Epidemiology of Brain Disorder

Ezra Susser, M.D., Dr.P.H., Chief of Psychiatric Research
Alan Brown, M.D., Deputy Chief, Psychiatrist Research II
Jennie Kline, Ph.D., Research Scientist VI
Richard Neugebauer, Ph.D., Research Scientist V
Daniel Herman, D.S.W., Research Scientist IV
Pamela Collins, M.D., M.P.H., Psychiatrist Research II
Ramin Mojtabai, M.D., Ph.D., M.P.H., Research Scientist III
Michaeline Bresnahan, Dr.PH., Research Scientist II
Daniel Pilowsky, M.D., Ph.D., Staff Psychiatrist

OVERVIEW
The Department of Epidemiology of Brain Disorders has two main areas of research. The first, on prenatal determinants of schizophrenia and other neuropsychiatric disorders, involves a series of follow-up studies of neuropsychiatric disorders in “prenatal” cohorts. Previous investigators collected uniquely valuable prenatal data and biological specimens in these cohorts, providing a window on fetal experience. This strategy enables us to elucidate possible fetal origins of disorders including schizophrenia, affective disorders, and autism. Our work on schizophrenia is the most advanced, and has produced important findings on prenatal exposures (infection, nutrition, toxins) that may play a role in the pathogenesis of schizophrenia. The selected cohorts are located at various sites in the United States, and in other countries such as the United Kingdom, Holland, Norway, and Israel.

The second area of research investigates the course of schizophrenia. This work has two components: 1) observational studies on the incidence and the “natural history” of schizophrenia and other psychotic disorders, and 2), randomized clinical trials of psychosocial interventions which are designed to improve outcomes for the most disadvantaged patients with schizophrenia, e.g., homeless patients. The latter include “Critical Time Intervention” (CTI) to reduce homelessness, and “Sex, Games and Videotapes,” a 15-session AIDS prevention curriculum. The CTI project has become a model for programs conducted in many locations throughout the US, and in other regions of the world.

While these two main areas involve most of the faculty of the department, individual investigators also have other important research foci. These include elucidating the causes of chromosomal trisomy (some of which lead to significant neurodevelopmental disorders); depression after miscarriage; and assessing the immediate and long term impact of the World Trade Center disaster.

CURRENT RESEARCH
As chief of the Department of Epidemiology of Brain Disorders, Ezra Susser initiated several areas of the research efforts described below. As others take up leadership roles in these areas, Dr. Susser often continues as co-Principal Investigator on grants, and senior author on publications. He continues to investigate the influence of fetal events on schizophrenia; interventions to improve the lives of people with severe mental illness; and the inter-relatedness of mental health and other health domains over the life course. He is Principal Investigator of EDAH (Early Determinants of Adult Health), a multisite collaborative study that includes investigators from Epidemiology of Brain Disorders, Epidemiology (MSPH), Harvard School of Public Health, and other institutions. He is also the co-author of Psychiatric Epidemiology: Searching for Causes (in press).

Alan Brown has continued his research into prenatal infectious and nutritional etiologies of schizophrenia. He and his colleagues demonstrated that serologically documented exposure to influenza in the first half of gestation was associated with a three-fold elevated risk of schizophrenia spectrum disorders among offspring. This is the first serologic evidence for prenatal influenza in the etiology of schizophrenia. In a related study, he demonstrated elevated second trimester levels of the cytokine interleukin-8 in individuals who later developed schizophrenia, compared to controls. He has also shown an increase in maternal exposure to toxoplasmosis among offspring destined to be diagnosed with schizophrenia. With regard to prenatal nutritional factors, he showed that elevated third trimester levels of homocysteine were associated with an increased risk of schizophrenia in the offspring. Furthermore, he has continued his study of early developmental insults and structural and functional brain abnormalities in schizophrenia, and has initiated work on precursors of early onset mood disorders in a large birth cohort in Bristol, England.

Jennie Kline and colleagues completed the second test of their hypothesis that the strong association between advancing maternal age and trisomic pregnancy arises as a function of the size of the oocyte pool. They tested whether three indicators of a smaller oocyte pool–low antral follicle count, low inhibin B level, and elevated FSH level–were associated with trisomic spontaneous abortion. The data did not support their hypothesis. They leave open the possibility, however, that changes in follicular development unrelated to the size of the oocyte pool influence abnormal chromosome segregation. In an analysis of prospective data from women first identified for a case-control study of spontaneous abortions in 1974-1986, Kline and colleagues evaluated whether menstrual cycle characteristics predicted nearness to the menopause. Among women aged 44-55, a report of amenorrhea lasting 60 days or longer in the preceding year showed very good sensitivity, specificity and predictive value for occurrence of ascertained menopause in the subsequent 2 and 4 years. This finding has potential application in clinical practice in advising women about their nearness to menopause. Jennie Kline, Dorothy Warburton and colleagues began a new study to examine whether or not characteristics of the maternal X chromosomes, indicated in the first instance by the presence of skewed X-inactivation, are associated with either trisomic loss or with loss of chromosomally normal male conceptions.

Richard Neugebauer continued his research initiatives in two major areas: the investigation of the mental health effects of stressful life events and bereavement by means of observational epidemiological studies and the design, conduct and analysis of randomized controlled trials of manualized psychological interventions for depression. Accordingly, in 2004 Dr. Neugebauer published a substantive methodological paper on the contrasting clinical and epidemiological perspectives in bereavement research exemplified by using previously unpublished data on the psychiatric effects of miscarriage on depressive symptoms at 6-8 weeks after loss. He was also chiefly responsible for the design and analysis of a randomized controlled trial of group-based interpersonal psychotherapy for rural Ugandan adults depressed in the context of the HIV/AIDS epidemic. The results of that trial appeared in JAMA and have been covered widely in the news media, including a half page article in the New York Times. Finally, Dr. Neugebauer completed his pilot open and pilot randomized controlled trial of brief telephone-administered interpersonal counseling for women depressed following miscarriage.

Daniel Herman continued his research on service delivery for adults with severe mental illness. He is conducting a five-year randomized trial of a psychosocial intervention (Critical Time Intervention) designed to prevent homelessness among severely mentally ill men and women following discharge from state hospitals. Dr. Herman is also collaborating with researchers from the Nathan Kline Institute for Psychiatric Research on a second study of Critical Time Intervention with homeless families. He also continues to be involved in research documenting mental health service needs resulting from the terror attacks of September 11, 2001. He is co-principal investigator (with Dr. Carol North of Washington University) of a newly-funded epidemiologic study of long-term mental health needs among individuals survived the World Trade Center collapse and their families.

Pamela Collins is conducting a study of the mental health impact of the HIV epidemic in a South African community in Kwazulu/Natal.

Ramin Mojtabai and colleagues confirmed that nonaffective acute remitting psychoses are distinct and not yet adequately classified under DSM-IV or ICD-10.

Michaeline Bresnahan has contributed to the Prenatal Determinants of Schizophrenia project and its numerous publications, and the newly funded Autism Birth Cohort (Norway) supported by NICHD through Columbia. She has recently initiated an international research partnership to examine autism spectrum disorders in the Caribbean, and develop comparative research of Autism Spectrum Disorders within the region and with other developed country sites.

Mark Opler, Ph.D., a research fellow in our department, led a study demonstrating that elevated second trimester maternal levels of ?-Aminolevulinic Acid - a biomarker for lead exposure - was associated with a two-fold increased risk of schizophrenia in offspring. This is the first indication that gestational exposure to a common environmental toxin may influence risk of schizophrenia.

EDUCATION AND TRAINING
Most of the members of our department are mentors to postdoctoral research fellows and predoctoral students , and several are on the faculty of the Psychiatric Epidemiology Training Program. These fellows and students are actively encouraged to develop their own research projects under the mentorship of senior colleagues. Mark Opler, Ph.D. is a fellow in the Schizophrenia Research Fellowship Program of NYSPI. His focus is on the relationship between prenatal exposure to lead and risk of adult schizophrenia. Beverly Insel, Ph.D., a recent graduate of our psychiatric epidemiology training program, is working on a study of Rh incompatibility as a risk factor for schizophrenia.

AWARDS AND HONORS
Alan Brown received a 5-year K02 Independent Scientist Award from the National Institute of Mental Health

GRANTS
Early Determinants of Adult Health. PI: E. Susser ; Funding: NIA . Time line: 9/30/03 – 9/29/08

Developmental Insult and Brain Anomaly in Schizophrenia. PI: A. Brown, Funding: National Institute of Mental Health, Time line: 3/1/00-2/28/05

Serologic Studies of Prenatal Factors in Schizophrenia. PI: A. Brown, Funding: National Institute of Mental Health, Time line: 9/1/01-8/31/04

Independent Scientist Award, Epidemiology of Prenatal Exposures in Schizophrenia. PI: A. Brown, Funding: National Institute of Mental Health, 1K02-MH65422-01, Time line: 7/1/03 –6/30/08

Developmental Factors and Early Brain Abnormalities in Schizophrenia: A Pilot Study. PI: A. Brown; Funding: Ritter Foundation, Time line: 10/1/03-9/30/04

Epidemiology of ovarian age. PI: J. Kline. Funding: NIH. Time line: 5/1/98-4/14/05

Persistent Mental Health Impact on WTC Survivors. PI: C. North, Co-PI: D. Herman; Funding: NIMH; Time line: 9/25/03 to 6/30/08

BIBLIOGRAPHY
Bolton P, Bass J, Neugebauer R, Verdeli H, Clougherty KF, Wickramaratne P, Speelman L, Ndogoni L, Weissman M (2003). Group interpersonal psychotherapy for depression in rural Uganda: a randomized controlled trial. JAMA; 289:3117-3124

Bresnahan M, Susser E (2003). Investigating socio-environmental influences in schizophrenia: conceptual and design issues. In R Murray, P Jones, E Susser, J vanOs, M Cannon (Eds), Epidemiology of Schizophrenia. Cambridge University Press.

Bresnahan M, Menezes P, Varma V, Susser E (2003). Geographical variation in incidence, course and outcome in schizophrenia: a comparison of developing and developed countries. In R Murray, P Jones, E Susser, J vanOs, M Cannon (Eds), Epidemiology of Schizophrenia. Cambridge University Press.

Bresnahan M, Boydell J, Murray R, Susser E (2003). Temporal variation in the incidence, course and outcome of schizophrenia. In R Murray, P Jones, E Susser, J vanOs, M Cannon (Eds), Epidemiology of Schizophrenia. Cambridge University Press.

Brown AS, Begg MD, Gravenstein S, Schaefer C, Wyatt RJ, Bresnahan M, Babulas V, Susser E. Serologic evidence for prenatal influenza in the etiology of schizophrenia. Archives of General Psychiatry, in press.

Brown AS, Hooton J, Schaefer CA, Zhang H, Petkova E, Babulas V, Perrin M, Gorman JM, Susser ES (2004). Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am J Psychiatry; 161:889-895

Brown AS, Susser ES. (2003) Prenatal risk factors for schizophrenia. In: Cicchetti D, Walker EF (Eds), Neurodevelopmental Mechanisms in Psychopathology. Cambridge, UK. Cambridge University Press, pp 84-110

Factor-Litvak P, Hasselgren G, Jacobs D, Begg M, Kline J, Geier J, Mervish N, Schoenholtz S, Graziano J (2003). Mercury derived from dental amalgams and neuropsychologic function. Environ Health Perspect; 111: 719-723.

Herman D, Susser E, Aaron, B. (2003). An agenda for public mental health in a time of terror. In Coates S, Rosenthal J, Schechter D (Eds)., September 11: Trauma and Human Bonds. Analytic Press.

Herman, D. Methodological Issues in Studying the Relationship between Childhood Adversity and Adult Homelessness. In Alexander L, Solomon P (Eds), The Research Process in the Social Services. Wadsworth, in press.

Mojtabai, R, Susser, E, Bromet, EJ (2003). Clinical characteristics, four-year course and DSM-IV diagnosis of non-affective acute remitting psychosis. American Journal of Psychiatry: 160:2108-2115.

Neugebauer, R (2003). School-based interventions for children exposed to violence. JAMA;290(19):2541-2542.

Neugebauer R (2003). Depressive symptoms at two months after miscarriage: interpreting study findings from an epidemiological versus clinical perspective. Depression & Anxiety 2003; 17:152-161.

Opler MGA, Brown AS, Graziano J, Desai M, Zheng W, Schaefer C, Factor-Litvak P, and Susser ES (2004). Prenatal Lead Exposure, ?-Aminolevulinic Acid, and Schizophrenia. Environ Health Perspect 2004; 112: 548-552

Schupf N, Pang D, Patel BN, Silverman W, Schubert R, Lai F, Kline JK, Stern Y, Ferin M, Tycko B, Mayeux R (2003). Onset of dementia is associated with age of menopause in women with Down’s syndrome. Ann Neurol; 54: 433-438.

Susser E, Terry MB (2003). A conception-to-death cohort. Lancet 2003; 361(9360):797-8.

Taylor SM, Kinney AM, Kline JK (2004). Menopausal transition: predicting time to menopause for women 44 years or older from simple questions on menstrual variability. Menopause; 11: 40-48.

Verdeli H, Clougherty K, Bolton P, Speelman L, Ndogoni L, Bass J, Neugebauer R, Weissman M (2003). Adapting group interpersonal psychotherapy (IPT-G) for a developing country: experience in rural Uganda. World Psychiatry;2(2):114-119.

Wasserman GA, Factor-Litvak P, Liu X, Todd AC, Kline JK, Slavkovich V, Popovac D, Graziano JH (2003). The relationship between blood lead, bone lead and child intelligence. Neuropsychol Dev Cogn Sect C Child Neuropsychol; 9: 22-34.