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					                                                                                                                                 Volume 4, Number 7, Summer 2002




                                                                  THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY




UMDNJRESEARCH                                                      For the Research Community from the State University of the Health Sciences




PSYCHIATRY
RESEARCH
COMES OF AGE
AT UMDNJ
b y       J a v i e r                 I .       E s c o b a r

JAVIER I. ESCOBAR, MD, MS, PROFESSOR AND CHAIR, DEPARTMENT OF PSYCHIATRY,
UMDNJ - ROBERT WOOD JOHNSON MEDICAL SCHOOL




T
                        he 1990s were called the decade of the brain in North America, stimulating
                        significant research on basic and clinical neuroscience. During this period,
                        psychiatry, one of the clinical neurosciences, witnessed the development of
                        powerful tools for the study of brain-behavior relationships, saw the emergence of
                        safe and effective drugs for treating depression, anxiety and schizophrenia, and     UMDNJ’s Schools

confirmed the positive impact of traditional treatments such as psychotherapy, via the controlled            Graduate School of Biomedical Sciences
clinical trial. The fact that biology affects behavior, and conversely, that “stress” and other psycholog-   New Jersey Dental School

ical influences affect biology, results in new and exciting paradigms.                                       New Jersey Medical School

                                                                                                             Robert Wood Johnson Medical School
Other important highlights of this decade were:
                                                                                                             School of Health Related Professions
s   The “Global Burden of Disease,” an international study coordinated by the World Health Organization,
                                                                                                             School of Nursing
confirmed that mental disorders such as major depression are amongst the most prevalent and disabling        School of Osteopathic Medicine

health conditions worldwide.                                                                                 School of Public Health
                                                                                    continued on page 3
      C                   o                       n                       t                     e                       n          t                          s

1,6


      1
                                                                                                                             T
           Overview       by Javier I. Escobar                                                                                             he University of Medicine and
                                                                                                                                           Dentistry of New Jersey is a
           During the last 10 years, powerful tools for studying brain-behavior relationships have been developed,
           resulting in better diagnosis and safer, more effective therapies for psychiatric illness. This issue showcases                 statewide network of eight
           ongoing research on mental health issues at UMDNJ.                                                                schools on five campuses in Camden,
3
                                                                                                                             New Brunswick/Piscataway, Newark,

      3    Double trouble: co-occurring mental illness and addiction                              by Douglas Ziedonis        Scotch Plains and Stratford. The schools
                                                                                                                             include New Jersey Medical School,
           Some 50 percent of patients being treated for either mental illness or substance abuse have co-occuring mental
           illness and addiction. The cognitive function, psychiatric symptoms and treatment outcomes of mentally ill        Robert Wood Johnson Medical School,
           substance abusers are worsened unless both problems are addressed.                                                School of Osteopathic Medicine, New
5                                                                                                                            Jersey Dental School, Graduate School


      5    Psychopathy, violence and victimization                      by Cathy Spatz Widom
           How a traditional psychologist went from studying aggression, violence and psychopathy to studying
                                                                                                                             of Biomedical Sciences, School of Health
                                                                                                                             Related Professions, School of Nursing
           victims of violence.                                                                                              and School of Public Health. The
                                                                                                                             University has more than 4,500 students
8
                                                                                                                             in 38 degree and certificate programs,
      6    Studies of medically unexplained physical symptoms and mental
           health disparities by Javier I. Escobar                                                                           11,000 employees, including 2,075
                                                                                                                             faculty members, 17,000 alumni and
           Strategies to understand why some patients with mental disorders seek treatment of multiple unexplained
           symptoms; and a study of major mental disorders of Latino populations in New Jersey and across the country.       more than 200 education and health-
                                                                                                                             care affiliates throughout New Jersey.
10
      8    New approaches in adult psychopharmacology research                                   by Matthew Menza
           A look at the progress that has been made in developing medications for treatment of mental illness,
                                                                                                                             The University is dedicated to pursuing
                                                                                                                             excellence in the education of health
           including depression, schizophrenia and ADHD.                                                                     professionals and scientists, conducting
                                                                                                                             research, delivering health care, and
                                                                                                                             serving the community. UMDNJ is
12    10   Do thyroid hormones treat depression?                          by Russell T. Joffe
           While antidepressants are only partially effective in treating major depression, thyroid hormones may
                                                                                                                             ranked among the 100 top research

           augment antidepressant responses. Understanding the mechanism of action of thyroid hormones in                    universities in the country.
           depression may also help in understanding the biology of depression.


                                                                                                                             Please visit our website at

14
      12   Exploring the Hispanic paradox                   by William A. Vega

           Why is it that Latin-American immigrants with low access to healthcare experience about one-half the risk
                                                                                                                             h t t p : / / w w w. u m d n j . e d u

           of a lifetime mental disorder compared to the U.S. population at large?                                           E-mail us at
                                                                                                                             research@umdnj.edu
           Neuroscience and genetic approaches to psychiatric diseases                                                       to comment on this publication
      14   by Daniel Cowen and Paul Manowitz                                                                                 or to add someone to the mailing list.
14         Basic science and mental illness: studying transduction pathways that are involved in the pharmacological
           effects of antidepressants; and identifying possible genetic causes of alcoholism.



      16   Behavior and the immune system: influences & interactions
           by Steven Schleifer
16
           How the brain influences a full panoply of medical disorders through its effects on numerous physiological
           systems, among them the immune system.



      18   Alzheimer’s disease research: a search for solutions                              by Peter Aupperle

           With the number of Americans with Alzheimer’s disease topping 4 million, great efforts are underway to
18
           develop more effective treatments. This group is investigating new medications, as well as augmenting the
           standard ones with other compounds offering novel modes of action.                                                  UMDNJRESEARCH
                                                                                                                                                                            Principal photography: Paddy Eckersley; cover and p.21: Peter Byron




                                                                                                                               Volume 4, Number 7, Summer 2002



      19   Functional MRI in the study of face processing in autism spectrum disorders
           by Charles Cartwright
                                                                                                                               Stuart D. Cook, MD
                                                                                                                               President
19
           Face processing autism study uses functional magnetic resonance imaging, an innovative technology
           that holds promise in furthering our understanding of the neurobiology of this complex syndrome.                    L.M. Stephenson, PhD
                                                                                                                               Vice President for Research and
                                                                                                                               Editor-in-Chief

      21   Refining ECT as a treatment for severe depression                              by Charles H. Kellner
           Electroconvulsive therapy (ECT) is an important treatment for depression, but relapse and cognitive
                                                                                                                               Matthew Menza, MD
21                                                                                                                             Co-editor
           impairment after ECT are significant concerns. A study examines use of ECT as a maintenance therapy to
                                                                                                                                                                            A S S O C I A T E S




           prevent relapse, and alternative types of ECT to reduce memory loss.
                                                                                                                               UMDNJ Research is published by the
                                                                                                                               Department of Government and Public

      22   Research in behavioral medicine                    by Paul Lehrer
                                                                                                                                                                            +




                                                                                                                               Affairs, University of Medicine and
                                                                                                                                                                            M I L L E R




           This lab is investigating some of the emotional concomitants of physical disease, and the ways in which             Dentistry of New Jersey, Publications
22         physical and emotional disease affect each other.                                                                   Office, Stanley Bergen Building, 65
                                                                                                                               Bergen Street, Room 1328, Newark, N.J.
                                                                                                                                                                            Design: E R I C




                                                                                                                               07107-3000.
                                                                                                                               For permission to reprint an article,
           President’s message
      24                                        b y Stuart D. Cook
                                                                                                                               contact the editor. For change of address,
                                                                                                                               please include label.


24
continued from page 1


s   “Healthy People 2000,” an initiative of the U.S. Department of
Health and Human Services, included several mental health
outcomes among the leading health indicators.
s   “Mental Health: A Report of the Surgeon General” documented
the disabling nature of mental illnesses and showcased the strong
basic science behind effective treatments, while emphasizing the
importance of recognizing and treating mental disorders. The
supplement that followed, “Mental Health, Culture and Ethnicity,”
documented unfortunate ethnic disparities, particularly regarding
access to and quality of treatment.
      Entering the 21st century, psychiatric research looks very
vigorous, thanks to a decline in stigma of psychiatric illness,
significant lobbying by patient advocates and a net increase in avail-
able research funds. For example, the budget of the National
Institute of Mental Health (NIMH) reached the one billion dollar
mark in FY 2000, and continues to increase at a fast pace (about
10% yearly). Other NIH institutes relevant to psychiatric research,
such as NIDA and NIAAA, have followed pace. Major research
priorities at these NIH institutes include:
s   Studies on the brain, behavior and genetics.
s   Rapid translation of basic discoveries into research on mental
disorders.
s   Investigations impacting the treatment of individuals with                                                DOUGLAS ZIEDONIS, MD, MPH, ASSOCIATE PROFESSOR AND
                                                                                                    DIRECTOR, DIVISION OF ADDICTION PSYCHIATRY, UMDNJ-ROBERT WOOD
mental disorders.                                                                                                                         JOHNSON MEDICAL SCHOOL
s   Clinical trials, and treatment and prevention interventions
conducted in “real world” settings.
s   Childhood mental disorders.
s

s
    Suicide.
    Health disparities.
                                                           Double trouble: co-occurring
      Private foundations such as the Robert Wood
Johnson Foundation continue to invest heavily in
                                                           mental illness & addiction
the area of behavioral disorders. The pharmaceu-
tical industry is hard at work developing new              b y      D o u g l a s       Z i e d o n i s

drugs that look more specific and are better




                                                                                 A
tolerated than the old ones. All these major investments have placed psychi-                        bout 50% of the patients in either the mental health or
atric departments among the top research departments in academic                                    addiction treatment systems have co-occurring mental
institutions nationally. In fact, our two departments of psychiatry at UMDNJ-                       illness and addiction. Individuals with co-occurring disor-
Robert Wood Johnson Medical School (RWJMS) and New Jersey Medical                                   ders have a poor response to traditional treatments and a
School (NJMS) are now among the top 50 nationally.                                                  worse prognosis, including increased hospitalizations,
      In this issue of UMDNJ Research, we present a “sampler” of research        violence, illegal activities, suicide, homelessness, and transmission of HIV.
taking place in the departments of psychiatry at RWJMS and NJMS. While           I have published extensively about co-occurring mental illness and addiction,
the research highlighted includes faculty members from both medical school       focusing on better understanding the problem and improving treatment
departments, we need to acknowledge the outstanding contribution of              outcomes. These individuals consume 44% of all cigarettes, smoke at three
University Behavioral HealthCare (UBHC), our main clinical partner. Under        times the national rate and have increased morbidity and mortality secondary
the leadership of Christopher Kosseff, UBHC has become the main clinical         to tobacco-caused diseases. Stigma and misinformation have historically
research site for both departments. In this issue we present ongoing investi-    limited addressing tobacco dependence in this vulnerable population.
gations in our two departments ranging from the cell to the societal level.
s   Addiction (Drs. Ziedonis, Merrill, Atdjian, Williams).                            I am often asked three questions: 1) Why do so many individuals with
s   Psychosomatics, including psychological medicine, primary care psychiatry,   mental illness smoke cigarettes and abuse alcohol and other drugs?
neurophysiology and psychoimmunology (Drs. Escobar, Schleifer, Lehrer).          2) Other than increased medical problems and premature death, why
s   Psychopharmacology and psychoneuroendocrinology (Drs. Menza and              should we help these individuals quit smoking tobacco? and 3) Does treat-
Joffe).                                                                          ment work? During the past 12 years, I have been developing a program
s   The consequences of psychological trauma (Dr. Widom).                        of research aimed at better understanding and treating individuals with
s   Epidemiology, services research and special populations (Drs. Vega and       co-occurring mental illness and addiction. This area of research is relevant to
Escobar).                                                                        community psychiatrists, addiction treatment providers, and public health
s   Basic neuroscience (Drs. Cowen, Manowitz).                                   specialists; yet important gaps remain in the research literature that must be
s   Geriatrics (Dr. Aupperle).                                                   addressed. Mental illness and addiction commonly co-occur, and the combi-
s   Children (Dr. Cartwright).                                                   nation results in worse prognosis, treatment compliance, and outcomes
s   Special treatments such as ECT (Dr. Kellner).                                compared to either disorder alone. The mentally ill experiment with sub-

                                                                                                                                       continued on page 4



                                                                                     THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY                           3
    continued from page 3


    stances for the reasons anyone does — to “get high,” to fit in with others, or       vision to address this important public health and clinical problem, including
    because it seems to help relieve feelings of anger, loneliness, anxiety or depres-   fighting the stigma that lies at the root of this neglected issue. Recently we
    sion. The mentally ill are especially vulnerable to addiction given the              reported in the American Journal of Psychiatry that tobacco dependence
    changes in brain vulnerability and important psychosocial factors. At UCLA,          treatment outcomes improved for individuals with schizophrenia with the
    Yale, and now UMDNJ, my own research has included clinical                           nicotine replacement patch and behavioral therapy when they were
    epidemiology, behavioral therapy development, medication clinical trials,            prescribed the newer atypical antipsychotics compared to the traditional
    and health services research.                                                        antipsychotics. This finding is consistent with our prior work and highlights
         Our studies have found that mentally ill substance abusers worsen their         that better treating the “negative symptoms” of schizophrenia will improve
    cognitive functioning, psychiatric symptoms and treatment outcomes unless            tobacco dependence treatment outcomes and lessen the “self-medication”
    both problems are addressed in an integrated manner. These individuals often         function of smoking for this group. This year Dr. Jill Williams received a
    have low internal motivation to address their addiction. For treatment to be         five-year National Institute of Drug Abuse Career Development Award to
    effective, it must increase internal motivation and/or external motivators such as   study nicotine dependence and mental illness, and I will serve as her primary
    family support, money management, and legal pressure. Research supports the          mentor. Dr. Jonathan Foulds was recruited from the United Kingdom to
    need for new integrated treatment models to approach this population.                further strengthen our research efforts in tobacco and our linkage with the
    I developed and tested our Motivation Based Treatment Model that matches             UMDNJ-School of Public Health (SPH).
    specific treatment approaches to different motivational levels and utilizes our           Division of Addiction Psychiatry and the NJ Addiction Consortium:
    own integrated therapy approach — Dual Recovery Therapy. Many mental                 In 1998, I left Yale University to join UMDNJ and develop a new Division
    health treatment agencies and systems have adopted our model and therapy             of Addiction Psychiatry and co-lead the new NJ Addiction Consortium that
    approaches. We use them at the New Jersey Veterans Affairs Health Care               includes the RWJMS Department of Psychiatry, UMDNJ’s University
    System where Drs. Smelson, Losonczy and I have received funding for                  Behavioral HealthCare, and the Rutgers University Center for Alcohol Studies.
    numerous medication and psychosocial development studies. One of these is            Our efforts have included developing research, clinical, and training activities
    evaluating the effectiveness of a short-term intensive case management               and programs and recruiting new junior and senior faculty. We have been very
    intervention that uses a Critical Time Intervention combined with Dual               successful in obtaining research funding from the National Institute on Drug
    Recovery Therapy to reduce the rate of re-hospitalizations for individuals           Abuse, National Institute on Alcoholism and Alcohol Abuse, National Institute
    with substance abuse and schizophrenia. We have also been adapting our               on Mental Illness, Robert Wood Johnson Foundation, Center for Substance



                         OUR STUDIES HAVE FOUND THAT MENTALLY ILL SUBSTANCE ABUSERS WORSEN THEIR COGNITIVE FUNCTIONING, PSYCHIATRIC SYMPTOMS AND
    TREATMENT OUTCOMES UNLESS BOTH PROBLEMS ARE ADDRESSED IN AN INTEGRATED MANNER.



    interventions to address mental health problems in addiction treatment settings.     Abuse Treatment, and the pharmaceutical industry. In addition, we partnered
    A $1.3 million research grant from the Center for Substance Abuse Treatment          with the University of Pennsylvania to obtain a NIDA Clinical Trials Network
    (CSAT) is helping us to evaluate these integrated approaches and to train and        Center Grant. Several outstanding faculty within our department have strength-
    supervise substance abuse counselors in our model.                                   ened the Addiction Psychiatry Division, including Jeffrey Merrill, William
         We are also studying the effectiveness and relative role of medications in      Vega, Paul Lehrer, Paul Manowitz, Edward Johnson, Jonathan Foulds, Ava
    treating individuals with co-occurring disorders. Our studies have found             Stanley, David Smelson, Miklos Losonczy, John Williams, Calvin Chatlos,
    Antabuse helps improve cocaine addiction treatment outcomes, atypical                Jonathan Krejci, Jill Williams, and Sylvia Atdjian. The Division faculty have an
    antipsychotics help schizophrenic substance abusers, and antidepressants             outstanding clinical research team, including Trish Dooley, Marc Steinberg, Ivy
    improve outcomes for depressed cocaine addicts. Our work has been cited in the       Pearlstein, Carmela Santisi, Betty Sanchez, Donna Drummond, Tracy Dilascio,
    American Psychiatric Association’s Practice Guidelines in Substance Abuse            Farida Iqbal-Hussain, and Lauren Scher.
    Treatment. We currently are evaluating the use of atypical antipsychotics for
    cocaine abuse and schizophrenia, multiple nicotine replacement patches for           Douglas Ziedonis, MD, MPH, is an associate professor and director of the
    schizophrenic smokers, and buprenorphine for heroin addiction.                       Division of Addiction Psychiatry at RWJMS. He has a joint appointment as an
         Tobacco and Mental Illness: Through my studies of co-occurring disor-           associate professor in the Health Systems and Policy Division at the UMDNJ-
    ders, I have developed a special interest in tobacco use and dependence among        School of Public Health and serves as Medical Director for the Tobacco
    psychiatric patients. We have observed high rates of tobacco dependence among        Dependence Program. He is also a visiting professor at the Rutgers University
    this population, and found that heavy cigarette smoking is associated with other     Center of Alcohol Studies and the Princeton Theological Seminary. He has
    drug abuse. We found that patients with schizophrenia who smoke require high-        received numerous research grants from the National Institute of Mental
    er medication doses, experience more frequent hospitalizations, and                  Health, National Institute of Drug Abuse, Center for Substance Abuse
    demonstrate more hallucinations and delusions, but fewer negative symptoms           Treatment, Robert Wood Johnson Foundation, and other organizations, includ-
    (flat facial expression, depression, limited social interaction, and low motiva-     ing a five-year NIDA Scientist Career Development Award while at Yale
    tion) compared to non-smokers. Much of our work has been cited in the                University. He has served as a member of the New Jersey Substance Abuse
    American Psychiatric Association’s Practice Guideline For Treatment of               Prevention and Treatment Advisory Task Force and is the author of more than
    Patients With Nicotine Dependence. At UMDNJ, we have an outstanding team             75 articles and co-editor of three books. He has served on numerous NIH study
    focused on tobacco dependence and mental illness. Our group experienced a            sections, advisory committees, and is on the editorial board of The American
    profound loss with the recent death of John Slade, MD. We shared a common            Journal of Drug and Alcohol Abuse. ❧




4         THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY
                                                                                   LEFT TO RIGHT: CATHY SPATZ WIDOM, PhD, PROFESSOR OF PSYCHIATRY AND UNIVERSITY
                                                                                  PROFESSOR, UMDNJ-NEW JERSEY MEDICAL SCHOOL; NOAH SUSSWEIN; SALLY CZAJA, PhD;
                                                                                                           JEANNE KAUFMAN; JUANITA HOBSON; KIMBERLY DUMONT, PhD




Psychopathy, violence
                                                                                                   student. A year later, with two women students and two
                                                                                                   ex-convicts, this same young man was involved in a bank


and victimization                                                                                  robbery in which a policeman was killed.
                                                                                                        Fascinated by the problems that someone with a
                                                                                                   personality like this young man presents to psychology,
                                                                                                   mental health, and the law, I decided to switch areas of
by Cathy Spatz Widom
                                                                                                   study – from social psychology to personality and
                                                                                                   psychopathology – and undertook a doctoral dissertation
                   n encounter with a disruptive student more than 30 years     on psychopathy. Receiving a Woodrow Wilson Dissertation Fellowship, I




A                  ago was a career-changing event for me, stimulating my
                   scholarly interest in aggression and psychopathy. Since
                   that time, I have worked in departments of psychology,
                   criminal justice, and now psychiatry, and published exten-
sively on psychopathy, crime, and violence. More recently, I have begun to
focus on victims of violence as well as the perpetrators.
                                                                                conducted my research at Broadmoor Hospital (formerly Broadmoor
                                                                                Criminal Lunatic Asylum) in England, which had a large group of
                                                                                psychopaths serving indeterminate sentences (“at her Majesty’s pleasure”).
                                                                                    Since then, I have maintained an interest in issues related to the interface
                                                                                between crime, violence, and psychiatric disorders. For example, my publi-
                                                                                cations have focused on psychopathy, antisocial personality disorder, female
                                                                                criminality, and juvenile delinquency. I have also conducted research in the
    I entered graduate school planning to earn a doctorate in social            United States and abroad, with male and female offenders, and with youth
psychology. However, after a psychopathic former convict disrupted my           and adults. My interests have not been restricted to offenders, however, since
classroom when I was a graduate teaching assistant, it awakened my interest     I eventually became interested in child victims.
in the behavior of these difficult and dangerous individuals. I was leading         Newspapers across the country increasingly shock and dismay their
a discussion on “aggression, violence, and murder” when this tough-look-        readers with reports of the deaths of young children as a result of child abuse
ing man, clearly unlike the other students, entered the room, listened for a    or neglect. But what happens to the children who survive – the babies aban-
few minutes, and then shocked the class with his stunning departure. I          doned on streets or in hospitals, children left unattended for days without
soon learned he was an inmate from a nearby prison and that he was              food in filthy, roach-infested apartments, or children brutally abused? Many
participating in a special program at the university where I was a graduate     of those who survive childhood abuse and neglect become the focus of

                                                                                                                                       continued on page 6




                                                                                  THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY                             5
    continued from page 5


    front-page newspaper stories as adolescents and young adults. The court records       blood spot samples using an innovative technique to determine levels of
    of one 16-year-old young man who sexually assaulted and clubbed to death a 15-        cortisol and Epstein-Barr virus. With support from a grant from NICHD, we
    year-old classmate revealed a childhood of beatings with belts and fists, cruel       are also involved in a new multidisciplinary collaboration which involves
    words and indifference. Before he was sentenced to life in prison, this young         colleagues from psychology, medicine, psychiatry, child welfare, economics,
    man reportedly told a probation agent: “I lived like I was treated.”                  and epidemiology to study service use, economic productivity, exposure to
        These kinds of stories reinforced the widespread assumption that child            environmental hazards and toxins, and health status in a sample of middle
    abuse and neglect is linked to delinquency, crime, and violence. However,             aged individuals. We are developing an instrument to assess service utiliza-
    earlier research on the topic suffered from a number of methodological problems       tion (lifetime and past 12 months) and will be pilot-testing the instrument
    which detracted from its ability to provide a firm scientific basis. More than 15     with patients in the UMDNJ-University Hospital (UH) Ambulatory Care
    years ago, I obtained initial funding from the National Institute of Justice (NIJ)    Clinic. Our plan is to validate the information obtained from these individuals
    to examine the relationship between early child abuse and neglect and later           against medical case records from UH.
    delinquent, adult criminal, and violent criminal behavior using a design that             I began my academic career at Cornell University with a major in child
    overcame a number of the methodological limitations of previous research.             development and human relationships. More than 30 years later, I am still
        Through an examination of arrest records from three levels of law                 trying to understand the ways in which early childhood experiences influ-
    enforcement, we found that childhood victimization increases the likelihood           ence later life development, often focusing on the development of antisocial
    of delinquency, adult criminality, and violent criminal behavior. Childhood           and criminal behavior. In recent years, we have begun to think about what
    abuse (physical and sexual) and neglect significantly increase a person’s risk        leads to prosocial behavior and what predicts resilience in young children
    of arrest as a juvenile by 59%, as an adult by 27%, and for a violent crime           exposed to different early life adversities. We hope these questions will lead
    by 29%. The odds are almost two times higher that an abused and neglected             to better knowledge of the ways in which we might intervene in the lives of
    child will be arrested for a violent crime as a juvenile than a child of the same     children exposed to a variety of stressors and adversities and, ultimately, to
    sex, age, and race who grew up in the same neighborhood or who was born               facilitate their development in positive and fulfilling directions.
    in the same hospital at the same time. These findings were originally
    described in Science and a subsequent follow-up when the individuals were             Dr. Cathy Spatz Widom is a professor of psychiatry and University Professor
    older was published in 1996 in Archives of Pediatrics and Adolescent                  in the Department of Psychiatry at NJMS. A graduate of Cornell (BS, child
    Medicine (with Michael G. Maxfield).                                                  development and family relationships) and Brandeis (PhD, psychology), she
        We found that abused and neglected children are involved in official              is a fellow of the American Psychological Association and American
    criminal behavior more than a year earlier than non-abused and neglected              Psychopathological Association. A former faculty member at Harvard,
    children (18.1 versus 19.2 years, respectively). This is important because age        Indiana and SUNY Albany, Dr. Widom has received numerous awards for her
    of onset is often negatively related to the severity of a disorder (the earlier       research. She serves on the Committee on Law and Justice at the National
    the onset, the more severe the disorder). Abused and neglected children               Research Council (NRC) and was co-chair of a NRC Panel on Juvenile
    commit more offenses and are more likely to become recidivists and                    Crime: Prevention, Treatment, and Control.
    chronic offenders than non-abused and neglected children.                                 Also contributing to this research are: Kimberly DuMont, PhD, project
        We also investigated what has been called the “cycle of violence” (that is,       manager; Sally Czaja, PhD, statistician/data manager; Jeanne Kaufman,
    where children who experience violence in childhood are thought to become             research assistant; Noah Susswein, research assistant; and Juanita Hobson,
    perpetrators of violence when they grow up). We found that violence (physical         secretary. ❧
    abuse in childhood) begets violence, but so too does childhood neglect. Being
    physically abused in childhood increases a person’s likelihood of being
    arrested for a violent crime. However, we also found that being neglected as a
    child similarly increases the risk of arrest
    for violence.
        Despite this demonstration of an
    increased risk for crime and violence,
                                                          Studies of medically unexplained physical
    there was another very important finding
    from this research. Our results showed                symptoms and mental
                                                          health disparities
    that the majority of abused and neglected
    children did not have criminal records.
    Thus, one of the critical messages of this
    research is the recognition that these
    relationships are not deterministic or
    inevitable.                                            b y      J a v i e r          I . E s c o b a r

        Over the years, I have received
    funding from the National Institutes of




                                                                                         W
    Mental Health (NIMH), Alcohol Abuse and Alcoholism (NIAAA), Drug                                               e have developed strategies to recognize, recruit and
    Abuse (NIDA), and Child Health and Human Development (NICHD), as                                               retain patients with mental disorders presenting with
    well as NIJ and the Office of Juvenile Justice and Delinquency Prevention                                      multiple unexplained symptoms at primary care
    (OJJDP). At present, with support from NIMH, we are conducting a new                                           clinics. An effective treatment strategy specifically
    study to determine the effect of early childhood experiences on subsequent                                     developed to manage these patients is being current-
    development. One of the goals of this challenging project is to look more             ly tested, thanks to a large grant from the National Institute of Mental Health
    closely at the role of stress on physiological responsivity, and we are collecting    (NIMH). Preliminary results appear to be highly satisfactory.




6         THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY
                                                                                                         LEFT TO RIGHT: ANGELICA DIAZ-MARTINEZ, PsyD; LESLEY ALLEN, PhD;
                                                                                                            JAVIER I. ESCOBAR, MD, MS, PROFESSOR AND CHAIR, PSYCHIATRY,
                                                                                                     UMDNJ-ROBERT WOOD JOHNSON MEDICAL SCHOOL; CONNIE HOYOS-NERVI,
                                                                                                                       PsyD; MELISSA WARMAN, PhD; AND MICHAEL GARA, PhD




In efforts to further understand health disparities, we are looking at the            reframe their distress as a consequence of a psychiatric disorder, such as
prevalence of major mental disorders and quality of services offered to               depression or anxiety.
Latino populations both inside and outside New Jersey. These studies are                   These patients have frequent medical visits, and often it appears as if
also funded by NIMH.                                                                  medical care becomes a social support network for them. Paradoxically, they
                                                                                      often display chronic dissatisfaction with the care received, and may even
Somatization                                                                          seek financial compensation for their disability and alleged treatment errors.
Patients presenting with physical symptoms that cannot be satisfactorily              This latter factor, when added to excessive service use, makes somatization
explained by repeated physical and laboratory assessments are common in               one of the most expensive entities in medicine.
primary and specialty care. It is estimated that as many as one-third of                   While the problem of somatization has been variously labeled as hyste-
patients presenting to a primary care provider cannot be diagnosed with a             ria, ennui, hypochondria or neurasthenia, efforts at scientific inquiry have
physical illness.                                                                     begun only recently. In modern diagnostic systems, these disorders are clas-
      A general conception in psychiatry and psychology that has held for             sified among the "somatoform" disorders in psychiatry, while the other
more than a century is that multiple unexplained somatic complaints (somati-          specialties in medicine use labels that incorporate their own jargon. This has
zation) represent the expression of psychological distress in the form of             led to a proliferation of ambiguous terms such as atypical chronic fatigue and




A GENERAL CONCEPTION IN PSYCHIATRY AND PSYCHOLOGY THAT HAS HELD FOR MORE THAN A CENTURY IS THAT
                                      MULTIPLE UNEXPLAINED SOMATIC COMPLAINTS (SOMATIZATION) REPRESENT THE EXPRESSION OF PSYCHOLOGICAL
         DISTRESS IN THE FORM OF UNPLEASANT SOMATIC SENSATIONS INTERPRETED AS SIGNS OF DISEASE.




unpleasant somatic sensations interpreted as signs of disease. Exact mecha-           fibromyalgia, irritable bowel, atypical chest pain, pelvic pain, pseudo-
nisms mediating somatization are unknown. Nonetheless, the subjective                 seizures, atypical Lyme disease, and many others.
experience of having a physical illness is a compelling reality for the patient,           What makes this situation more confusing is that worldwide, a physical
which tends to persist despite reassurance from physicians that there is              symptom is the most common presentation for mental disorders. That is,
nothing physically wrong. Typically, these patients resist any efforts to             unexplained physical symptoms, particularly when appearing in clusters,
                                                                                                                                             continued on page 8



                                                                                   THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY                          7
    continued from page 7


    presage an underlying depression or anxiety problem. What is most intriguing,         ated studies of Latinos presenting to primary care. We are testing a number of
    however, is that once the patient firmly endorses these symptoms, the virulence       diagnostic instruments, assessing patients' mental health status and examining
    of the underlying syndrome worsens and traditional treatments lose punch.             their response to various therapeutic interventions. This represents an active
        Throughout my psychiatric practice, I have been baffled by the refractori-        collaboration with Drs. Denise Rogers and Eric Jahn at the Chandler Health
    ness and chronicity of somatization syndromes, and have examined this                 Center in New Brunswick.
    problem both clinically and epidemiologically. As co-principal investigator of            Finally, in terms of epidemiology, as part of the National Comorbidity
    the Epidemiological Catchment Area study (ECA), a national survey of major            Study, which examines the distribution of major mental disorders in the U.S.



    AN INTERESTING PARADOX IS THAT RECENT LATINO IMMIGRANTS ARE MUCH HEALTHIER THAN THEIR U.S.-BORN COUNTERPARTS,
                                           BUT THESE ADVANTAGES SEEM TO DISSIPATE WHEN THEY CONTINUE TO RESIDE IN THE U.S. AFTER A DECADE.


    mental disorders in the U.S. general population, I described a sub-threshold          population, there has been a recent emphasis on including representative
    cluster of unexplained symptoms known as “Escobar’s abridged somatization.”           samples of Latinos, African-Americans and Asian-Americans. Dr. William
    After coming to RWJMS as chair of psychiatry, I assembled a team of investi-          Vega and I are co-investigators in the study. We will direct the analyses of data
    gators, thus creating the infrastructure of an institute for the study of             on Mexican-Americans, by far the largest Hispanic group in the country.
    unexplained symptoms. It includes Michael Gara, PhD, an experimental social
    psychologist, Robert Woolfolk, PhD, a professor of clinical psychology at             Dr. Javier Escobar received his medical degree at the University of Antioquia
    Rutgers University, and Lesley Allen, PhD, who led a pilot study of a promis-         Medical School. After postgraduate training at the Complutense University in
    ing new intervention called Cognitive Behavioral Therapy (CBT).                       Madrid, he came to the U.S. in 1969. He completed a psychiatry residency and
        Encouraged by positive observations in several patients as well as reports        research fellowship on psychiatric genetics and received a Masters degree in
    supporting the efficacy of CBT on such functional syndromes as fibromyalgia,          psychiatry/medical genetics at the University of Minnesota. In 1994, Dr.
    and chronic fatigue and irritable bowel syndromes, we applied for and received        Escobar became professor and chair of psychiatry at RWJMS. He is currently
    a four-year, $ 1.5 million grant to compare the efficacy of CBT vs. “usual care”      a member of NIMH’s National Advisory Mental Health Council. In addition he
    on 240 primary care patients with high levels of medically unexplained symp-          has been an advisor to the World Health Organization (WHO) and co-director
    toms. I am principal investigator and Dr. Gara is the co-principal investigator       of the North American WHO Collaborating Center. His research focuses on
    of the study. Co-investigators include Drs. Woolfolk, Allen and Paul Lehrer.          epidemiology, diagnosis, clinical psychopharmacology and cross-cultural
    Other key personnel are Drs. Constanza Hoyos-Nervi, Angelica Diaz-Martinez            medicine and psychiatry.   ❧
    and Melissa Warman. Co-investigators from the Department of Family
    Medicine include Drs. David Swee, department chair,
    Beatrix Hamm and Steven Levin, and Eric Jahn from
    Chandler/General Internal Medicine. In just over one
    year, the study has recruited more than 50 patients,
    and thus far, observations have been very positive.
                                                                          New approaches in adult
    Researching mental health disparities
    According to the Census, Latinos are the largest U.S.                 psychopharmacology
    minority. Unfortunately, besides being quite disad-
    vantaged in terms of income, education and insurance
    coverage, minority groups such as Latinos are also
                                                                          research
    affected by significant health disparities. An interest-              by Matthew Menza
    ing paradox is that recent Latino immigrants are much
    healthier than their U.S.-born counterparts, but these
    advantages seem to dissipate when they continue to




                                                                                          P
    reside in the U.S. after a decade. Major health disparities affecting U.S. minor-                       sychopharmacology, the study of the use of medications for
    ity groups are not related to higher prevalence of certain diagnoses as is the case                     mental illness, is one of the most rapidly growing areas in all
    with other medical specialties (e.g., hypertension, diabetes), but unfortunately,                       of pharmacology. Important new drugs released over the past
    to the type and quality of the services they receive. This was clearly document-                        few years have improved the treatment of many psychiatric
    ed in the recent supplement to the Surgeon General's Report.                                            illnesses. Our progress has been made possible by advances
        Thus, disparities in diagnosis have been documented that may result from          in our understanding of the basic neuroscience and biology of mental illness, as
    a physician's bias as well as linguistic and cultural misunderstandings. Because      well as increased sophistication of our clinical research methodology.
    most Latinos with mental disorders do not use specialty mental health care,             Despite this progress, our current treatments for these illnesses leave
    efforts have to be made to study them in primary care settings.                       considerable room for improvement. Of all patients started on current
        Unfortunately, the absence of solid clinical and epidemiological informa-         antidepressants, roughly 70 to 80% will improve, but most will continue to have
    tion on minority populations is a major problem. Our group, which includes            some residual symptoms and impairment. Very few patients with schizophrenia,
    William Vega, Constanza Hoyos-Nervi, Angelica Diaz-Martinez, Teresa                   despite vastly improved medications, will return to work after treatment.
    Miskimen, Humberto Marin, Frank Escobar and Maria Rueda, in coordination                The Division of Clinical Psychopharmacology at UMDNJ-Robert Wood
    with the federally funded Latino Research Program Project (LRPP), has initi-          Johnson Medical School is studying innovative treatments across the range of




8        THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY
                                                                                                          LEFT TO RIGHT: MATTHEW MENZA, MD, CHIEF, DIVISION OF CLINICAL
                                                                                           PSYCHOPHARMACOLOGY AND ASSOCIATE PROFESSOR OF PSYCHIATRY AND NEUROLOGY,
                                                                                                         UMDNJ-ROBERT WOOD JOHNSON MEDICAL SCHOOL, AND CO-EDITOR;
                                                                                                        RACHEL SOKOL-OPPER, PhD; BETTY VREELAND, MSN, RN; ED KIM, MD;
                                                                                                                                            AND HUMBERTO MARIN, MD




adult psychiatric illnesses, including depression, schizophrenia, attention          modify central stress reactions, and MK-0869 is the first substance P blocker to
deficit/hyperactivity disorder, anxiety disorders (including posttraumatic           reach large-scale clinical trials.
stress disorder), traumatic brain disorders, sexual dysfunction and manic                 Another interesting approach, called augmentation, involves the addition
depressive illness. This article highlights some of our research.                    of a second medication to the primary antidepressant. We have studied medica-
                                                                                     tions from different classes, such as atypical antipsychotics and stimulants. This
Depression                                                                           approach can be very useful for some patients.
Depressive disorders are serious, disabling illnesses. It is estimated that one in
five individuals are affected by a mood disorder in his or her lifetime. The eco-    Residual symptoms in depression. We have focused on patients who have
nomic costs are enormous. In the U.S. alone, the estimated monetary costs for        had some positive response to treatment but continue to have significant



 DEPRESSIVE DISORDERS, INCLUDING MAJOR DEPRESSION AND DYSTHYMIA, ARE SERIOUS, DISABLING ILLNESSES. IT IS
                                                   ESTIMATED THAT ONE IN FIVE INDIVIDUALS ARE AFFECTED BY A MOOD DISORDER IN HIS OR HER LIFETIME.


depression exceeded $44 billion in 1990. Higher mortality and impairment in          symptoms, including fatigue, anxiety, sleep problems or sexual dysfunc-
multiple areas of functioning reflect the personal costs.                            tion. Dr. Rachel Opper, a postdoctoral fellow in our division, recently
     Most patients who are treated with currently available antidepressants          received a grant to study the effects of a cognitive behavioral therapy in
derive some benefit from these medications. However, roughly 20% are not             patients with treated depression who are still fatigued. The treatment will
helped by antidepressants and of those who do derive benefit, the majority           focus on changing lifestyle habits that may contribute to ongoing fatigue.
continues to have symptoms or side effects. Our research group has focused on
these patients who have not done well on available treatments.                       Depression and Parkinson’s disease. Depression is found in about 40%
                                                                                     of those with Parkinson’s disease, causing personal suffering, impairing
Treatment-resistant depression. We have focused on novel treatments and              functioning and appearing to speed the worsening of movements and
additive treatments, including a very interesting new medication: a substance P      memory. The use of antidepressants is not well understood in these
(NK1-receptor) blocker, called MK-0869, made by Merck. There has been a lot          patients and we have conducted a series of trials to help to understand
of excitement in the field regarding this class of drug, which is thought to         their use.

                                                                                                                                             continued on page 10



                                                                                         THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY                             9
     continued from page 9


     Sexual dysfunction and depression. In conjunction with RWJMS researcher                terrorist incidents, serious accidents, or violent personal assaults like rape.
     Dr. Ray Rosen’s sexual dysfunction group, we have investigated the                     People who suffer from PTSD often relive the experience through nightmares
     interrelationship between sexual dysfunction and depression. In an article             and flashbacks, have difficulty sleeping, and feel detached or estranged. We are
     published in the American Journal of Psychiatry in 2001, we showed that the            currently conducting a trial of an antidepressant, venlafaxine, in these patients.
     treatment of erectile dysfunction in men with depression was effective and
     also improved the depression significantly.                                            Matthew     Menza,      MD,     is   chief   of   the   Division   of   Clinical
                                                                                            Psychopharmacology and an associate professor of psychiatry and neurol-
     Attention deficit/hyperactivity disorder in adults (ADHD). Approximately               ogy at RWJMS. He attended Temple University Medical School and did his
     4% to 6% of the U.S. population has ADHD, which usually persists through-              residency training at NYU/Bellevue Hospital. He also completed a fellow-
     out a person’s lifetime. It is not limited to children. Approximately one-half to      ship in psychosomatic medicine at Harvard/Massachusetts General
     two-thirds of children with ADHD will continue to have significant problems            Hospital. He is Vice-Chair for Research in the Department of Psychiatry,
     with symptoms and behaviors as adults. We have focused on new treatments in            and his research focus is in general psychopharmacology as well as in the
     this disorder and have been involved in the development of a novel compound,           psychiatric aspects of Parkinson’s disease. ❧
     atomoxetine, a norepinephrine reuptake inhibitor currently being evaluated for
     use by the FDA.

                                                                                            FOR FURTHER INFORMATION, PLEASE VISIT OUR WEBSITE AT WWW.UMDNJ.EDU
     Schizophrenia
     Schizophrenia is a chronic, severe, and disabling brain disease, found all over
     the world. More than 2 million Americans suffer from the illness in a given
     year. People with schizophrenia often experience
     terrifying symptoms, such as hearing internal
     voices not heard by others, or believing that other
     people are reading their minds, controlling their
     thoughts, or plotting to harm them. Available
                                                                    Do thyroid hormones
     treatments can relieve many symptoms, but most
     people with schizophrenia continue to suffer
     symptoms throughout their lives; it has been esti-
                                                                    treat depression?
     mated that no more than one in five individuals                by R u s s e l l T. J o f f e
     recovers completely.
         This is a time of hope for people with
     schizophrenia and their families. As research gradually leads to new and                                  ntidepressants are the main treatment for major depression
     safer medications and unravels the complex causes of the disease, we have
     been involved in several studies. Dr. Robert Stern has been investigating the
     use of a novel medication, aripiprasole, in the treatment of patients who have
     not responded well to currently available treatments. This new medication
     works in a wholly unique way and may be highly beneficial; its use is cur-
     rently being reviewed by the FDA.
         One of the most significant health problems facing patients with schizo-
                                                                                           A                   but are only partially effective. Thyroid hormones, particu-
                                                                                                               larly triiodothyronine (T3) may augment antidepressant
                                                                                                               responses. T3 may differ from thyroxine (T4) in this
                                                                                                               effect. Understanding the mechanism of action of
                                                                                            thyroid hormones in depression may help in the understanding of the
                                                                                            biology of depression.


     phrenia is obesity and the related disorders of diabetes, hypertension and                  Major depression is a chronic and recurrent psychiatric disorder affect-
     cardiovascular disease. Betty Vreeland, APN, received a grant to study the use         ing about 5 to 10% of the population. It has a high mortality rate mostly
     of motivation, diet and exercise for weight control, and her results suggest that      associated with suicide. Major depressive disorder places a significant burden
     it is possible for schizophrenic patients to lose weight with these methods.           of suffering on patients and their families, and the medical outcomes study
     Dr. Humberto Marin, our psychopharmacology fellow, is studying the effect of           carried out by the RAND Corporation concluded that major depressive
     changing medications on the weight, lipid profile and insulin measures in obese        disorder caused a degree of global dysfunction comparable to other major
     schizophrenic patients. It is hoped that the results of this study will help guide     medical illnesses such as cardiovascular disease and more than other chronic
     medication selection in these patients.                                                illnesses such as diabetes or arthritis.
                                                                                                 Antidepressants of several different classes are the primary treatment for
     Acquired brain injury                                                                  major depressive disorder. However, even if given optimally, there are two main
     Dr. Ed Kim is interested in the neurobehavioral consequences of acquired brain         challenges in the treatment of the depressed patient. First, only about half of
     injury (ABI) due to stroke and traumatic brain injuries (TBI). He currently has        depressed patients will have a complete and sustained response to the first anti-
     two funded studies to investigate the use of olanzapine, an antipsychotic, and         depressant used. Even with successive antidepressant trials, a substantial
     oxcarbazepine, an anticonvulsant, to reduce agitation and aggression due to            minority of depressed patients will fail to respond or have an incomplete
     brain injury. He is also studying the prevalence and severity of prior head            response to antidepressant therapy. Second, with all classes of antidepressants,
     injuries in psychiatric inpatients and in the efficacy of cholinesterase inhibitors    about 4 to 6 weeks of therapy is required to achieve a complete response. This
     to improve cognitive functioning in patients with ABI.                                 lag in onset of therapeutic action poses a great challenge for the treating physi-
                                                                                            cian as the patient continues to be profoundly depressed, dysfunctional, and
     Posttraumatic stress disorder (PTSD)                                                   often suicidal.
     PTSD is a psychiatric disorder that can occur following the experience or                   Over the last 150 years, there have been rich clinical descriptions in the
     witnessing of life-threatening events such as military combat, natural disasters,      scientific literature of the association between clinical thyroid disease and




10        THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY
                                                                                                            RUSSELL T. JOFFE, MD, DEAN AND PROFESSOR OF PSYCHIATRY
                                                                                                                               AT UMDNJ-NEW JERSEY MEDICAL SCHOOL




psychiatric symptomatology. In particular, the relationship between                    Although all these studies had serious methodological limitations, their
depression and clinical hypothyroidism has been well described. This              conclusions were remarkably consistent. However, the use of T3, either as a
prompted investigators in the 1960s, when there were few treatment                strategy to accelerate or augment antidepressant response, never achieved
options for depression, to propose the use of thyroid hormones for the treat-     widespread clinical utility. In the case of antidepressant augmentation, other
ment of depression. They suggested that these hormones may have a                 strategies, particularly the use of lithium, achieved widespread use. For many
therapeutic benefit in depressed patients based on the observation that in        years it was widely accepted clinical lore that lithium was the most effective
clinical hypothyroidism depressive symptoms frequently resolved with treat-       antidepressant augmentation strategy and certainly more effective than T3. Our
ment of the underlying endocrine disorder. Early studies using thyroid            studies were the first to confirm the augmentation effects of T3 using rigorous-
hormone alone proved to be inconclusive, although these early studies would       ly designed clinical trial methodology and also to directly compare the
not meet the current standards for definition of depressed patients nor would     augmentation effect of lithium and T3, showing them to be comparably



              THE MEDICAL OUTCOMES STUDY CARRIED OUT BY THE RAND CORPORATION CONCLUDED THAT
MAJOR DEPRESSIVE DISORDER CAUSED A DEGREE OF GLOBAL DYSFUNCTION COMPARABLE TO OTHER MAJOR MEDICAL ILLNESSES SUCH AS CARDIOVASCULAR
                                                DISEASE AND MORE THAN OTHER CHRONIC ILLNESSES SUCH AS DIABETES OR ARTHRITIS.


they meet the current standards for design of an antidepressant clinical trial.   effective. As T3 is generally safe and better tolerated than lithium, we have
These early investigators did, however, make two important preliminary            established a much more substantial database to support the use of T3 as an
observations. First, in several small studies in the late 1960s, they observed    augmentation strategy for antidepressant nonresponders.
that the addition of the thyroid hormone triiodothyronine (T3) at the out-             The antidepressant accelerating effect of T3 has been largely ignored
set of an antidepressant trial accelerated the therapeutic response to the        since initial observations in 1970. This is surprising, considering that there
antidepressant, reducing the delay in onset of action from weeks to days,         has been a substantial effort both from scientists and the pharmaceutical
particularly in women. These observations were supported by other inves-          industry to reduce the lag in therapeutic onset of antidepressants. In a recent
tigators in studies published during the 1970s. Second, they also showed          meta-analysis, Altshuler and collaborators from UCLA showed that there
that adding T3 when a patient had failed to respond to an antidepressant          was a significant antidepressant accelerating effect of T3 in these early
produced a therapeutic benefit in approximately one-half to two-thirds of         studies. The promising effect of T3 is being pursued by our group to
cases. This augmentation of antidepressant response was supported by              determine whether it has clinical utility in reducing the delay in therapeutic
several studies over the next 25 years.                                           response to antidepressants.

                                                                                                                                               continued on page 12



                                                                                          THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY                        11
     continued from page 11


         In the early studies, T3 rather than thyroxine (T4) was used, mainly for        actually experience about one-half the risk of a lifetime mental disorder
     pragmatic reasons. T3 has a half-life of approximately eight hours, whereas         compared to the U.S. population. How do we resolve such powerful contradic-
     T4 has a half-life of one week. The early investigators considered that if there    tions? These results have important implications for scientific research about
     were any unwanted side effects of their experimental treatment, the shorter         causes and treatments of mental illness as we face the greatest wave of
     half-life of T3 would prove less problematic. It had always been assumed that       immigration in U.S. history since Ellis Island was a turnstile for Europe’s
     T4 would have similar antidepressant effects to T3, bearing in mind that T4         dispossessed a century ago.
     is often considered a pro-hormone and that T3 is broadly regarded as the
     active thyroid hormone. We were the first to directly compare the antide-                Reconciling that very poor immigrants with low access to healthcare
     pressant augmentation effect of T3 and T4. We showed T3 to be superior to           can have superior mental health undermines the foundation of psychiatric
     T4 in a controlled clinical trial. Although this controversial finding requires     epidemiology; thus, it has been referred to as the Hispanic Paradox. My
     further study, the observation has raised several important issues. First, it       studies indicate that the most common psychiatric disorders, depression,
     may well be that in the brain, T4 and T3 have a differential effect on brain        anxiety, and substance dependence, are 40% to 60% less likely to occur in
     thyroid hormone levels and therefore on mood and cognition. A recent study          the lifetimes of Hispanic immigrants than in the U.S. population. These rates
     by Bunevicius and colleagues in the New England Journal of Medicine                 do increase with time spent in U.S. residence. Some epidemiologists believe
     concluded that T3 and T4 replacement therapy may also have                          the explanation is selective migration — only the fittest would undertake to
     differential effects on mood and cognition in patients receiving replacement        leave their homelands and settle in a new nation with different customs and
     therapy for clinical hypothyroidism. This finding indirectly supports our           language. When I was professor of public health at the University of
     observation in depressed patients. Second, it also raises the issue of whether      California at Berkeley, I used comparative studies to negate the selective
     there is a specific perturbation of the thyroid axis in depressive illness. Last,   migration explanation. Mexicans with less than a decade in the United States
     the mechanism of action of T3, both in accelerating and augmenting antide-          had similar rates of psychiatric disorders as residents of Mexico City.
     pressant effect, requires further clarification and study. It remains to be         Mexican Americans who were born in the U.S. had rates that were virtually
     determined whether the therapeutic benefit of this hormone is related to            identical to the U.S. population. To better understand how this vulnerability
     correction of some underlying abnormality of the thyroid axis in these              to behavioral health problems develops I conducted a longitudinal study of
     patients or whether the benefit achieved is a pharmacological effect analo-         Hispanic, African American, and European adolescents. The results are highly
     gous to the use of steroids to treat various autoimmune or dermatological           informative in showing how environmental, family, and adolescent stressors
     conditions. Both issues are being actively explored by our group. These are         are related and affect the psychological well being of Hispanic
     important questions in their own right, but once elucidated may also provide        children. It is also clear that ethnicity influences age of onset for drug use,
     us with clues about the etiology of depression, which to date remains elusive.      risk and protective factors. Immigrants who arrive as children have greater
          This work was completed with the important collaboration of Dr. William        vulnerability to psychiatric disorders and substance abuse dependence than
     Singer, associate professor of medicine (endocrinology) and Dr. Anthony Levitt,     immigrants who arrive in adulthood.
     associate professor of psychiatry, at the University of Toronto.                          Population prevention research is a natural extension of epidemiology. I
                                                                                         have developed and conducted multiple large-scale community trials with
     Dr. Russell Joffe is Dean and Professor of Psychiatry at NJMS. His clinical         diverse aims: preventing depressive symptoms among low-income Hispanic
     and research interests are in the refractory mood disorders and the role of         women, improving birth outcomes among impoverished Hispanic adolescents
     thyroid hormones in the biology of mood disorders. ❧                                in situations of social isolation, and testing cardiovascular risk reduction strate-
                                                                                         gies with Hispanics and European American families. Currently, I am a
                                                                                         co-investigator in a NIH-sponsored intervention to prevent violence among
     FOR FURTHER INFORMATION, PLEASE VISIT OUR WEBSITE AT WWW.UMDNJ.EDU
                                                                                         African American adolescents that is headed by my colleague Dr. Paulette
                                                                                                        Hines. I believe prevention offers the best hope of making a
                                                                                                        major reduction in population behavioral disorders and prob-
                                                                                                        lems. Because of this strong commitment to prevention, I was a
                                                                                                        co-founder and now serve as president of the National Latino
                                                                                                        Council on Tobacco and Alcohol Prevention.

     Exploring the                                                                                            One of the most important reasons for estimating rates of
                                                                                                        psychiatric disorders in the community is to assess the need for


     Hispanic paradox                                                                                   services. My studies have shown that a miniscule percentage of
                                                                                                        immigrants receive mental health treatment for recent psychi-
                                                                                                        atric disorders. For every individual who uses a mental health
                                                                                                        specialist, nine others use primary care. The barriers are sever-
     by W i l l i a m A . Ve g a
                                                                                                        al, and include more than just the absence of insurance. These
                                                                                                        studies have pointed out how complex the issue of improving
                       tudies of mental hospital patients 80 years ago concluded that    access to care really can be when issues such as lack of information, insur-




     S                 immigrants were highly prone to mental illnesses and this
                       information was used to support federal legislation to stem
                       the tide of European and Asian immigration. Fifty years ago
                       the first community psychiatric surveys in New York City
     reported that the poorest sector of the population, including immigrants, expe-
     rienced the greatest vulnerability to mental health problems. My research has
                                                                                         ance, fear, discrimination, stigma, scarcity of transportation, and language
                                                                                         barriers are present. Similar issues influence the quality of treatment, yet these
                                                                                         issues have remained fundamentally neglected in research for many decades.
                                                                                         It was this realization that led me to accept a position two years ago as a pro-
                                                                                         fessor of psychiatry at RWJMS.
                                                                                              As director of the Behavioral Research and Training Institute of
     shown that exactly the opposite is true for Latin American immigrants, who          University Behavioral HealthCare (UBHC) I have initiated, along with




12         THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY
                                                                                                                  WILLIAM A.VEGA, PhD, PROFESSOR OF PSYCHIATRY,
                                                                                                    UMDNJ-ROBERT WOOD JOHNSON MEDICAL SCHOOL AND DIRECTOR,
                                                                                   BEHAVIORAL RESEARCH AND TRAINING INSTITUTE, UNIVERSITY BEHAVIORAL HEALTHCARE




colleagues Drs. Shula Minsky and Michael Gara, a program of services          culturally competent clinical care. I believe the Institute provides a unique
and treatment studies using the UBHC database. I am also heading a large      and outstanding opportunity to fill this vacuum with a research-supported
research project, with Jeffrey Merrill and Douglas Ziedonis, to address       training program using state-of- the-art media technology for dissemina-
disparities in health services and treatment among European American,         tion. The target is improved outcomes based on improved diagnostic
African American, and Hispanic heroin addicts in New Jersey. Jeffrey          procedures, medication management, and treatment adherence across




RECONCILING THAT VERY POOR IMMIGRANTS WITH LOW ACCESS TO HEALTHCARE CAN HAVE SUPERIOR MENTAL HEALTH UNDERMINES
                                           THE FOUNDATION OF PSYCHIATRIC EPIDEMIOLOGY; THUS, IT HAS BEEN REFERRED TO AS THE HISPANIC PARADOX.


Merrill, Javier Escobar and I are developing an international study for       ethnic lines. Although UBHC is the intended user for these products
estimating cost and need for substance abuse and addiction services in 14     through the Institute’s internal training program, a manualized approach
Latin American nations supported by international agencies. I am a            would permit other end users to implement our program using our Web site
co-principal investigator with Dr. Escobar in a national epidemiologic        and an interactive CD-ROM.
study that will estimate rates of major disorders and services utilization
patterns among Hispanics and Asians in the U.S. The results will be           William A. Vega, PhD, is a professor of psychiatry at RWJMS and Director,
comparable to other studies currently underway in the U.S., sponsored by      Behavioral Research and Training Institute, UBHC. He has conducted field
the NIH, and in 24 other nations. I was a co-founder of the International     research projects about health, mental health, and substance abuse across the U.S.
Consortium of Psychiatric Epidemiology, situated at Harvard, which was        and internationally. His studies have collected data on more than 100,000 respon-
instrumental in launching this global research initiative.                    dents and resulted in feature articles in the New England Journal of Medicine and
     My vision for the Behavioral Research and Training Institute is to       Archives of General Psychiatry. His specialty is psychiatric epidemiology, includ-
integrate training and research. I want to focus on three areas, public       ing substance abuse, and mental health services research in a cross-cultural
mental health in the community, services research, and treatment outcome      context. He has published more than 120 articles and chapters as well as several
studies. One goal is to develop a NIH-funded research program, and to         books. Before coming to UMDNJ he was a professor of public health at the
link findings to our established training programs. A second goal is to       University of California, Berkeley, where he received his doctorate degree. ❧
develop a clinical cultural competency research and training program.
Despite the proliferation of cultural competency and disparities-oriented
                                                                              FOR FURTHER INFORMATION, PLEASE VISIT OUR WEBSITE AT WWW.UMDNJ.EDU
research literature, there is no evidence-based, best practices program for




                                                                                       THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY                        13
                                                                                                                  AT LEFT: DANIEL COWEN, MD, PhD, ASSISTANT PROFESSOR, PSYCHIATRY
                                                                                                    AND NEUROSCIENCE & CELL BIOLOGY, UMDNJ-ROBERT WOOD JOHNSON MEDICAL SCHOOL

                                                                                                    ABOVE: PAUL MANOWITZ, PhD, PROFESSOR OF PSYCHIATRY AND ADJUNCT PROFESSOR OF
                                                                                                                      NEUROLOGY AT UMDNJ-ROBERT WOOD JOHNSON MEDICAL SCHOOL




     Neuroscience and                                                                                one of which might be required. We grow cells in culture dishes to


                              approaches
                                                                                                     study the cellular signals elicited by activation of those receptors.

     genetic                                                                                         Specifically, we look at activation of signals that we think might be
                                                                                                     important for the actions of antidepressants.


     to psychiatric                                                                                       As a psychiatrist whose career combines clinical practice and
                                                                                                     basic research, my interest in improving the treatment of depression is



     diseases
                                                                                                     the inspiration for my work. Although many antidepressants are
                                                                                                     available, none is truly optimal. Each takes weeks for onset of efficacy,
                                                                                                     and each has only a 60 to 70% response rate. A stumbling block to
                                                                                                     designing more effective antidepressants is a lack of knowledge of
     by    Daniel Cowen and Paul Manowitz                                                            how current antidepressants treat depression.
                                                                                                          However, as a starting point, we do know that medications which
                                                                                                     selectively increase the neurotransmitter serotonin (5-HT) are effec-
                    wo of the great mysteries in psychiatry are: 1) How do                  tive antidepressants. Therefore, I have focused my efforts on answering two




     T              psychotherapeutic medications exert their effects? and 2) Which
                    genes increase susceptibility to psychiatric disorders? Two mem-
                    bers of the Department of Psychiatry at UMDNJ-Robert Wood
                    Johnson Medical School (RWJMS) are pursuing biologically-
     based research to find answers to these questions. Regarding the first mystery,
     Dr. Daniel Cowen is studying signal transduction pathways that are involved in
                                                                                            very specific questions relevant to understanding the mechanism of action of
                                                                                            these antidepressants: 1) Which cellular signals are modulated by receptors for
                                                                                            5-HT? and 2) Why are there so many receptors for 5-HT (at least 16)?
                                                                                                Concerning the first question, I am most interested in identifying cou-
                                                                                            pling of receptors to signals known to activate protein synthesis. Changes in
                                                                                            neuronal protein synthesis are induced by treatment with antidepressants,
     the pharmacological effects of antidepressants. Concerning the second mystery,         and are thought to mediate the long-term effects of antidepressants.
     Dr. Paul Manowitz and his colleagues have tentatively identified a gene predis-        Traditionally, nerve growth factors (neurotrophins), including brain-derived
     posing to alcoholism and are in the process of verifying this finding.                 neurotrophic factor (BDNF), have been associated with such long-term
                                                                                            changes, while monoamines, such as 5-HT, have been associated with short-
     Daniel Cowen: Signal Transduction Pathways                                             term intracellular changes. However, our studies have been designed to
     My lab is interested in better understanding how antidepressants work. The             demonstrate that 5-HT can, in fact, activate many of the pathways known to
     newer medications are known to selectively increase levels of the brain chemi-         mediate the actions of neurotrophins. Two such pathways are Akt (protein
     cal serotonin. However, not much is known after that. There are at least 16            kinase B) and the ERK MAP kinases which inhibit apoptosis (programmed
     receptors (proteins on the surface of cells that act as antennas) for serotonin, any   cell death) and are required for normal neuronal function. Our studies have



14         THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY
demonstrated that 5-HT1 receptors couple to activation of both of these path-                                 This enzyme is of particular interest because of its link to human
ways, as well as activation of p70 S6 kinase and NF-κB, two pathways similarly                       behaviors. Severe deficiency of this enzyme activity leads to metachro-
associated with cell survival. Additionally, we have found that 5 - HT7 receptors                    matic leukodystrophy, a neurological disease. The initial symptoms of the
couple to activation of ERK in hippocampal neurons. In summary, these find-                          adult form of this disease are psychiatric in nature and may include
ings show that receptors for 5-HT can                                                                                                                 attentional problems, hyperactivity,
directly activate many of the cellular                                                                                                                impulsivity, and emotional liability.
pathways activated by neurotrophins that                                                                                                              Many of these same symptoms are
are known to be neuro-protective and                                                                                                                  observed in alcoholic patients. In the
postulated to be relevant to the actions of                                                                                                           adult form of metachromatic leukody-
antidepressants.                                                                                                                                      strophy, these psychiatric symptoms
     Regarding the second focus of my                                                                                                                 may last decades before the onset of
lab, receptors for 5-HT are currently                                                                                                                 neurological symptoms.
grouped into seven families based, in                                                                                                                      Arylsulfatase A, a lysosomal
part, on their coupling to intracellular                                                                                                              glycoprotein, is a key enzyme in the
signals. For example, all 5-HT1 receptors                                                                                                             degradation of sulfatides, a major
(5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and                                                                                                                  component of myelin in the nervous
5-HT1F) couple to inhibition of adenylyl                                                                                                              system. The mutation results in an
cyclase, and a consequent decrease in                                                                                                                 enzyme that lacks an attachment site
cyclic AMP. My hypothesis has been that                                                                                                               for an oligosaccharide and results in
although all of the receptors within a                                                                                                                an approximately 50% decrease in
family couple to the particular signal                                                                                                                enzyme activity compared to wild type
required for that classification (e.g.,                                                                                                               enzyme in cultured human fibroblasts.
                                                       Fig. 1. A molecular model of arylsulfatase A. Dr. Manowitz has
cyclic AMP), they may not all couple to                                                                                                                    My current research, funded by a
                                                       proposed that a variant of this enzyme is a susceptibility factor
other individual signals. My lab has                   for alcoholism.                                                                                grant from the National Institute on
identified functional differences in sub-                                                                                                             Alcohol Abuse and Alcoholism, is to
types of 5-HT1 receptors. We have                                                                                                                     study this genetic mutation in alcoholics
demonstrated that although 5-HT1A,                                                                                                                    and their siblings. This research will
5-HT1B and 5-HT1D receptors all utilize                                                                                                               not only examine the mutation’s
G proteins within the Gi family, they                             N-Glycosylation Site                          Poly-A Signal Site                    hypothesized relationship with alco-
                                                       G ATC             G ATC           G ATC       G ATC          G ATC              G ATC
exhibit differences in selectivity regard-                                                                                                            holism, but also its relationship with
                                                 G                                                                                               C
ing subtypes of Gi. These results suggest        G                                                                                               T
                                                                                                                                                 A
                                                                                                                                                      behavioral/neuropsychological deficits.
                                                 T
                                                 T                                                                                               T
differences in coupling to cellular              C                                                                                               T        Identifying genes that increase
                                                 C                                                                                               G
signals. In fact, we have found in trans-        A                                                                                               C    susceptibility to alcoholism may enable
                                                 C                                                                                               A
                                                 T                                                                                               T
fected cells that 5-HT1B receptors couple        G                                                                                               C*   the development of improved prevention
                                                 T                                                                                               A
more efficiently to activation of ERK            A*                                                                                              T    and treatment strategies, including phar-
                                                 A                                                                                               T
                                                 C                                                                                               G
MAP kinases and to inhibition of                 C                                                                                               T    macogenomic approaches to treatment.
                                                 C                                                                                               G
adenylyl cyclase than do 5-HT1A recep-           G                                                                                               G
                                                                                                                                                 T
                                                                                                                                                 C
tors. Identification of such differences                 Subj.1           Subj.2         Subj.2      Subj.1          Subj.2           Subj.2
                                                                                                                                                      Dr. Daniel Cowen received his PhD in 1989
                                                                         clone ‘a’       clone ‘b’                  clone ‘a’        clone ‘b’
may be relevant to understanding the                                                                                                                  and MD in 1991 from the NIH-sponsored
pathology of depression and improving                   Fig. 2. Autoradiograph of DNA sequence analysis of genomic                                    Medical Scientist Training Program at Case
its treatment.                                          clones from individuals with an arylsulfatase A mutation.                                     Western Reserve University School of
                                                                                                                                                      Medicine. He did his residency training in
Paul Manowitz: Identification of                                                                                                                      psychiatry and a fellowship in neuropsy-
Alcoholism Susceptibility Genes                                                                                                                       chopharmacology at the Hospital of the
     I am interested in finding out what factors a person inherits from his                          University of Pennsylvania. He is currently an assistant professor of psychiatry and neu-
or her parents that may influence whether that person becomes an                                     roscience & cell biology at RWJMS. Also contributing to Dr. Cowen’s research at
alcoholic. If these factors were identified, this would potentially aid in the                       UMDNJ are Dr. Stanley Lin and Nadine Farley.
diagnosis, prevention and treatment of alcoholism.                                                            Dr. Paul Manowitz is a professor of psychiatry and adjunct professor of neurol-
     Previous research, based primarily on twin and adoption studies, has                            ogy at RWJMS, visiting professor at the Center of Alcohol Studies of Rutgers
demonstrated the role of genetic factors in alcoholism. However, the number                          University, and a research consultant at the Veterans Administration New Jersey
and identity of the genes in alcoholism are unknown. Like most complex                               Health Care System. He has been a member of the editorial board of the Journal of
diseases, it is likely that mutations of several different genes increase                            Studies on Alcohol since 1993. He came to RWJMS in 1972 and published his first
susceptibility to alcoholism.                                                                        article on arylsulfatase A in 1977. He has pursued research on the relationship
     My research has led to the identification of a mutation in the arylsul-                         between genetic abnormalities in arylsulfatase A and psychiatric disorders ever since
fatase A gene that occurs more frequently in alcoholics than in control                              then. Also contributing to Dr. Manowitz’s research at UMDNJ are: Lai-Yoong Wong,
subjects. Initially, this was found in a Veteran Administration (VA)                                 Sheryl Zeger, Smith Jean, William Sribney, and Drs. Srinivasa Raghavan,
population. More recently, this result has been verified in a Korean                                 Chinnaswamy Kasinathan, and Douglas Ziedonis. ❧
population. The latter was chosen for study because Korea has a relatively
                                                                                                     FOR FURTHER INFORMATION, PLEASE VISIT OUR WEBSITE AT WWW.UMDNJ.EDU
homogeneous racial/ethnic population, apparently without subpopulations.




                                                                                                          THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY                                     15
                                                                                                                      TOP RIGHT, CLOCKWISE: STEVEN SCHLEIFER, MD, PROFESSOR,
                                                                                              DEPARTMENT OF PSYCHIATRY, UMDNJ-NEW JERSEY MEDICAL SCHOOL; ANNE BARTLETT, MD;
                                                                                                                                 STEVEN KELLER, PhD; AND STEVEN ZALCMAN, PhD




     Behavior & the immune system:                                                                                                experiences and psychiatric disorders


     influences & interactions
                                                                                                                                  such as depression on the immune
                                                                                                                                  system. Reciprocal effects on behavior of
                                                                                                                                  immune mediators (cytokines) such as
                                                                                                                                  Interleukin-2, Interleukin-6, interferon,
     by    Steven Schleifer
                                                                                                                                  and TNFα have also been investigated.
                                                                                                                                  Current psychoneuroimmunology (PNI)




     T
                    here is considerable scientific information and increasing           research has implications for understanding the onset and course of a range of dis-
                     general interest in the bidirectional relationship between the      eases, including infections, cancer, and autoimmune disorders. These disorders
                    brain and psychological states and somatic systems. Early            have, in turn, been associated with behavioral changes and psychopathology.
                    psychosomatic concepts asserted that brain and behavioral            Recently, psychological effects of immunotherapies for these disorders have
                    states had important influences only on certain diseases, and        come under clinical investigation and can also serve as a model for the study of
     postulated psychodynamic mechanisms for such effects. It is increasingly            CNS-immune interactions.
     apparent that the brain, states of mind and behavior, as well as psychiatric
     symptoms and syndromes, have the potential to influence the full panoply of         Effects of Stress and Depression on Immunity
     medical disorders through effects on numerous physiological systems.                For more than 25 years, our group has worked to delineate behavioral factors
     Among these, the immune system has been of particular interest. In addition         influencing the immune system. Of special interest has been the “family” of




               IT IS INCREASINGLY APPARENT THAT THE BRAIN, STATES OF MIND AND BEHAVIOR, AS WELL AS PSYCHIATRIC SYMPTOMS AND SYNDROMES, HAVE
     THE POTENTIAL TO INFLUENCE THE FULL PANOPLY OF MEDICAL DISORDERS THROUGH EFFECTS ON NUMEROUS PHYSIOLOGICAL SYSTEMS.


     to CNS effects on immunity, it has also become apparent that,                       depressive states, including clinical depressive disorders, normal grief, stress
     conversely, immune activation (itself a consequence of infection and other          reactions, and depression induced by hormones (e.g., corticosteroids) or other
     diseases) influences the brain and emotional and cognitive states. Faculty of the   factors such as cytokines. Early studies I conducted with Dr. Steven Keller
     Department of Psychiatry at UMDNJ-New Jersey Medical School (NJMS) have             found that bereavement was associated with decreased lymphocyte prolifera-
     been among the pioneers in these areas, studying the impact of stressful life       tion. Since major depressive disorder is phenomenologically similar to normal




16         THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY
grief, we conducted similar studies with depressed patients, and found            coexisting depression. We found that the severity of the patient’s pain and
changes comparable to those seen in the bereaved. However, the associa-           depressive symptoms each contributed to decreased lymphocyte prolifera-
tion of depression with altered immunity was linked to the severity of the        tion. Another group we studied, persons with chronic alcohol dependence,
depression and the age of the patient. While increasing severity of depres-       also suffer high rates of depression and increased susceptibility to infections
sive symptoms was associated with progressively decreased lymphocyte              and other medical disorders. However, inner-city homeless alcoholics, in
activity, age-related interactions revealed decreased lymphocyte activation       contrast to abusers of other substances, had surprisingly low rates of HIV
and CD4+ cells in older depressed persons but increased activation in             infection. This appears to be attributable to less risky sexual behaviors among
younger depressives. These studies have been extended to new samples of           those who abuse alcohol exclusively compared with other substance abusers,
younger adults, children and adolescents (described below).                       and may also relate to the state of the immune system in alcoholics.
     We have also asked whether immune system changes are specific to             Alterations in immune measures in chronic alcoholics were surprisingly
depression or a common consequence of human stress and distress. We have          modest, with substantial immune decrements appearing only with the devel-
studied patients with other psychiatric disorders, schizophrenia and panic dis-   opment of the medical sequelae of alcoholism (e.g., liver damage).
order. In both patient groups, in contrast to depressed patients, we found few         The complex interaction of psychological states, medical disorders, and
or no differences in a broad battery of immune measures compared with             immunity has been of interest to the newest member of our group, Dr. Denise
matched control subjects. We also examined family members of patients             Dixon, a health psychologist who recently completed an NIH postdoctoral
brought to UMDNJ-University Hospital for life-threatening trauma. During          fellowship in PNI. Focusing on minority populations, Dr. Dixon has studied
the first few days following trauma, we found decreased lymphocyte prolifer-      social support as a predictor of HIV sexual risk behavior among Puerto Rican
ation, but only among those who reacted to the stress with feelings of            women, and has investigated the buffering effects of social support on PTSD
depression. Family members who showed predominantly symptoms of anxi-             symptoms and HHV-6 antibody titers in HIV+ gay men (following Hurricane
ety tended to have increased lymphocyte activity. A different pattern was         Andrew). She has also studied the interaction of obesity, stress and immunity in
noted, however, for another immune measure, natural killer (NK) cell activity,    Latino children. In the latter studies, Dr. Dixon found, contrary to findings in
for which decreased activity was found among all stressed family members.         adults, that the cytokine TNF-α was higher in non-obese than obese children,
Effects of stress on the immune system therefore appear to be specific to         although obesity was associated with greater insulin resistance.
certain types of mental distress as well as to specific immune measures.
                                                                                  Immune System Effects on Brain and Behavior
Developmental Psychoneuroimmunology                                               Studies of the short- and long-term effects of the immune response and
Most early PNI studies in humans were undertaken in adults. Our work at           cytokine challenge on brain neurochemistry have been conducted by
NJMS was among the first to investigate stress, depression, and immune            Dr. Steve Zalcman. He has focused on behavioral effects of immune activa-
function in children and adolescents. In earlier work, we found that an           tion in animals including stereotyped behavior, exploration, and cognitive
early life stress, premature maternal separation (in rat pups), led to lifelong   performance. These behaviors are relevant to the pathophysiology of
decrements in immune function and disease resistance. Our findings, noted         disorders such as autism, schizophrenia, depression, and Parkinson’s disease.
above, that effects of depression on immunity were age-dependent across           Viruses and bacteria have long been suspected of triggering behavioral
the adult life span further supported the need to assess patterns of depres-      changes, including profound psychiatric abnormalities, and these changes
sion-related immune change in childhood.                                          have been linked to the immune activation triggered by infection. Cytokines
     Childhood depression is an intriguing clinical entity that has an            have been implicated in the etiology of disorders such as schizophrenia, and
unclear relationship to adult onset depression, although probably repre-          psychiatric abnormalities are common in cancer and AIDS patients receiving
senting an earlier onset, more severe form of the adult disorder for some.        cytokines at therapeutic doses. Dr. Zalcman and colleagues helped establish
Our studies of immunity in childhood depression, under the direction of           that immune activation, via cytokines, induces marked alterations of brain
Dr. Anne Bartlett, revealed changes affecting similar systems as those            neurochemical activity that regulate the ongoing immune response and under-
found to be altered in depressed adults, suggesting that similar biological       lie adaptive and, in some cases, maladaptive behavioral changes.
processes may apply. Our studies with prepubertal depressed children                   In sum, basic and clinical research in the Department of Psychiatry at
found increased mitogen responses, similar to that seen in younger, but not       NJMS is exploring the broad field of brain-behavior-immune interactions and
older, depressed adults. As in most studies of depressed adults (across the age   the consequences of such interactions for health and disease. The coalescing
range), we found lower NK activity in the depressed children. In addition,        of a research program addressing bidirectional and multifactorial relation-
both stress and depression were associated with diminished granulocyte            ships in the interface between the CNS and the immune system will help us
killing of phagocytized Staphylococcus aureus bacteria. Further, depressed        better understand why and how we get sick.
mood was related to lower circulating lymphocytes even among children
not suffering from clinical depression. These studies supported our earlier       Steven J. Schleifer, MD, professor of psychiatry at NJMS, completed
observations in adults that both clinical depression and “simple” mood alter-     undergraduate studies at Columbia College and his MD at the Mount Sinai
ations may independently influence immunity. We are further exploring the         School of Medicine (1975). Following residency at Mount Sinai, he joined
extent to which altered mood and cognition are related to immune changes in       the Mount Sinai faculty, conducting                pioneering research in
otherwise healthy children.                                                       psychoneuroimmunology and serving as liaison psychiatrist in
                                                                                  neoplastic diseases. Dr. Schleifer came to NJMS as Director of
Medical-Psychiatric Comorbidity and Immune Change                                 Consultation-Liaison Psychiatry in 1987, continuing research in
In an extension of our studies of depression and immunity, we have been           behavioral immunology in collaboration with Dr. Steve Keller and other
investigating medical disorders with a high incidence of comorbid depres-         faculty. He was appointed Acting Chair of Psychiatry in 1991 and served
sion. We studied patients with temporomandibular (TMJ) pain syndromes             as Chair for 10 years. Dr. Schleifer is known for his studies on the
with the late Dr. Joseph Marbach of UMDNJ-New Jersey Dental School.               influence of stress, depression, and alcoholism on the immune system and
Such patients rarely have underlying medical disorders, but have high rates of    on depression in the medically ill. ❧




                                                                                      THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY                           17
                                                                                                  LEFT TO RIGHT: JULIE COLEMAN, RN, BSN; STEVEN SOHNLE, PsyD; PETER AUPPERLE, MD,
                                                                                               DIRECTOR, DIVISION OF GERIATRIC PSYCHIATRY, AND ASSOCIATE PROFESSOR OF PSYCHIATRY,
                                                                                                                 UMDNJ-ROBERT WOOD JOHNSON MEDICAL SCHOOL; SHAILAJA SHAH, MD;
                                                                                                                                                        AND WILLIAM REICHMAN, MD




     Alzheimer’s disease research:                                                                                            Piscataway, and the Institute is a key com-
                                                                                                                              ponent of the Division of Geriatric


     a search for solutions                                                                                                   Psychiatry      at   UMDNJ–Robert Wood
                                                                                                                              Johnson Medical School (RWJMS). This
                                                                                                                              research team is currently engaged in
     by    Peter Aupperle                                                                                                     15 active projects funded by the National
                                                                                                                              Institutes of Health (NIH), major universi-
                                                                                                                              ties,    and     numerous        pharmaceutical
                                 ith the number of individuals with Alzheimer’s dis-      companies, either as investigator-initiated single site protocols or multi-center




     W                          ease (AD) in the United States estimated at over 4
                                million, intensive efforts are being made to develop
                                more efficacious treatments. Researchers at
                                UMDNJ’s COPSA Institute for Alzheimer’s disease
     are collaborating with other medical schools and pharmaceutical companies to
     develop better diagnostic tests for AD as well as compounds to decrease the
                                                                                          projects. Primary areas of focus include: research on biological factors, the
                                                                                          development of novel cognitive enhancers, and targeted treatment of the
                                                                                          behavioral complications. I am the principal investigator of the COPSA
                                                                                          Institute, and Julie S. Coleman, RN, BSN, is research coordinator.
                                                                                               Two current research protocols focus on biological markers and risk
                                                                                          factors for AD. Due to the difficulty of accurately and rapidly diagnosing AD,
     incidence of the illness in cognitively intact individuals.                          COPSA is collaborating with Johns Hopkins Medical School to test the
          In addition, numerous studies are being conducted to provide even               specificity of a proposed diagnostic procedure. Researchers have discovered a
     greater cognitive benefit for patients than the current FDA-approved                 potassium channel that is dysfunctional in AD, and this same channel is located
     medications by augmenting the standard cognitive enhancers with new                  in fibroblast cells of the skin. Hence, a small punch biopsy is taken and the activ-
     compounds with novel modes of action, or by adding already approved                  ity of this specific channel is assessed. The results of this project may potentially
     medications utilized for other indications.                                          have tremendous public health impact, since AD is markedly under-diagnosed.
          Researchers at COPSA are also involved in several trials focused on more             As part of a NIA grant to Columbia University, COPSA researchers are
     effectively treating the behavioral complications of AD that can be so stressful     investigating the effect of estrogen in reducing the incidence of AD. In this
     for caregivers. Finally, usage of the currently approved cognitive enhancers to      study, a cohort at increased risk of developing AD (women over the age of 65
     treat dementias other than Alzheimer’s is also being explored.                       who have a first-degree relative with AD) will be given either placebo or
                                                                                          hormone replacement therapy and the incidence of AD will be monitored over
          The COPSA Institute for Alzheimer’s Disease (AD) and Related                    a five-year period.
     Disorders is New Jersey’s designated center for state-of-the-art clinical research        Numerous pharmaceutical sponsored multi-center clinical trials have been
     in AD. COPSA receives support via a Department of Health and Senior                  conducted at COPSA with acetylcholinesterase inhibitors. These compounds
     Services grant to UMDNJ-University Behavioral HealthCare (UBHC) in                   all act by preventing the breakdown of acetylcholine in the synaptic neuronal




18         THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY
cleft. Three of these medications have been approved by the FDA (donepezil,            Peter M. Aupperle, MD, MPH, is Medical Director of Geriatric Services and
rivastigamine, and galantamine), and they now constitute the current class of          Principal Investigator of the COPSA Institute for Alzheimer’s Disease and Related
drugs that are approved for AD patients with mild to moderate impairment of            Disorders at UMDNJ’s University Behavioral HealthCare. He is also Director of the
cognition. All of these trials require detailed neuropsychological testing,            Division of Geriatric Psychiatry and associate professor of psychiatry at RWJMS, and
which is performed by Steven S. Sohnle, PsyD, mental health clinician at               director of the Geriatric Psychiatry Fellowship Training Program. He received both
UBHC and adjunct assistant professor of psychiatry at RWJMS.                           his MD and MPH degrees at Columbia University, and completed his postgraduate
     The current focus of clinical trials is on compounds with new mecha-              training at Mount Sinai Medical Center. He is board certified in both geriatric and
nisms of action. One new investigational medication currently being                    general psychiatry and is also the principal investigator on numerous multi-center
studied is memantine, which modulates glutamatergic neurotransmission                  national clinical trials.   ❧
by selective deactivation of NMDA receptors. In addi-
tion, one current phase II study is evaluating the
efficacy of CP-457, an experimental compound
believed to have memory-enhancing effects.                                  Functional MRI in the study of                               face
    In addition to single agents, combination treat-
ments are being explored to see if additive or perhaps
                                                                                    autism
                                                                            processing in
even synergistic effects can be demonstrated. COPSA
has already been a site for two such multi-center trials.
                                                                            spectrum disorders
One evaluated the ability of Premarin to augment the
                                                                            by      Charles Cartwright
benefit of donepezil, and the other assessed the effica-
cy of sertraline to augment the cognitive benefit of
                                                                                                            ur group at UMDNJ-New Jersey Medical School (NJMS)




                                                                                      O
donepezil. The results of both of these studies are pending publication.
Another trial just completed assessed the efficacy of the “cocktail” of                                     is conducting a functional magnetic resonance imaging
memantine and donepezil for treating patients with AD.                                                      (fMRI) study (funded by the New Jersey Governor’s
    We are currently enrolling patients in an investigator-initiated protocol to                            Council on Autism) to identify the brain regions activated
test the ability of divalproex sodium (Depakote) to augment cognition in AD                                 in young adult males (ages 18-30) with high-functioning
patients already on donepezil. Depakote is currently used to stabilize be-             autism and Asperger’s disorder while processing facial expressions (as com-
havioral complications (such as agitation), but recent research points to a            pared with a matched typical control group). Two experimental tasks are
potential additional neuroprotective property. In addition to neuropsycholog-          carried out within an event-related fMRI design. Subjects are presented with
ical testing, all patients will receive volumetric MRI scans before and after the      photographs showing different facial expressions (happy, fearful, neutral) and
study to assess for any stabilization in the change in size of the                     are required to attend to, and identify, the emotional content of the face
hippocampus typically seen in AD.                                                      (‘explicit’ task) or the gender of the face (‘implicit’ task). We are examining
    Numerous protocols are exploring the potential of the current class of             activation patterns within ventral temporal cortical and limbic brain regions.
cognitive enhancing compounds for other indications beyond the current                 In addition, the association between neuroimaging findings and the extent of
FDA approval of mild to moderate AD. COPSA has participated in a multi-                the subjects’ social deficits is explored. This study aims to contribute to the
center protocol of rivastigmine for moderate to severe AD and is currently             emerging field of enquiry into whether the neurocircuitry of face processing
enrolling patients in a trial of donepezil in severely cognitively impaired AD         may identify potential biological markers of the reciprocal social deficits of
patients. In addition, we are studying the benefit of donepezil in vascular            autism spectrum disorders (ASDs).
dementia patients. Shailaja Shah, MD, assistant professor of psychiatry at
RWJMS, is the principal investigator on a multi-center project assessing                    ASDs are neurodevelopmental disorders characterized by impairments
the use of donepezil as an agent for delaying the onset of AD in Down’s                in reciprocal social behavior, deficits in language and communication and the
syndrome patients. This is an all too frequent complication in these                   presence of restricted interests and repetitive, stereotypic behaviors. The
individuals at a tragically young age.                                                 deficits in social reciprocity and social cognition are a core feature of ASDs
    The research team is also involved in protocols focusing on ameliorating           and include difficulties in recognizing, appropriately interpreting and
the behavioral complications of AD. One trial, “Clinical Antipsychotic Trials          responding to social cues and being capable of engaging in socially and
of Intervention Effectiveness,” is a NIH funded “head-to-head”                         emotionally reciprocal relationships.
comparison of the treatment of psychosis in the context of AD with risperi-                 There is considerable variability in the expression and severity of symp-
done, olanzapine, or quetiapine. In addition, William E. Reichman, MD,                 toms within the ASDs, justifying their conceptualization on a spectrum. As
Vice-Dean, UMDNJ-New Jersey Medical School (NJMS), is enrolling                        many as 63 children per 10,000 have an ASD and, of these, 16.8 children per
patients in an open-label trial of the use of mirtazapine for the treatment of         10,000 have the more narrowly defined autistic disorder. Autism is one of
the agitation often associated with Alzheimer’s disease.                               the most strongly genetically based of the developmental disorders, with
    In conclusion, the COPSA Institute for Alzheimer’s disease is engaged              environmental factors contributing to its expression.
in a host of cutting-edge clinical research projects. The number of studies has             Individuals with autism demonstrate failure to make appropriate eye
doubled over the past two years and current total external funding is well over        contact and apparent inattentiveness to and disinterest in the faces of others.
$1 million. We hope these endeavors will contribute to stabilizing the course          It is hypothesized that they perceive and process faces differently than
and improving the quality of life for the rapidly growing number of AD                 typical individuals. From a young age they tend to show a lack of interest in
patients. The staff welcomes inquiries or comments via its Web site at:                faces and a preference for inanimate objects and they demonstrate signifi-
http://www2.umdnj.edu/~coyne/copsa.html or by contacting Julie Coleman,                cantly lower rates of eye contact. The lack of social interest shown by
RN, or Peter Aupperle, MD, at 732-235-4907.                                            children with ASDs may be an important factor in the development of
                                                                                       aberrant face processing strategies in early childhood.
                                                                                                                                                 continued on page 20




                                                                                            THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY                              19
                                                                                               LEFT TO RIGHT: GUDRUN LANGE, PhD; SHIRLEY BERGER, MA; CHARLES CARTWRIGHT, MD,
                                                                                           ASSISTANT PROFESSOR, DEPARTMENT OF PSYCHIATRY, UMDNJ-NEW JERSEY MEDICAL SCHOOL;
                                                                                                       MELISSA FREDERIKSE, MD; STEVEN SCHLEIFER, MD; BENJAMIN MARTIN BLY, PhD


     continued from page 19



          Functional neuroimaging is a promising tool in our efforts to link the          of assigning a mental state to pictures of eyes, or were required to
     clinically observed social impairments in ASDs with neurobiological                  identify the gender of faces that displayed various emotional expressions
     substrates. Face processing develops on the basis of the integration of both         (‘implicit’/non-conscious processing of facial emotion).
     visuospatial and socio-emotional processing, and a convergence of evidence               The goals of our fMRI study are to replicate the findings reported in the
     supports the role of the ventral temporal cortex in the visuospatial aspect of       fMRI studies above, and to further elaborate on the functional neurocircuitry of
     face processing and the role of the amygdala and limbic circuitry in the             face processing. We will shortly undertake a similar funded study with ado-
     socio-emotional processing. fMRI studies have provided convincing                    lescents (ages 13-17) diagnosed with ASDs. Our research is part of the
     evidence that, in typically developing individuals, face viewing/processing          broader field of enquiry that is investigating the link between face process-
     uniformly engages specific regions of the fusiform gyrus (FG), collectively          ing deficits, social-emotional deficits and brain regions, including the
     referred to as the ‘fusiform face area’ (FFA). These neural sites are maximally      fusiform gyrus and the amygdala. In so doing, the identification of biologi-




     OUR RESEARCH IS PART OF THE BROADER FIELD OF ENQUIRY THAT IS INVESTIGATING THE LINK BETWEEN FACE PROCESSING DEFICITS,
                                                     SOCIAL-EMOTIONAL DEFICITS AND BRAIN REGIONS, INCLUDING THE FUSIFORM GYRUS AND THE AMYGDALA.



     responsive to faces. The amygdala, a complex mesial-temporal brain structure         cal markers may be possible and this would prove useful for genetic studies,
     that is part of the limbic system, plays a crucial role in normal emotional learn-   the diagnosis of ASDs and the assessment of the efficacy of treatments
     ing during early development and is centrally involved in assigning emotional        targeting social-emotional deficits in this population.
     meaning to facial stimuli.                                                               The New Jersey Governor’s Council on Autism has funded several
          fMRI studies of adults with ASDs have demonstrated their failure to             studies based at UMDNJ. The coordination of our research has been
     activate the FFA when looking at faces. In a study of face recognition, the          enhanced by the launch of The Autism Center of NJMS in November 2001.
     autism group failed to activate the FFA and processed faces using an area of         NJMS has also recently submitted an application to the NIMH for funding
     the brain that is typically used to process objects (inferior temporal gyrus).       of an Autism Center of Excellence (Principal Investigator: Linda
     Another study showed that during ‘explicit’/conscious processing of facial           Brzustowicz, MD, Department of Psychiatry). As part of this, we submitted
     emotion, the autism group did not activate the FFA as compared to the                a proposal for a functional and structural neuroimaging study.
     control group. In addition, a number of studies have demonstrated reduced                In conducting our fMRI study, we are fortunate in being able to draw
     amygdala activation in subjects with ASDs when subjects performed the task           on the skills and talents of a diverse team, including Benjamin Bly, PhD,




20        THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY
                                     Gudrun Lange, PhD, Melissa
                                     Frederikse, MD,        Michael
                                     Brimacombe, PhD, Jagriti
                                     Arora, BS, Edward Garay,
                                     BS, Shirley Berger, MA, and
                                     Jason Steffener, MS. We are
                                     grateful for the help provided
                                     by the fMRI laboratory
STEPHEN R. BAKER, MD, PROFESSOR      within the Department of
AND CHAIR, DEPARTMENT OF
RADIOLOGY, UMDNJ-NEW JERSEY          Radiology at NJMS, in partic-
MEDICAL SCHOOL
                                     ular the services provided by
                                     Wen-Ching Liu, PhD, and
Leo Wolansky, MD. Future fMRI studies in autism at our
institution will be greatly enhanced by the recent opening of the
Advanced Imaging Center at NJMS which houses the 3T
Siemens Allegra system, a state-of-the-art, head-only MRI.


Charles Cartwright, MD, completed a general psychiatry residency
in Cape Town, South Africa and, following this, a fellowship in child
                                                                                                                       CHARLES H. KELLNER, MD, PROFESSOR AND CHAIR,
and adolescent psychiatry at New York University/Bellevue Hospital.                                                                       DEPARTMENT OF PSYCHIATRY,
                                                                                                                                  UMDNJ-NEW JERSEY MEDICAL SCHOOL
He was a research fellow at the Seaver Autism Research Center
(Mount Sinai School of Medicine) and was awarded the two-year
National Alliance for Autism Research/Bristol-Myers Squibb
Research Fellowship in Autism and Neuropharmacology. In August
2000 he joined the Department of Psychiatry at NJMS, and is a member of the        Modern indications for ECT
multi-disciplinary team that forms part of The Autism Center of NJMS. He also           ECT was originally developed to treat schizophrenia, but by the 1940s it
serves as Medical Director of the Partial Care Program (for children and adoles-   became clear that it was more effective for severe depression. Today it is
cents) at UMDNJ-University Behavioral HealthCare. ❧                                recognized that ECT is effective for both phases of mood disorders (depres-
                                                                                   sion and mania), as well as some symptoms associated with schizophrenia and
                                                                                   other psychoses. ECT is also dramatically effective for the relief of symptoms
                                                                                                   of catatonia, and has some benefit in treating neurological
                                                                                                   disorders, including Parkinson’s disease.
                                                                                                        ECT is actually a simple and straightforward proce-

Refining ECT as a treatment for                                                                    dure. Brief general anesthesia is induced with


severe depression                                                                                  methohexital, followed (after loss of consciousness) with a
                                                                                                   bolus dose of succinylcholine. A blood pressure cuff
                                                                                                   inflated on the patient’s right ankle excludes the
                                                                                                   succinylcholine from the foot, so the motor manifestations
by    Charles H. Kellner
                                                                                                   of the induced seizure can be observed. The seizure is then
                                                                                                   induced by passing a brief electrical current across
                  lectroconvulsive therapy (ECT) remains an important treat-       electrode pads on the forehead. A typical ECT seizure lasts 20 to 60




E                 ment for severe depression.         Its acute efficacy as an
                  antidepressant is unequalled. However, relapse of depression
                  after successful ECT and cognitive impairment caused by
                  ECT are significant concerns. Research into the use of ECT
as a maintenance therapy to prevent depressive relapse is described, as well as
the use of an alternative type of ECT (bifrontal electrode placement) to reduce
                                                                                   seconds and ends spontaneously.
                                                                                        For a severe episode of depression, a typical course of ECT consists
                                                                                   of six to 12 treatments, given three times a week. Treatments are contin-
                                                                                   ued until the depression has resolved (in over 80% of cases) or side effects
                                                                                   are limiting or the patient is not remitted after more than 12 treatments.
                                                                                        Side effects may be classified as “medical” or “cognitive.” The
memory loss. Until other therapies come along to replace ECT, it will remain       former are typically minor (headache, nausea, muscle aches) and rarely
an important medical procedure for the treatment of severe depression.             serious. The cognitive side effects of ECT are what patients are most
                                                                                   concerned about. Almost all experience some memory loss, but this is
     Electroconvulsive therapy (ECT), a treatment for severe depression, has       typically mild and often temporary. Occasionally it is more serious and,
been in use since 1938. Despite being nearly universally acknowledged by           very rarely, may be severe and permanent.
physicians as the single most effective therapy for major depression, it                While ECT is remarkably effective as an acute antidepressant, a signif-
remains misunderstood and feared. This results in reluctance by some               icant problem remains relapse of depression six to 12 months later. To reduce
psychiatrists to prescribe it, and by patients to consider it. In fact, many       this risk, antidepressant and mood-stabilizing medications are frequently
severely mentally ill patients who could benefit from ECT cannot gain access       used after ECT. Dr. Harold Sackeim, a researcher at Columbia University,
to it, because of limited availability. Yet negative attitudes towards ECT are     recently completed a clinical trial in which patients were randomized to (1)
changing, and active research efforts are under way to improve and better          nortriptyline (an antidepressant), (2) nortriptyline and lithium (a mood
understand this important procedure.                                               stabilizer) or (3) placebo. Shortly after this study was begun, our group, the

                                                                                                                                          continued on page 22



                                                                                      THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY                            21
     continued from page 21



     Consortium for Research in ECT (known as C.O.R.E.) launched the comple-                Cedars-Sinai Medical Center in Los Angeles, followed by a three-year fellowship in
     mentary study described below. The results of the Columbia group’s study               biological psychiatry at the National Institute of Mental Health, and was on the faculty
     showed a relapse rate of about 80% in the placebo group and about half that in         of the Medical University of South Carolina from 1984 to 2002. He has been editor-in-
     the group taking the combination nortriptyline and lithium. Dr. Max Fink,              chief of the Journal of ECT since 1994 and is a member of the American Psychiatric
     ECT expert and C.O.R.E. investigator, suggested comparing maintenance                  Association Committee on ECT. ❧
     ECT to nortriptyline/lithium as a strategy for preventing
     relapse. Maintenance ECT, as opposed to a course of ECT
     for the acute treatment of a depressive episode, is use of a               Research in                 behavioral
                                                                                medicine
     single outpatient ECT given at an interval of one to four
     weeks to prevent recurrence of depression. Since it is pure-
     ly preventive, it may be given to a patient who is
     completely well at the time.
          In 1996, the C.O.R.E. investigators (UT Southwestern
     Medical Center, Mayo Clinic, Hillside Hospital-Long                        by    Paul Lehrer
     Island Jewish Medical Center and originally Medical
     University of South Carolina, now the UMDNJ-New Jersey Medical School                                          ur group at UMDNJ-Robert Wood Johnson Medical School
     site) embarked upon a study comparing the efficacy and safety of maintenance
     ECT vs. nortriptyline/lithium in combination. Adults suffering from major
     depression (unipolar type) are treated with a standard course of bilateral ECT.
     Those who remit and stay remitted for one week on no therapy are then ran-
     domized to receive a schedule of ECT (10 treatments over five months, initially
     weekly, then biweekly, then monthly) or nortriptyline and lithium. Patients
                                                                                            O                       (RWJMS) is investigating emotional concomitants of
                                                                                                                    physical disease, and the ways in which physical and
                                                                                                                    emotional disease can affect each other. We are working on
                                                                                                                    voluntary control of heart rate variability and baroreflex
                                                                                                                    control, and a new biofeedback method for stabilizing
                                                                                            autonomic reactivity. We are also studying how respiration interacts with
     remain in the study for six months and then return to their treating psychiatrists     psychological states, and are applying these methods to understanding and
     for ongoing therapy (which might be medication or additional ECT). To date,            treating asthma, and the interactions between asthma and anxiety.
     522 patients have started the initial ECT course in the study and 173 have been                  Other teams are working with us in investigating physiological
     randomized to the two treatment arms.                                                  concomitants of depression and fatigue. Dr. Linda Patrick-Miller is examin-
          The results so far confirm ECT’s acute effectiveness with over 80% remit-         ing the relationship between these feelings and immune system function
     ting. Interestingly, patients with the psychotic subtype of depression, despite        among patients with cancer, while Drs. Christine Skotzko and Lynn Clemow
     being more severely ill, actually did even better than patients without psychot-       are studying their commonly observed relationship to heart disease.
     ic symptoms. Also, older patients had an even more robust response than
     younger ones.                                                                          Respiratory Psychophysiology
          The seven-year study is now in its fifth year and the “blind” for the             Everyone knows the major effect of respiration: air exchange. But respiration
     randomized part of the trial has yet to be broken. Thus, we are not yet able to        has other important functions, including speech, postural adjustment, and the
     provide results of either the neurocognitive testing or the head-to-head               production of oscillatory rhythms that are present throughout the body and
     comparison of maintenance ECT vs. nortriptyline/lithium in preventing relapse.         which play an important regulatory role.
     When completed, our study will provide definitive data on the role of mainte-               We are all familiar with these functions. Think of the expressions, “It took
     nance ECT in preventing relapse, as well as safety and side effect data.               my breath away,” “I held my breath in anticipation,” “Now we can breathe easy.”
          Given concerns about side effects of ECT, the C.O.R.E. will soon embark           Also, training in control of respiration is an integral part of various Eastern med-
     upon another study, comparing the cognitive side effect profile and antidepres-        itative and martial disciplines, which have been applied as “alternative” methods
     sant efficacy of three different ECT techniques. Originally, ECT was done with         for treating illness.
     bilateral electrode placement (in which electrodes are placed on both sides of              Research in my laboratory has investigated how changes in respiration
     the forehead). In the 1970s a modified technique called right unilateral (or           affect various psychological states, and vice versa, and looked at some
     non-dominant) electrode placement became popular because it produced much              implications for respiratory and psychiatric disease.
     less memory impairment. However, at times, right unilateral ECT is not as                   For example, many symptoms of panic disorder are closely related to
     effective an antidepressant therapy as bilateral ECT. In recent years, a third         symptoms of hyperventilation (breathlessness, pounding heart, etc.) and these
     technique, known as bifrontal ECT, has been offered, with the suggestion that          symptoms are often very similar to symptoms of asthma. Indeed, the two diseases
     it combines the best properties of the other two: a benign cognitive profile and       co-occur much more frequently than would be expected by chance. People with
     high antidepressant efficacy. Our proposed study will compare, in a larger             both disorders often confuse symptoms of the two problems, and sometimes take
     cohort of patients, the efficacy and safety profile of these three types of ECT.       treatments for the wrong disorder, which can lead to disastrous consequences,
          As we refine the technique of ECT, we are mindful of the need to                  including death in some cases. We have investigated these relationships and
     continue the search for alternative therapies. Recent enthusiasm for “high             devised a special behavioral therapy for patients with both disorders. We are
     tech” approaches, such as vagal nerve stimulation or transcranial magnetic             now conducting an NIH-sponsored evaluation of this treatment.
     stimulation, has yet to translate into clinically useful treatments in the real                  My laboratory has also investigated some ways in which psychologi-
     world. ECT will eventually be replaced by a treatment that is easier to                cal tasks (such as mental arithmetic, a reaction time task, and watching gory
     administer and has fewer side effects. Until that time, however, ECT is                movies) affect airway resistance in both disorders. Throughout all tasks and at
     effective in relieving the suffering of patients with severe depression.               rest, patients with asthma, as expected, had higher respiratory resistance than
                                                                                            healthy people. However, unexpectedly, patients with panic disorder had lower
     Charles Kellner, MD, is professor and chair of the Department of Psychiatry at NJMS.   respiratory resistance than healthy people. Among panic patients there was no
     He received his undergraduate and MD degrees from Cornell. He did his residency at     differentiation among tasks: Their airways were chronically dilated. Airway




22         THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY
dilation in panic disorder means that the same respiratory
effort brings more air into the system, thus predisposing
these patients to hyperventilate.
     Bringing more air to the system is, in fact, part of the
body’s general preparation for muscular action, so panic
patients, even at rest, appear poised for the “fight or flight” reac-
tion. Asthma patients and healthy people also show decreases
in respiratory resistance when exposed to activating tasks, but
only panic patients show this effect at rest, indicating that they
always seem prepared for the fight or flight reaction.
     Could this mean that an activating task or even panic
might be beneficial for asthma patients during an asthma
attack, despite the common observation that stress can
sometimes bring on an asthma attack? Indeed, we also
found that utilizing deliberate relaxation strategies decreas-
es airway function in asthma patients in the short run. So,
stress and active coping may be helpful during an acute
asthma episode, and relaxation may be harmful. (Perhaps
this theory will produce a new application for hand-held
                                                                                                                             PAUL LEHRER, PhD, PROFESSOR OF PSYCHIATRY,
computer games.)                                                                                                           UMDNJ-ROBERT WOOD JOHNSON MEDICAL SCHOOL
     The longer-term effects of learning to relax seem to be
beneficial for asthma, however. When people learn to relax,
they tend to show less physiological reactivity to all kinds of
stressors, and this may neutralize some of the situations that otherwise could     assistant professor of psychiatry, RWJMS, along with Professor Howard
exacerbate asthma.                                                                 Leventhal, PhD, (Rutgers University), tested the commonly held belief that
      In Russia, widespread use has been made of a biofeedback technique           you are more likely to catch a cold or the flu when you are under a great deal
for treating asthma that seems to have more reliable effects than relaxation.      of stress. The team found that after receiving preventive vaccinations,
Patients learn to increase the size of their “respiratory sinus arrhythmia”: the   volunteers who had undergone more stressful life events in the past year, or
changes in heart rate that occur with breathing. Biofeedback seems to stimu-       who had more anxious and depressed moods, produced significantly less
late reflexes that augment these capacities. This procedure stimulates a set of    antibody, the specific immune protein that provides the vaccinations’ protec-
reflexes called “baroreflexes,” important components in controlling blood          tion, than their less-stressed peers.
pressure, and, more generally, autonomic and emotional arousal. Increased               The relationship between psychological factors and the immune system is
amplitude of baroreflex function occurs over time at rest as well as during        bidirectional. After healthy volunteers were given injections with substances
biofeedback. This effect appears to help asthma.                                   that would stimulate their immune systems without generating illness, they did
                                                                                   indeed experience psychological changes that did not occur in response to
Behavioral Cardiology                                                              placebo. The changes were consistent with what was expected: an initial peri-
Other teams are investigating the common finding of fatigue and depression         od (24 hours) of increased energy was followed by a period (48-72 hours) of
among patients with heart disease. Dr. Christine Skotzko, associate professor      increased fatigue.
of psychiatry, RWJMS, has found that, in exercise testing, depressed patients           This research could explain the common observations that people do not
feel they are functioning more poorly than they actually are. Their actual         think as clearly when they have colds, or when they receive treatment with a
maximal heart rate and oxygen consumption in an exercise test was found            class of agents called biological response modifiers (BRMs). Patients with
to be similar to those who are not depressed, but they seemed to exert             multiple sclerosis, hepatitis C, and cancer, treated with BRMs, immunological-
themselves less. Working with Drs. Lynn P. Clemow (adjunct associate               ly active agents such as interferon-α, interferon-β and GM-CSF, are more likely
professor of psychiatry, RWJMS), Raymond Rosen (professor of psychiatry,           to develop psychological changes such as cognitive slowing, memory impair-
RWJMS) and other collaborators, a concise assessment battery has been              ment, and depression, than patients receiving other treatments. Patients with
developed to improve diagnostic accuracy of depressive disorders and               high levels of depressed affect before treatment are at increased risk for devel-
functional limitations in this population.                                         oping these psychological changes once treatment begins. In her role as
      Skotzko has worked extensively with chronic heart failure patients under-    Director of Behavioral Sciences at The Cancer Institute of New Jersey (CINJ),
going evaluation for cardiac transplantation. Psychosocial difficulties in these   Dr. Patrick-Miller recently launched a program to assess the level of
individuals predicted increased medical complications and hospitalizations         psychological distress, depression and anxiety of each new patient.
when they were followed prospectively through and after cardiac transplanta-
tion. Individuals with moderate to severe psychosocial impairment had              Dr. Paul Lehrer is a professor of psychiatry at RWJMS, where he has taught for more
increased levels of infection and graft rejection following transplantation. A     than 30 years. He currently heads the Center for Stress Management and Behavioral
trend toward increased mortality was also seen for the moderate to high psy-       Medicine (UMDNJ). He has published over 100 papers in his field of research:
chosocial impairment group, with 89% versus 80% survival at 12 months.             biofeedback, stress management, and psychophysiology. He received his PhD in
                                                                                   clinical psychology from Harvard University in 1969, and is senior editor of the
Psychoneuroimmunology                                                              widely used text, Principles and Practice of Stress Management (NY: Guilford
Psychoneuroimmunology (PNI) focuses on the role the immune system plays            Publications, 2nd edition, 1993). He currently is president of the Association for
in the relationship between stress and illness. Linda Patrick-Miller, PhD,         Applied Psychophysiology and Biofeedback. ❧




                                                                                   THE UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY                              23
Investigating the causes and treatments of psychiatric illness
B   Y      S    T      U    A   R   T    D   .     C   O   O   K




U
                           MDNJ is truly a university on the move, and research is a        As research helps us understand more about the function of the brain
                           top priority. Our National Institutes of Health (NIH)       and the molecular basis for psychiatric illnesses that affect behavior, great
                           funding has increased more than 85 percent in the last      progress will be made in treatment and prevention. UMDNJ is at the forefront
                           four years, a rate of growth well ahead of the 49 percent   of such research, investigating all aspects of mental health, from depression and
                           national average for U.S. medical schools. We have          anxiety to schizophrenia and autism.
recruited nine University Professors to UMDNJ, all leaders in their fields                     At our University, research in these areas has a unique advantage —
who come to us with large NIH grants. We plan to recruit 16 addi-                                a partnership among the departments of psychiatry at our medical
tional University Professors over the next two to three years.                                      schools and our behavioral health network, one of the largest
Each significantly broadens the scope of our research activities                                     providers of mental health services in the country. University
in areas of particular interest to the University.                                                    Behavioral HealthCare (UBHC) treated approximately 30,000
    One such area is behavioral health, a field of intense focus                                      people at 14 centers throughout New Jersey last year alone. Its
for our scientists and clinicians. Mental illness carries with it a                                   impact is felt even beyond our state borders. In the aftermath of
heavy burden, and one that has been greatly underestimated.                                         the September 11 terrorist attacks, UBHC staff trained 600
Psychiatric disorders are among the most prevalent and disabling health                         mental health professionals, who in turn helped individuals across
conditions worldwide. Yet because they are not “killers,” like cancer and heart        the country cope with this national tragedy.
disease, their serious effects are often overlooked. They shouldn’t be.                     These opportunities for collaboration create an environment conducive
    Behavioral disorders affect millions in the U.S., debilitating some                to leading-edge work in behavioral health, as you can see in these pages. We are
5 percent of adult Americans. In addition, as many as 13 percent of children           pleased to share some of the outstanding research being conducted on our
ages 9 to 17 have serious emotional disturbances and substantial functional            campuses to explore the links between biology and behavior.
impairment. Four of the 10 leading causes of disability in this country are
psychiatric — major depression, bipolar disorder, schizophrenia and obses-
sive compulsive disorder. They cost our society more than $150 billion
                                                                                       Stuart D. Cook, MD
annually; of that, $67 billion is for direct healthcare costs and the rest             President
                                                                                       Ruth Dunietz Kushner and Michael Jay Serwitz
includes social services, disability payments and lost workdays.                       Chair in Multiple Sclerosis at UMDNJ-New Jersey Medical School




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