When they found him in the basement of his home in Bethesda, Md., in the summer of 1977, the young man was rigid, mute and immobile, the closest thing to a human statue that scientists from the nearby National Institutes of Health had ever seen.
Little did they know at the time that this bizarre case would have profound implications in the scientific quest for environmental factors that trigger or cause mental disorders, a key development in the revolution of brain research.
At first psychiatrists diagnosed the 22-year-old college chemistry major as a catatonic schizophrenic. But a neurologist, sensing the pleading in the eyes of the stony patient, thought the symptoms resembled a severe case of Parkinson`s disease.
No one, however, had ever seen advanced Parkinson`s in such a young person. Following his hunch, the neurologist gave the patient L-dopa, the drug that replaces the important brain chemical dopamine in Parkinson`s patients. Without dopamine their muscles become frozen, although they can hear and see. Suddenly the human statue began to move and speak: ”What have you guys been doing to me?” He said he had been confused and frightened because he could see and hear things but couldn`t speak or move.
Realizing that they were onto something hot, a team of scientists headed by Dr. Irwin Kopin, director of the division of intramural research at the National Institute of Neurological and Communicative Disorders and Stroke in Bethesda, investigated the fascinating case of the young chemistry student.
”He went to school apparently for the sole purpose of learning how to synthesize drugs that he could use,” Kopin said.
One of the drugs he synthesized was a derivative of Demerol, a morphinelike painkiller. It was after taking several doses of his homemade potion that the young man turned to living stone.
Among the contaminants found in the potion was a chemical called MPTP. Scientists tested it on mice and rats, but it did not produce abnormal changes.
Despite his harrowing experience, the young man continued to abuse drugs and died two years later of an overdose. In an autopsy, scientists found that the youth`s dopamine-producing brain cells had been destroyed just as they are in older people with Parkinson`s disease.
After that, their investigation didn`t make much progress until the early `80s, when several more cases of Parkinson`s-like disease appeared in young people in California. They had also consumed designer drugs that were Demerol derivatives.
The scientists tested MPTP again but this time in monkeys. The monkeys showed the typical signs of Parkinson`s disease. An examination of their brains revealed that MPTP had selectively destroyed only their dopamine cells. It was a key discovery. Not only did it give scientists the first animal model of Parkinson`s disease, but it refocused attention on things in the environment that may play a role in mental illness.
Environmental insults to the brain may be extremely subtle, making them hard to determine. MPTP, the toxic contaminant in the Demerol derivative, was more precise than any surgeon`s scalpel. Of the billions of cells in the brain, MPTP destroyed only about 22,000, the critical dopamine-producing cells. Different toxins may affect other groups of cells that are responsible for various brain functions, resulting in a variety of mental diseases.
”We know that Parkinson`s disease is not inherited,” Kopin said.
”Therefore it`s environmental. What in the environment is it? Is it a virus, a combination of neurotoxins, the way we cook our food? Nobody really knows.”
The AIDS epidemic also underscores the potentially devastating hazards to the brain from things in the outside world. The deadly AIDS virus has two main targets, master cells of the immune system and brain cells. In 10 to 15 percent of the people who carry the virus, their only symptom of infection is dementia, a deterioration in intellectual and emotional functioning.
How the AIDS virus cripples the mind is being pieced together by Mark Gurney, a University of Chicago researcher who discovered a growth factor called neuroleukin. The growth factor, among a little-understood group of brain chemicals, plugs into receptors on brain cells and acts to maintain the health of cells. But part of the AIDS virus can plug into the same receptors as the growth factor, blocking neuroleukin`s important maintenance role. When that happens, the cell`s health declines, and it can no longer do its job.
These findings come at a critical time. Three major trends are at work that are bound to have dramatic repercussions on the way people think about mental illness and how they deal with it.
One trend is the disturbing new evidence that the rate of mental disorders in this country seems to be increasing, primarily among Baby Boomers.
Ten years ago it was estimated that 15 percent of the population suffered from some form of diagnosable mental disorder. Recent results of the largest study yet show that 19.1 percent of all Americans suffer from a diagnosable mental problem. Much of this increase is attributed to better reporting, but a significant part of it is thought to be a true and ominous increase.
The second trend, which may help explain the first, is the growing understanding that environmental factors appear to play a bigger role than previously thought in precipitating mental disorders, especially those linked to genetic vulnerability.
In most of these disorders, people are not born with an overt disease but with a genetic susceptibility to it. What triggers this vulnerability into manifesting disease may be the wear and tear of aging, toxic chemicals, social stress or some other environmental insult.
”None of these mental disorders are going to be single-factor disorders,” said Dr. Darrel Regier of the National Institute of Mental Health in Bethesda. ”They`re going to be like heart disease. There are going to be multifactorial causes for disorders like depression, including biological and genetic. And then there will have to be some kind of environmental exposure, which can be anything from toxins to stress to nutrition.”
Scientists are searching for the mysterious factor or factors that may be responsible for the increase in mental illnesses.
Is modern life more stressful than ever before? Are more young people abusing drugs and alcohol and handicapping their brains? Are there
undiscovered infectious agents afoot, such as the AIDS virus, that are affecting the brain? Do environmental toxins that damage brain cells accumulate as people live longer to cause such neurological disorders as Parkinson`s or Alzheimer`s disease?
The third trend is a major new effort to bring mental disease out of the closet. Scientists in the last few years have come to the realization that many disorders can be effectively treated but that most are not even diagnosed. Only about 1 in 5 of the estimated 9 million Americans with severe depression, for example, is being treated.
Based on its recent findings that short-term psychotherapy and drugs can control 80 percent to 90 percent of all major depression, the Institute of Mental Health launched a recent landmark public education program to alert the medical and mental health professions as well as the public to the need for diagnosis and treatment.
Drugs for manic-depressive illness are 70 percent to 80 percent effective. A single drug, lithium, the mainstay of manic-depressive therapy since the late `60s, has saved the nation an estimated $20 billion to $30 billion in treatment costs since its development. Lithium appears to correct a chemical imbalance in the brain, but its precise mechanism of action is unknown.
The Institute`s Depression Awareness, Recognition, Treatment (DART)
program is patterned after the highly successful public education campaign that brought high blood pressure, one of the nation`s most neglected disorders in the `60s, to the ranks of its best treated.
At the same time the institute is gearing up to tackle the most difficult mental illness of all, schizophrenia. Called the Schizophrenia Initiative, the program is designed to bring the powerful new tools of modern neuroscience to bear on this devastating disease.
Environmental causes of mental disorders are not new, but they tended to be ignored until recently.
Physicians noted an increase in the number of schizophrenia and Parkinson`s cases after the great flu pandemic of 1918, and some speculated that the flu virus might be involved.
More recently University of Southern California researchers, following a large Finnish population, found an increased risk of schizophrenia among people whose mothers had a viral infection during the last two-thirds of pregnancy.
”We suggest that it is less the type (of viral infection) than the timing of the disturbance during fetal neural development that is critical in determining risk for schizophrenia,” Dr. Sarnoff A. Mednick, a University of Southern California researcher, reported in the Archives of General Psychiatry.
While some scientists believe there is a link between viral infections during fetal development and schizophrenia, others are equally convinced that genetics plays the dominant role. If one identical twin, for instance, has schizophrenia, the other has an extremely high risk of having the same disorder, even if they were reared apart from birth. Nonidentical twins do not share this high risk.
Some mental disorders that used to be major problems have virtually disappeared after their causes were discovered.
At the turn of the century 1 in 10 mental hospital beds was occupied by patients suffering from brain damage caused by syphilis. The discovery of penicillin basically eliminated that source of dementia.
The same thing happened with pellagra, once a major cause of depression. The discovery that pellagra was a nutritional disease caused by a deficiency of nicotinic acid (a B vitamin) led to the virtual disappearance of this form of depression. All that was needed was a well-balanced diet.
Likewise, the mental retardation caused by German measles, which only a few decades ago accounted for 4 percent to 6 percent of all institutionalized people in the U.S., has been abolished. The development of the German measles vaccine in the 1960s broke the deadly chain of infection in which a mother passed the virus to her unborn infant.
The destructive neurological disease known as kuru, which afflicted New Guinea headhunters, was traced to a slow virus in the brain. When the natives stopped eating the brains of their victims, they stopped passing on the virus, and kuru abruptly declined.
Last year researchers at Albert Einstein College of Medicine in New York announced that they may have solved the puzzle of Guam disease. The scientists discovered a ”slow toxin” known as BMAA in a common food eaten by natives of the Pacific island. The natives have an unusually high rate of three neurological disorders: Parkinson`s, Alzheimer`s and amyotrophic lateral sclerosis, known as Lou Gehrig`s disease.
The slow toxin was isolated from the seed of the false sago plant, which the natives started eating regularly during the Japanese occupation, when food was scarce. When given to monkeys, BMAA produced a number of brain cell abnormalities, including Parkinson`s-like symptoms.
Ferreting out potential neurotoxins will be a major task of the University of Chicago`s ”minibrains.” These small clusters of neurons, which grow in culture the same way they do in the brain, are being used to assess the damage to brain cells caused by environmental toxins. The National Institute of Drug Abuse is funding a three-year $450,000 project to use the minibrains to test the potential damage of drugs that are abused.
”There may be an interaction between toxins, genetics and viruses that leads to specific brain-cell death, and specific cell death leads to disease,” said Dr. Alfred Heller, chairman of the University of Chicago`s department of pharmacological and physiological sciences.
”The crazy thing about it is that you don`t have to kill a lot of cells. You can kill a very small number of cells and you get a devastating disease,” Heller said.
When former President Jimmy Carter asked the National Institute of Mental Health to assess the state of the nation`s mental health in 1978, it estimated that about 1 in 7 Americans had some type of mental disorder. But their estimate was based on data that was at least 30 years old.
To get a more accurate assessment, the institute launched a 10-year, $21 million study of more than 20,000 people. The shocking results-that 1 in 5 Americans was found to be suffering from mental problems-spurred the institute to look for new treatments. Experts were also alarmed to find that there appeared to be a big increase of mental illness among younger people.
”The higher rates of anxiety and affective disorders (such as depression and manic-depressive illness) are in the younger age groups,” said the institute`s Regier, who heads the Epidemiological Catchment Area survey. ”We also know that the age of onset of many of these disorders begins in adolescence, earlier than we had previously thought.”
While some scientists argue over whether the increase in mental problems is real or due to better reporting, others point out that similar increases, particularly for depression, have been noted in at least five other countries. All report the same pattern, a major increase in depression since the 1940s.
”I`m pretty convinced that something rather profound happened in our society from about 1950 to 1980 and that it had its greatest impact on young people,” said Dr. Gerald Klerman of the New York Hospital-Cornell Medical Center.
”It could be some virus or some toxin in our food or water, or it could be these social forces that are changing the family, or urbanization, or the changing role of women, or stress,” he said.
The dramatic change in traditional family values may also affect mental health, Klerman said.
”We`ve come to value immediate consumption and gratification over investment in the future,” he continued. ”A 29-year-old woman or man confronted with the choice of having a child, which is an investment in the future, or buying a Porsche will more likely buy the Porsche. They`ll also decide to delay getting married, delay having kids, have fewer kids and for the wife to work. I think that has an adverse effect on human investment in terms of the family.”
A study by the Institute of Mental Health of 700 relatives of people with depressive or manic-depressive diseases showed that their risk of developing similar disorders doubled from 21.7 percent in 1910 to 40.6 percent after 1940. Suicides increased tenfold over the same period. Using relatives of patients provides a magnified look at what is going on in the general population because they share genetic and environmental influences.
It is a dramatic increase and a growing public health problem, said Dr. Elliot S. Gershon, the institute`s neurogeneticist who conducted the study.
”We`ve just become aware of it,” he said. ”It`s so speculative now as to what`s causing it. My personal suspicion is that it`s caused by increased exposure of these later-born people to alcohol, tobacco and drugs of abuse.” ”Angel dust” or PCP, for instance, can induce memory problems and symptoms of schizophrenia. Cocaine has been linked to seizures, and
”ecstasy” (MDMA) has been found to cause brain damage in animals.
It`s a genetic-environmental interaction, he said. Something in the last 40 years has made a big difference so that people who are genetically vulnerable to these disorders are now more likely to express them.
Even if the rate of mental illnesses does not continue to increase, the problem will get worse, said Gershon. The reason is that the new trend for younger people to develop mood disorders is superimposed on the old pattern in which these disorders typically occurred in older age groups.
”I would predict that we will have a lot more mood disorders, including mania and depression, and a lot more suicides in the population in 20 to 30 years than we do now,” he said.
Dr. Lee N. Robins of Washington University in St. Louis, who took part in the institute survey of the nation`s mental health, said older people don`t have as much depression as younger people even though they`ve lived longer.
”We think that maybe lifestyle has something to do with it,” she said.
”We explained it in part by the increase in drugs and broken marriages but not entirely. We really don`t know why it`s happening.”
Seeking the reasons has become a top priority of the institute. Once a cause is found, changes in lifestyle may be able to reduce a susceptible person`s risk of developing depression, schizophrenia or other disorders. Heart disease, for instance, is a biological disorder, yet many of the measures used to prevent it are psychosocial: stopping smoking, controlling diet, exercising more.
A second shocking finding of the mental health survey was that most people with depression are either not diagnosed or inappropriately treated.
A person with clinical depression has four or more symptoms: sad, depressed or empty mood; feelings of guilt, helplessness, hopelessness;
thoughts of death or suicide; decreased energy; sleep disturbances; eating disturbances; diminished ability to think or concentrate for two weeks or more. This is not the everyday kind of depression that everyone experiences because of setbacks and disappointments.
Although 1 woman in 5 and 1 man in 8 will suffer from severe depression at some point in their lives, many do not recognize it. Many who do recognize the symptoms are reluctant to seek help because they regard depression as a character weakness. Doctors are reluctant to diagnose depression for fear of angering their patients.
Only about 1 in 3 depressed people seeks help, said Joyce Lazar, director of the Institute of Mental Health`s DART program. Of those who go to primary- care physicians, only 1 in 5 to 1 in 10 is accurately diagnosed, she added.
The results of the mental health survey, along with a second study showing that 80 percent to 90 percent of depressives can be treated, led to the unprecedented DART program, Lazar said.
The second study revealed that two forms of relatively brief psychotherapy produced the same rate of success after 16 weeks as imipramine, a widely used antidepressant. The psychosocial interventions involved cognitive behavioral therapy, which tries to alter a person`s distorted views about himself and his environment, and interpersonal therapy, which attempts to ease role conflicts, grief and destructive interpersonal relationships.
”Because we saw that depressed people were getting no treatment or inappropriate treatment, the first thing we initiated was training programs for professionals-physicians, psychologists and psychiatrists,” Lazar said.
There are nowhere near enough psychiatrists to treat the estimated 9 million depressed Americans, she said. Primary-care physicians see the bulk of depressed patients, and they have to be educated to recognize the disorder and treat it, she said.
Psychologists who treat many depressed patients with psychotherapeutic intervention, but who cannot prescribe antidepressant drugs, must be encouraged to work with doctors, Lazar said. The physician can prescribe the medication, and the two working together can decide on the best course for a patient, which may include a combination of drugs and psychotherapy, she explained.
Eventually state laws may be changed to permit psychologists to prescribe antidepressant drugs, just as optometrists now are allowed to prescribe certain eye medications, she said.
The next phase, which is expected to start soon, is a massive public education campaign. As part of its Community Partners program, the institute is enlisting the help of such groups as the National Mental Health
Association, the National Alliance for the Mentally Ill, state mental health departments and other groups. Their goal is to spread the word about how widespread depression is and that it can be diagnosed and adequately treated. Early treatment of depression, schizophrenia and other major mental disorders may have an important secondary benefit. Studies indicate that people placed on antipsychotic medications when the first psychotic episodes occur have fewer problems in the long run than patients whose treatment is delayed.
”The more you can postpone a depressive episode, the fewer episodes there are likely to be, and perhaps we can prevent them altogether,” Lazar said.
