Winter 1999 
NEWSLETTER

THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE
DEPARTMENT OF PSYCHIATRY AND BEHAVIORAL SCIENCES

INTRODUCTION

This is the fourth newsletter in our efforts to: a) keep research participants and interested parties up to date on our progress; b) describe new studies which may be of interest and; c) provide information on scientific advances in the study of psychiatric conditions. Families and individuals who have participated in our studies are an integral part of our research, and we want you to be fully informed about our progress. We also send this newsletter to other individuals who have requested to be on our mailing list.

Dr. Ann E. Pulver, Sc.D, directs our research program. Dr. Pulver is a psychiatric epidemiologist and an Associate Professor of Psychiatry. Dr. Pulver began the program in 1983 at the Maryland Psychiatric Research Center (University of Maryland Medical School). In 1989, Dr. Pulver joined the faculty at The Johns Hopkins University School of Medicine and moved her entire research program to the JHU Department of Psychiatry and Behavioral Sciences.

Between 1983 and 1989, the goal of the program was to identify and collect information about a large sample of individuals who were hospitalized. During this six-year period, we screened psychiatric admissions to 15 hospitals in the greater Baltimore area and enrolled 1,670 individuals into our study. Individuals in this group, now referred to as the Maryland Epidemiologic Sample (MES), were interviewed while they were in the hospital.

We also interviewed family members to complete a family tree and collect information about the medical and psychiatric histories of the participants’ relatives. We analyzed the clinical and family history information about the individuals in the MES using statistical tests that allowed us to answer questions about the epidemiology of severe psychiatric conditions. Epidemiology is the study of illness from a population perspective. Epidemiologic studies focus on describing risk factors for illness in groups of individuals. The results of our analyses have been published in several scientific journals.

Since their initial enrollment in our study, we have recontacted individuals in the MES over the years. We have re-interviewed many of these participants and have enrolled them in other studies such as genetic studies and neuroimaging (MRI) studies. Dr. Karen Swartz, a member of our research team, is currently conducting a follow-up study of the individuals in the MES who were initially enrolled during their first psychiatric hospitalization. Some of you may be hearing from Dr. Swartz over the next several months. She will be interested in setting up a time that she can meet with you to complete an in-person interview. Another collaborator, Dr. Godfrey Pearlson, is conducting neuroimaging studies of individuals with various psychiatric diagnoses. A group of you in the MES have already participated in Dr. Pearlson’s study. We will be recontacting you in the next few months to see if you are interested in participating in another phase of Dr. Pearlson’s research.

Because of advances in laboratory methods, in 1989 our focus turned toward identifying and evaluating families for molecular genetic studies. We began by identifying families with more than one individual affected with schizophrenia. All first degree (parents, siblings, and children) and second degree (uncles, aunts, and grandparents) relatives of affected family members were seen for an in-person interview and blood drawing. DNA samples from individuals in these families have been analyzed using molecular genetic techniques to identify regions of the genetic information that may contain genes that put an individual at risk for developing schizophrenia. The findings we have reported for the first group of 100 families that we studied are summarized later in this Newsletter.

In 1996, we made two major changes in our study enrollment criteria: 1) we began to focus on families of Jewish ancestry and 2) we began to include families where only one individual was affected with schizophrenia.

We are not focusing on the Jewish population because we think there is an increased risk for schizophrenia in this community. We are focusing on the Jewish population because the community has evolved from a limited number of ancestors, and because Jewish individuals have historically married individuals of the same ethnic background. This similarity in ethnic background allows researchers to more easily locate disease-causing genes in specific chromosome regions. We have enrolled families with only one individual affected with schizophrenia because of advances in the field of statistics that enable us to use such families in genetic studies.

A potential link between genetic susceptibility to schizophrenia and bipolar disorder led us to begin to study families with bipolar disorder in 1998 (bipolar disorder is described in detail later in the Newsletter). Again, we have focused on families of Jewish descent for the same reasons as described above. We do not think there is a higher rate of bipolar disorder among Jewish individuals as compared to the general population. We are focusing on this community because of genetic characteristics that may allow us to more easily locate susceptibility genes.

To date, our research program has enrolled over 5,000 individuals in our studies. Our current studies are enrolling families of Jewish descent that contain at least one living relative diagnosed with schizophrenia, schizoaffective disorder or bipolar I disorder. We ask the family member(s) diagnosed with schizophrenia, schizoaffective disorder or bipolar I disorder to allow a member of our research group to visit him or her to complete an in-person psychiatric evaluation and blood draw. Other relatives in the family (primarily the parents of the affected individuals, if they are available) are also asked to participate in the study by donating a small blood sample. We may also ask the parents to complete the psychiatric examination as well. Since 1996, we have enrolled 550 Jewish families in these studies. Our research grants require that we enroll 500 more families over the next three years.

CHANGES IN THE RESEARCH GROUP STAFF

We would like to bid a very fond farewell to Gail Ullrich, MSW. Ms. Ullrich has worked with our research group since 1984 and has for years been the primary contact-person with participants in our studies. Ms. Ullrich recently fulfilled a long-awaited change in her career by accepting a clinical position at a hospital here in Maryland. We were all sad to see her go, but wish her the best in her new career.

We would like to welcome the following new staff members:

Holly Peay, M.S.: Ms. Peay, who is a board-certified genetic counselor, joined our group in May. Ms. Peay is responsible for heading up our Family Outreach/ Recruitment Team. Members of this team are responsible for publicizing our studies nationwide. Ms. Peay and her staff develop advertising campaigns, conduct mass mailings to distribute our flyers and brochures, organize presentations at mental health facilities, Jewish organizations and conventions, and organize focus groups.

• Cindy Hunter, Ph.D.: Dr. Hunter, who is a clinical psychologist, joined our group in October. Dr. Hunter is responsible for heading up our Family Intake/Fieldwork Scheduling Team. Members of this team respond to all incoming referrals to our studies. This includes determining eligibility and scheduling relevant family members to be seen by a member of our research group.

• Crystal Ecker, B.A.: Ms. Ecker joined our group in July as a Research Assistant. Many of you have interacted with Ms. Ecker around scheduling blood drawings and signing release forms.

• Sherrie Morris: Ms. Morris joined our group last year as Dr. Pulver’s Administrative Assistant.

FUNDING

Our current work is predominantly funded by two research grants from the National Institute of Mental Health. Individuals are welcome to make a financial contribution to the research study. Donations of any size can help lead us to our goal. Checks should be written to Johns Hopkins School of Medicine--Dr. Ann E. Pulver Research Account. Please mail checks to:

Dr. Ann E. Pulver

Epidemiology/Genetics Program

The Johns Hopkins University School of Medicine

P.O. Box 1997

                    Baltimore, MD 21203

WHAT IS NEW?

We have made great progress in several areas of our research aimed at identifying genes contributing to the probability that a person develops schizophrenia. We have been able to narrow the genome down to several Ahotspots@ where we think genes may be located. In the September 1998 edition of Nature Genetics, volume 20, we reported on these Ahotspots,@ which are located on chromosome 13, chromosome 8, and chromosome 22. In addition, when we compared our data to that of groups researching the genetics of bipolar disorder, we found similar "hotspots." This may mean that bipolar disorder is also linked to some of the same genetic regions, and thus may be caused by a similar mechanism as schizophrenia. There is a great deal of work that still needs to be done to identify the individual genes.

The laboratory work described above was the result of a large collaborative effort. We have worked with many laboratories, including those at the University of Pennsylvania (Dr. Haig Kazazian), the University of Geneva (Dr. Stylianos Antonarakis), the Massachusetts Institute of Technology (Dr. David Housman) and Novartis Pharmaceuticals. We have recently entered into a collaboration with a French laboratory called Genset. Genset is very interested in schizophrenia research. They are collaborating with us to pursue the identification and description of schizophrenia susceptibility genes. Using over 300 families from our sample, Genset will employ advanced genetic techniques to determine the exact location of susceptibility genes on chromosomes 13, 8, and 22.

Many research teams, including ours, are getting close to discovering risk genes for schizophrenia and bipolar disorder. While it is impossible to predict exactly when such a discovery may be announced, it is likely that gene findings will occur within the next one to two years for both conditions.

_ WHAT WILL A GENE DISCOVERY MEAN?

We are very excited about the potential benefits of gene location and announcement. As you can imagine, a schizophrenia and/or bipolar disorder gene announcement is going to have a large impact on the public. Since schizophrenia and bipolar are both common conditions (each affecting about 1% of the population,) a gene announcement will be important to many families. Anticipating the impact that an announcement may have, we will try to address some of the concerns that study participants and family members may have.

It is important to keep in mind that we still believe that serious mental illness is caused by the interactions of several genes and the environment. Finding the first susceptibility gene will be just the beginning of a long learning process about the causes of serious mental illnesS

HOW WOULD A GENE DISCOVERY BE USED?

The exciting thing that could come out of a gene discovery is a more complete understanding of the causes of mental illness. If we can understand the biochemical basis of these disorders, scientists have the potential to develop treatments that are much more effective. In addition, we hope that determining the biological basis of mental illness will help reduce stigma.

It is important to understand that a gene discovered in some families with a particular disorder will most likely not be found in all families with the same disorder. Also, it is clear that mental illness susceptibility is caused by more than one gene, and that environmental factors are important as well. In addition, it is likely that we will find that a proportion of those with the susceptibility gene(s) will never develop the condition. All together, this makes it very unlikely that locating a gene will allow clinical genetic testing to determine susceptibility for mental illness at any time in the near future.

When study participants learn of a gene discovery, they are often concerned that a third party (i.e. their employer or insurance company) will learn whether or not their family

has the gene. At Johns Hopkins, we make every effort to ensure that confidentiality is complete. We do not disclose the names or contact information of any study participants without their express permission. In addition, the DNA samples provided by study participants have been randomized, which means that no identifying information is with the sample. This ensures that the laboratory personnel cannot trace samples back to the donor families. Only a selected number of staff at the Johns Hopkins office has access to information that allows identification of samples.

_ WHAT ARE WE DOING TO PREPARE FOR RISK GENE DISCOVERY?

While it is extremely exciting to be close to a gene discovery, we are aware that we need to be prepared to educate both the public and health care professionals. To that end, Dr. Pulver established The Foundation for Genetic Education and Counseling, and obtained initial financial backing from Genset Laboratories to get the Foundation up and running.

The Foundation for Genetic Education and Counseling is a non-profit independent organization directed by Joseph McInerney, M.S. Mr. McInerney was chosen to direct the Foundation due to his previous experience heading a large organization devoted to science education, and his tremendous expertise in the field of molecular genetics and human variation.

The Foundation recognizes that the identification of susceptibility genes for complex disorders, such as schizophrenia, offers new possibilities for developing medications and approaches to prevention that will improve health and alleviate human suffering. However, these discoveries also might provoke confusion, fear and stigma in a population that may not understand the fundamentals of genetics or appreciate the complexities of human variation.

The Foundation was created to promote >genetic literacy= for the general public and serve as a resource for genetic counseling information for both the general public and health care professionals. The Foundation will emphasize educational programs for individuals affected by or at risk for complex diseases.

For more information on the Foundation for Genetic Education and Counseling, you can contact Joseph McInerney by phone at 410-614-9013 or by e-mail.

joemcinerney@genetic-medicine.org.

It is anticipated that the identification of the genes involved in mental illness will allow us to better understand the biological basis of these diseases. Once we understand what conditions exist in the body that predispose to schizophrenia and bipolar disorder, we hope that scientists will be able to develop new treatments.

This newsletter may be the first mechanism by which participants in our schizophrenia studies can learn about our efforts to determine the genetics of bipolar disorder. As described earlier in the newsletter, our group is studying bipolar disorder because of the potential overlap in risk genes for schizophrenia and bipolar disorder.

Bipolar disorder, also known as manic-depressive disorder, is a condition that affects one’s mood, emotions, and behavior. This section will describe the common symptoms of the disease, but bear in mind that there are a wide variety of clinical presentations of the disorder.

A person with bipolar disorder experiences mood episodes. These mood episodes can include depressive episodes, manic episodes, and mixed episodes. During depressive episodes, individuals usually experience sad mood, diminished interest in usual activities, and disturbances in sleep, appetite, energy, and concentration. Manic episodes typically involve either extremely happy or irritable mood, accompanied by other changes in behavior, such as increased activity, decreased need for sleep, grandiose thinking, and racing thoughts. Mixed episodes involve the simultaneous occurrence of depressive and manic symptoms. Sometimes individuals with bipolar disorder experience psychotic symptoms (such as delusions and hallucinations) during the mood episodes, but these psychotic symptoms go away when their mood returns to normal.

The duration of mood episodes typically lasts from a couple of weeks to many months. Between episodes people with bipolar disorder often return to their usual functioning and personality. Some people with the disorder can enjoy healthy, stable mood for many years between episodes, while others rapidly go in and out of mood episodes almost continually, while still others experience mood episodes at frequencies between these two extremes.

In the current popular diagnostic classification system (DSM-IV), a distinction is made between bipolar I disorder and bipolar II disorder, and many people are curious about the difference. People with bipolar II disorder have so-called hypomanic episodes, as opposed to the full-blown manic episodes experienced by those with bipolar I disorder. Both hypomanic and manic episodes involve the same symptoms (e.g., elevated mood, increased activity, decreased need for sleep, grandiosity, racing thoughts, excessive involvement in pleasurable activities, etc.), but there are several important differences. The most important difference is severity; that is, hypomanic episodes themselves do not cause significant distress or greatly impair one’s work, family, or social life, but manic episodes do disrupt these things.

As mentioned earlier in this newsletter, there is some evidence that there might be some common genetic causes of schizophrenia and bipolar disorder. This is not too surprising, since there is symptom overlap between the two disorders as well. Specifically, some people with bipolar disorder experience hallucinations and delusional ideas during mood episodes, while individuals with schizophrenia also can have these psychotic symptoms. Also, many people with schizophrenia experience episodes of manic or depressive symptoms. It is the timing and overlap of mood and psychotic symptoms that differentiate these two diagnostic categories.

Treatment for bipolar disorder often involves a mood-stabilizing medication, such as Lithium, Neurontin, Depakote, or Tegretol. Those individuals with bipolar disorder who also experience psychotic symptoms might also be treated with an antipsychotic medication, such as Haldol or Zyprexa. Therapy, support, and education about the illness are also important elements of a good treatment plan.

Coming soon! The Foundation for Genetic Education and Counseling is putting the finishing touches on a paper entitled AThe Genetics of Bipolar Disorder,@ which will be available on the Foundation for Genetic Education and Counseling site at http://www.genetic-medicine.org or by calling 410-614-9013.

The following books are recommended:

Goodwin, F.K. and Jamison, K.R. (1990). Manic-Depressive Illness.

Mondimore, Frank (1999). Bipolar Disorder: A Guide for Patients and Families.

NAMI: The National Alliance for the Mentally Ill

200 N. Glebe, Suite 1015, Arlington, VA 22203

Phone 703-524-7600 or 1-800-950-6264

Website: http://www.nami.org

National Depressive and Manic Depressive Association

730 N. Franklin Street, Suite 501

Chicago, Illinois 60610-3526

1-800-826-3632

National Institute of Mental Health (NIMH), Division of Communications

5600 Fishers Lane, Rockville, MD 20857

(301) 443-4536.

You may be interested in information on the NIMH website, including their fact sheets on mental illness at http://www.nimh.nih.gov/publicat/index.cfm

National Mental Health Association (NMHA), National Mental Health Information Center

1021 Prince Street, Alexandria, VA 22314

(703) 684-7722 or 1-800-969-6642.

___________________________________

By: Stephen L. Vincent, Ph.D. and Jill Bolte Taylor, Ph.D., Harvard Brain Bank

The use of postmortem human brain tissue in research has played a critical role in helping scientists demonstrate that the severe mental illnesses of schizophrenia and bipolar disorder are, in fact, biologically based brain disorders that can be successfully treated with medication. Using human brain tissues in research provides a one-of-a-kind window into the brain that helps scientists better understand the complex roles that brain chemicals, neuronal cell wiring, brain development, genes, and the neuro-stress response may play as possible co-contributors to the cause and emergence of these severe brain disorders.

The Harvard Brain Tissue Resource Center, at McLean Hospital, is a not-for-profit, federally funded "brain bank" that specializes in providing postmortem human brain specimens to scientists all over the country. The neuroscientists who have dedicated their careers to this type of research are completely dependent upon the goodwill of families with mental illness to donate brain specimens to brain banks for use in state-of-the-art research programs. However, to continue to explore the brain biology of psychotic disorders, scientists must have a continuous supply of these precious specimens available for comparison with brains from individuals with no psychiatric history.

To keep the research momentum going and to insure that this valuable tissue resource remains available in the future, the Harvard Brain Bank encourages affected families to consider the option of brain donation. Families who have previously participated in the brain donation process speak of their deep personal satisfaction in making such an enormous contribution to a growing nationwide effort that will, ultimately, lead to the development of new and more effective treatments.

For more information on the Harvard Brain Bank, call 1-800-BRAINBANK, or visit the website.

http://www.brainbank.mclean.org:8080/

1. If you have any specific questions about this study, or any questions in general, please feel free to contact us.

2. If you change residence or change your phone number, please notify us via phone, email or mail a change of address card.

3. If you or a relative have been diagnosed with a psychiatric disorder since the time we completed our psychiatric interview, please contact us and let us know. This is very important to our study.

4. Give us your comments about this newsletter by returning the attached form.