Write-Up of Oral Presentation given to Ethics in the Era of Genetics class at Dowling

College on January 27, 2000.

My presentation today is on Genetics and its effect on mental disorders. I will briefly explain what a mental disorder is, talk about some of the research that is currently being done and touch upon some ethical issues.

The Diagnostic and Statistical Manual of Mental Disorders IV lists approximately 450 different classifications of mental disorders. Mental disorders affect a person's mood, thinking, feeling, behavior and motivation and ability to relate to others.

The disorder that is the focus of my presentation today is schizophrenia. The reason is that it is one of the most frequently occurring mental disorders. It is very common in that it occurs in about 1 out of every 100 people. There is a 10% risk to a person if a mother, father, sister or brother has the disease. There is a 40% risk if both parents have it. With respect to twins, there is a 15% chance if a non-identical twin has it and a 50% chance if an identical twin has the disease. The reason that the rate of occurrence for identical twins is not 100% is that when the genes are bent or folded, they are altered somewhat. Therefore, twins are not truly identical.

The symptoms of schizophrenia fall into two categories, positive and negative symptoms. Some of the positive symptoms are impaired thinking, talking gibberish or to oneself, and experiencing hallucinations of hearing, seeing, smelling, or tasting things that are not present. The schizophrenic might experience command hallucinations which are voices that direct them to harm themselves or others. Schizophrenics frequently experience delusions where they believe themselves to be a famous person. Psychosis, the state of being out of touch with reality, is common, as is paranoia, where they believe that they are being observed by some outside force. The features of negative symptoms are blunted or flat effect, where the person's face registers no emotion, avolition, where the schizophrenic has no motivation or initiative, anhedonia, where the schizophrenic cannot experience pleasure and has no interest in life and attention deficits where the schizophrenic is unable to concentrate. In addition, there are several types of schizophrenia.

As you can see this is a very complicated disease. Some doctors think it is a syndrome, or collection of diseases. It is also speculated that there is more than one gene. responsible. Researchers refer to this as polygenic. Perhaps one gene exists for the positive symptoms and one for the negative. To complicate matters further, schizophrenics frequently have other mental disorders such as depression, anxiety disorder and personality disorder.

Researchers also feel strongly that the disease has an environmental component. Some of the theories under investigation are exposure to a virus, some form of nutritional deficiency where the body lacks, or is unable to metabolize a chemical, and obstetric complications during birth. In addition, researchers have determined that the use of illegal drugs and stress, while not a cause, can trigger symptoms.

It has long been suspected that schizophrenia might be inherited. However, this suspicion had little impact on psychiatric research into genetic causes. Researchers focused on life events that were easily observable or could be evaluated through a life history. Environment could be changed. Heredity could not.

That mindset changed when the knowledge of DNA's structure and function of genes, as well as specific gene variants (alleles) began to be investigated. There was new excitement in the research community because once disease-causing alleles were found, new drugs could specifically designed to counteract symptoms.

Although research led to the discovery of the gene variant for Huntington disease in the early 1990's, psychiatric discoveries have been slow in coming. While researchers suspect it is a genetic disease, it does not fit dominant or recessive patterns in that the transmission from generation to generation is weaker than Huntington Disease. In addition, unlike Huntington disease, parents of people with schizophrenia generally don't have the disease. Its weaker inheritance pattern is characteristic of a large category of familial diseases called complex diseases in that they require the orchestrated cooperation of particular alleles of several different genes in order to become activated. This differs from a Mendelian disease such as Huntington disease that is monogenic and the inheritance pattern is very specific. Schizophrenia is suspected to have susceptibility gene variants that contribute to vulnerability without causing them. There may be multiple genes and different combinations of susceptibility genes may play a part. This is referred to as genetic heterogeneity.

So far researchers have found that a specific sequence on chromosome 8 boosts susceptibility to schizophrenia for people who have the signature sequence on chromosome 13. Also, a genetic link to chromosome 13 and 8 found in families in which some members had schizophrenia and others showed eccentric and withdrawn habits that have been diagnosed as schizophrenia spectrum personality. They have also found a chromosome 13 sequence in family members diagnosed with bipolar disorder. This has led some researchers to suspect that schizophrenia and bipolar disease may share some susceptibility genes. An unidentified gene on chromosome 6 contributes to disorganized thinking, delusions and hallucinations. There is also a genetic link to chromosome 13 in families where several members have mood disorders, hallucinations, and delusions

Researchers are unable to determine why the disease has not undergone extinction since most people with schizophrenia reproduce at an extremely low rate. The rate of schizophrenia is not higher in families where inbreeding occurs. Only one-third of individuals with schizophrenia have a family history. Two-thirds do not. An alternate explanation is that it is not a genetic disease. Rather, it involves a genetic predisposition like breast cancer or bowel cancer that needs to be exposed to an environmental agent for expression to occur.

Researchers have focused on Dopamine, a neurotransmitter that transmits information between nerve cells in the brain. They suspect that an excess of dopamine is one of the causes of schizophrenia. When amphetamines are administered in high doses, they produce a rise in dopamine levels while at same time produce symptoms similar to schizophrenia. L-Dopa, a drug that the body turns into dopamine, makes schizophrenic symptoms worse while drugs that block dopamine are effective in quelling symptoms of this disease.

In 1997 the Genetics Workgroup was formed at the direction of the National Institute of Mental health. Their mission was to make recommendations regarding future research of the various mental disorders. It was their recommendation that psychiatric genetics should be integrated with medical genetics rather than remaining an isolated field. They evaluated various mental disorders and decided that attention should be focused on the most promising targets for finding genes based on the strength of evidence for heritibility and other practical factors. They agreed that schizophrenia and bipolar disorder would be the best candidates for large-scale studies. The reasons are that the risk to first degree relatives is ten-times greater than the general population. Families with these disorders are numerous, have volunteered for studies and have contributed DNA samples. Additional volunteers are ready to assist. The fact that these diseases are frequently occurring in the population and pose medical, financial and sociological implications makes them a public health problem.

The researchers considered major depression. Although it is a more predominant in that it affects 5% of people at some time in their lives, it was not selected for study since the risk to first degree relatives is only twice as great as the general population. In addition, the role of genes is not as clear. Autism was considered since the risk to siblings is 4%. This is a larger percentage than it occurs in the general population. However, it does not occur frequently enough for a sufficient number of study samples to be collected.

The Genetics Workgroup did make a controversial recommendation that there be mandatory sharing of information by researchers. While they recognize that it limits the ability of researchers to compete for personal recognition and that competition fosters scientific discovery, they also state that the success of research depends on a sufficient accumulation of samples that can only be accomplished by sharing. They recommend that a balance between competition and cooperation be found.

Researchers estimate that considerable progress will be achieved within a decade. By that time the entire genome will be sequenced, screening tools will become available, and a large collection of DNA samples will have been collected. Researchers are optimistic because genes for other complex disorders, such as Alzheimer disease and diabetes, have been recently identified.

The National Bioethics Advisory Commission was established by President Clinton in order to evaluate issues and formulate policy. In December 1998 the Commission prepared and submitted to the President a report entitled Research Involving Persons with Mental Disorders That May Affect Decision-Making Capacity. They made recommendations that provide protection to individuals with diminished decision making capacity such as informed consent and surrogate consent.

There was a great deal of controversy regarding the categorization of levels of risk established by this Commission where research may be conducted on subjects with no expectation of personal benefit. Researchers objected to surrogate consent for research designated as Minor Increase Over Minimal Risk. It was their contention that the need to obtain permission for procedures where probability of harm or discomfort, including psychological harm and loss of privacy or other aspects of personal dignity are only slightly greater than the performance of routine physical or psychological examinations or tests would hamper research in that it would be time-consuming and might be difficult to obtain.

The examples given as falling under this category are positron emission tomographic (PET) scans (due to the injection of radioisotopes), magnetic resonance imaging with sedation, insertion of catheters for short durations or a lumbar puncture (with local anesthesia).

At this point the class was engaged in a discussion as to their opinions regarding this controversy. An interesting discussion ensued where class members either gave their opinion that these procedures should remain as those requiring consent, or that some the procedures should be divided into the two other categories of requiring no consent versus panel approval. Dr. Perring contrasted the need for approval with that of parents giving or withholding approval for procedures that might be done on children. When polled, none of the class members indicated that they would approve of the procedures being done on their children if it was not going to directly benefit them.

While it was uncomfortable to make a presentation to, and be evaluated by, peers, I was pleased to see I was rated very favorably by them on the evaluation sheets.

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Harvard Mental Health Letter, May 1999, Vol. 15, No. 11.

Keefe, Richard S. E. and Philip D. Harvey. Understanding Schizophrenia: A Guide to the New Research on Causes and Treatment. New York: The Free Press, 1994.

NAMI (National Alliance for the Mentally Ill) What is Mental Illness

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Oldham, John M., Stephan Haimowitz and Susan J. Delano. "Protection of Persons With Mental Disorders From Research Risk: A Response to the Report of the National Bioethics Advisory Commission." Archives of General Psychiatry. August 1999, Vol. 56, No. 8.

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