both platelets from healthy volunteers, and rat prefrontal cortex, chronic in vivo administration of lithium produces a significant increase in the pertussis-catalyzed [32P] ADP-ribosylation. Preliminary studies from our laboratory suggest that chronic lithium administration impairs the ability of GTP? S to dissociate Gi, suggesting a post-translational process stabilizing the inactive heterotrimeric (? ? ? ) form of the protein; the possibility that lithium’s effects on Gi are mediated via intracellular "cross-talk" is supported by our studies, demonstrating that the concomitant intracerebroventricular administration of myoinositol blocks not only lithium-induced PKC alterations, but also the increase in pertussis toxin catalyzed [32P]ADP-ribosylation. We have obtained strikingly similar effects of lithium and valproate (VPA) on the PKC signaling pathway, with both drugs producing isozyme selective reductions in the levels of PKC a and e. Consistent with their effects on PKC isozymes, we find that both lithium and VPA exert major effects on a major PKC substrate (MARCKS), and on the activity of AP-1 (a transcriptional factor know to be regulated by PKC).

We have also investigated carbamazepine’s effects on signal transduction pathways, and have found that incubation of C6 glioma cells with CBZ produces a concentration-dependent attenuation of both basal and forskolin stimulated cyclic AMP accumulation, without having any effect on phosphodiesterase activity. To ascertain that these effects of CBZ also occurred in the intact animal in vivo, we have utilized in vivo microdialysis measurements of cAMP from rat prefrontal cortex. Similar to what we observed in vitro, CBZ concentration-dependently reduced FSK stimulated cAMP levels in the dialysate. We have therefore used a FSK affinity column to purify ACs from rat brain, and find that CBZ also exerts a significant inhibitory effect on the purified ACs. Overall, the results suggest that signal transduction pathways are targets for the actions of mood stabilizing agents; given their key roles in the amplification and integration of signals in the central nervous system, these findings have clear implications not only for research into the etiology/pathophysiology of manic-depressive illness, but also for the development of innovative treatment strategies.

Biography

Dr. Manji is Director of the Schizophrenia and Mood Disorders Clinical Research Division and Neuropsychiatric Research Unit, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine. He has been conducting research into the molecular and cellular basis of bipolar affective disorder, as well as the mechanisms of action of mood-stabilizing agents. He is the director of a new neuropsychiatric research unit which conducts an integrated series of clinical and preclinical studies to elucidate the biochemical basis of bipolar affective disorder, and to develop innovative treatments. Many of the novel treatment strategies focus on signal transduction pathways, targeting proteins inside nerve cells, which may lead to the development of more potent and more rapidly acting treatments for bipolar affective disorder. Dr. Manji’s preclinical research focuses on identifying genes which are regulated by mood-stabilizing agents. The identification of these genes offers the potential for improved therapeutics and may provide important clues about the factors underlying the predisposition to bipolar affective disorder. Dr. Manji is a previous recipient of the A.E.Bennett Award for Neuropsychiatric Research. He has published articles on bipolar affective disorder, and mechanisms of action of mood-stabilizing agents in several peer-reviewed journals. He is a member of numerous scientific and professional societies, sits on the editorial board of Neuropsychopharmacology, and is a reviewer for many neuroscientific and psychiatric journals including the Journal of Neurochemistry, Brain Research, Archives of General Psychiatry, American Journal of Psychiatry, and Biological Psychiatry. Dr. Manji serves as an ad hoc Grant reviewer for the NIMH, and is a member of the National Board of Medical Examiners Behavioral Science Test Committee, and a member of the USMLE Step 1 Test Material Development Committee for Behavioral Science.

Novel Neuroleptics
Mauricio Tohen, M.D., Dr.P.H.
Medical Advisor
Lilly Research Loboratories
Eli Lilly and Company

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Abstract

Antipsychotic agents have been used commonly in the treatment of bipolar disorder. This presentation will review the evolution of the use of antipsychotic agents and their role in the acute and maintenance treatment of bipolar disorder. The focus will be on neuroleptic drugs, the atypical antipsychotic drugs (risperidone and clozapine), and two of the new atypical antipsychotic drugs.

Biography

Dr. Tohen graduated as a Doctor of Medicine in 1976 from the National University of Mexico and as a Doctor of Public Health from Harvard Medical School in 1988. His postdoctoral training includes a residency in psychiatry at the University of Toronto (1979-1985). From 1988 to 1997, he was Clinical Director of the Bipolar and Psychotic Disorder Program at McLean Hospital. Dr. Tohen has published extensively in the area of bipolar disorder and major psychotic disorders. At present, Dr. Tohen is Associate Clinical Professor of Psychiatry at Harvard Medical School and also a Global Medical Advisor at Lilly Research Laboratories.

Beyond Carbamazepine and Valproic Acid: Exploring the Potential of Lamontrigine and Other Anticonvulsants
Charles L. Bowden, M.D.

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Abstract

Over the past decade, consistent reports of more circumscribed benefits of lithium have stimulated interest in other treatment options for bipolar disorder. The demonstrated effectiveness of divalproex, and its remarkable acceptance by psychiatrists, has further stimulated interest in new treatments which might yield better outcomes in the complex spectrum of bipolar disorder. Most of this interest has centered on medications first studied in epilepsy, although there is no reason that other medications which act on neuronal intracellular signaling systems might not also be effective in this disease. Whereas valproate and carbamazepine were recognized as useful in bipolar disorder in serendipitous observations by physicians, and were supported by consistently-positive published open trials, current efforts entail commencing study with randomized, placebo-controlled, double-blind trials in the absence of any substantial accrued clinical experience. The multiple end points possible in bipolar disorder contribute to a unique set of methodological difficulties in these studies. Studies are in progress, or planned, for lamotrigine, gabapetin and topaprax. Only for lamotrigine are there systematically-developed early results. This presentation will compare and contrast the neurochemical profiles of these putative agents with lithium, divalproex and lamotrigine. The early and encouraging results with lamotrigine will be presented.

Biography

Dr. Charles Bowden is Interim Chairman and Chief of the Division of Biological Psychiatry, Department of Psychiatry, University of Texas Health Science Center at San Antonio. Dr. Bowden received his training in psychiatry at the New York State Psychiatric Institute and Presbyterian Hospital in New York. He is professor both in the departments of psychiatry and pharmacology and holds the Nancy U. Karren Chair of Psychiatry. He is a member of the Board of Trustees of the American Psychiatric Association. He is author of over 150 publications. His research interests are principally in mood disorders and psychopharma-cology, particularly the pharmacodynamics of psychotropic drugs. He has been principal investigator for 39 studies funded by pharmaceutical companies, NIMH, and foundations. He frequently serves as consultant to pharmaceutical companies and governmental agencies, and is named in Best Doctors in the America in the area of mood Disorders.

Complex Combination Therapy for Refractory Bipolar Patients
Robert M. Post, M.D.
Chief, Biological Psychiatry Branch
National Institute of Mental Health

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Biography

Over the past 25 years, Dr. Post has been intensively involved at the NIMH in the study of the neurobiology and treatment of patients with affective disorders. His work has focused on the longitudinal unfolding of the illness; i.e., its tendency for deterioration over time if untreated. He has used novel preclinical models of sensitization and kindling to help to conceptualize the progressive nature of the illness and its treatment implications. In kindling, repeated electrical stimulation of the brain results in increasing spread and duration of afterdischarges, culminating in full-blown seizures to a previously subthreshold stimulation. If kindled seizures are induced often enough, spontaneous seizures emerge. In behavioral sensitization to psychomotor stimulants, (and/or stressors), increasing behavioral pathology becomes manifest on each repetition of the drug or stressor. Both kindling and sensitization have an impact on gene expression. Taken together, these two paradigms help conceptualize how psychosocial stressors may not only be involved in the induction of initial episodes of affective illness, but how, with successive recurrences, episodes occur more autonomously or spontaneously; i.e., a prediction now well documented in the clinical research literature. This approach of considering the impact of experience on gene expression provides a framework for the integration and interaction of psychosocial stressors and neurobiological processes in the development and evolution of the affective disorders, rather than seeing the two realms as mutually exclusive.

The kindling formulations also provided an additional rationale for Dr. Post to begin controlled studies and document the therapeutic effects of the limbic anticonvulsant carbamazepine in the acute and prophylactic treatment of bipolar illness. Thus, he has helped to introduce a major new treatment modality for patients with lithium-refractory manic-depressive illness utilizing the anticonvulsant carbamazepine. This work, in turn, has led to his intensive preclinical and clinical efforts to understand the mechanisms of action of carbamazepine. Dr. Post and his collaborators have discovered that the drug acts, in part, through the so-called peripheral-type benzodiazepine receptor system; i.e., a different neurotransmitter system from that involved in actions of the typical benzodiazepines, clonazepam and diazepam, which act at central-type receptors. His studies also suggest that the anticonvulsants carbamazepine and valproate may play an important role in treating patients late in the course of their illness, which is often characterized by rapid cycling. Most recently, he has found that the calcium channel blocker nimodipine may stabilize mood in patients with ultra-ultra rapid (ultradian) cycling, further suggesting that different drugs may be effective in different phases of illness evolution, as predicted by the kindling model.

Dr. Post has also begun to explore the phenomenon of loss of efficacy of tolerance to the long-term prophylactic effects of the mood stabilizers lithium, carbamazepine, and valproate. He has found that 40% of the lithium-refractory patients referred to the NIMH showed a pattern of response consistent with tolerance. While some patients have maintained their improvement for long durations of time (10 to 12 years), a subgroup develop breakthrough episodes and appear to show tolerance to the anticonvulsants as well. This pattern of loss of efficacy is being explored in preclinical seizure models and appears to represent a unique form of tolerance called contingent tolerance, as it only develops when animals are treated with the drug before seizures, and not when they are given the drug after seizures have occurred. This type of tolerance is associated with the failure of endogenous adaptive responses to occur. The preclinical model also helps focus on potential therapeutic approaches to this problem of loss of efficacy, suggesting the potential utility of periods of drug discontinuation in the face of tolerance (so that the endogenous adaptations can become manifest), or switching the patient to other drugs with different mechanisms of action which do not show cross-tolerance.

Dr. Post’s group also uncovered a possible role for carbamazepine not only in inhibiting cocaine-induced seizures and their associated lethality, but also in decreasing cocaine self-administration in rhesus primates, findings that are propelling investigation of this agent as a clinical treatment for cocaine abuse.

At the NIMH, Dr. Post has progressed from Clinical Associate to Chief of the Section on Psychobiology and now Chief, Biological Psychiatry Branch. Throughout his tenure at the NIMH, he has not only helped pioneer new treatment strategies for patients with affective disorder, but has been a teacher and advocate for better understanding and treatment of the recurrent affective disorders. He takes pride in the fact that he has been responsible for the training and development of numerous young investigators who have now gone on to make important contributions to the field in their own right.

Molecular Analyses of Brains from Individuals with
Bipolar Disorder-Evidence of Viral Infections
Robert H. Yolken, M.D.
Professor of Pediatrics
Johns Hopkins University School of Medicine
Pediatric Infectious Diseases
Stanley Neurovirology Laboratory

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Abstract

Epidemiological studies have indicated that viral infection may play a role in human neuropsychiatric diseases. The recent availability of well preserved post-mortem brain samples from diseased individuals and controls has allowed us to apply molecular techniques to address the relationship between viral infections and bipolar disorder.

Nucleic aci