CHAPTER 1
Letter 1
Science and Mental Diseases
My first letter starts with mental diseases because this is where my research as a medical student began. My primary interest then was the cure of mental diseases. How did it come about that now, some forty-five years later, I am doing basic research on membranes?
Wagner-Jauregg, a famous Viennese psychiatrist who received the Nobel Prize in 1927 for his treatment of patients suffering from syphilitic general paresis dementia paralytica, said in his first lecture to medical students in Vienna: There are two kinds of psychiatrists. First there are those who came to the profession with conviction and devotion, who knew from the first semester of medical school that psychiatry was their field of interest. They are fascinated by mental diseases and not afraid to confront the violence and confusion of the mind. They want to cure psychotics and neurotics, they are psychiatrists at heart. Then there are the other types of psychiatrists who got into the field by accident, because they really didn't know what else to do. They didn't want to get up in the middle of the night to deliver babies or they happened to be offered a well-paying job in a state mental hospital. "I want you to know," said Wagner-Jauregg, "that I belong to the second category." He was very suspicious of the first category and coined the phrase that the major difference between the psychiatrists and the patients in a mental hospital is that the psychiatrists had a key.
I must confess that I belonged to the first category. I wanted to work with patients with mental disorders and I wanted to have a key — a key to the building but also a key to the understanding of the deranged mind. I was impressed with the relevance of the problem, the enormity of the economic burden to society which has to take financial responsibility for millions of mentally sick people. But most of all, I wanted to help these patients out of their nightmares.
Having been raised in Vienna to the music of psychoanalysis and the lullaby of the Oedipus complex, I turned first to the psychoanalytical approach, but I was soon plagued by doubts whether psychoses could be approached by psychoanalysis. In fact, Freud believed in the organic basis of the genesis of psychosis. He said in his book Beyond the Pleasure Principle (New York, 1924): "The shortcomings of our description would probably disappear if for the psychological terms we could substitute physiological or chemical ones." He continued: "Biology is truly a realm of limitless possibilities; we have the most surprising revelations to expect from it, and cannot conjecture what answers it will offer in some decades to the questions we have put to it. Perhaps they may be such as to overthrow the whole artificial structure of hypotheses."
In 1938, an invasion of a mass psychosis took place from Germany to Austria, and I hurriedly left for England. There I came across an article by J. H. Quastel, a brilliant British biochemist, on "Biochemistry and Mental Disorder" (in the book Perspectives in Biochemistry, Cambridge, England, 1936). I went to work with Dr. Quastel in a state mental hospital in Cardiff, Wales, on the effect of drugs on brain metabolism.
Quastel's hypothesis of mental diseases was this: The proteins of our food are digested in the body to amino acids, which are the building blocks of proteins. By splitting off one molecule of carbon dioxide, amino acids are then metabolized to toxic substances called amines. If there is something wrong with either the rate of production or the removal of these amines, brain metabolism is affected and mental disease may arise. There were two experimental facts on which this hypothesis was based. One, certain amines when given in large doses cause psychosis-like conditions. I mention three such drugs which are widely known: Mescaline, LSD, and amphetamine. LSD can precipitate a psychosis, and the chronic use of amphetamine may cause a clinical picture remarkably similar to schizophrenia. Two, Quastel found that various amines inhibit the metabolism of rat brain slices in the test tube.
Quastel's idea was that since sugar is the major food of the brain, we should look for changes in sugar metabolism induced by toxic amines. One of the experiments I did in Cardiff, with all the optimism and enthusiasm of youth, was to expose rat brains to the blood of schizophrenic patients. I reasoned that if toxic amines were present in their blood, they should inhibit the sugar metabolism of the rat brain. These experiments were doomed to failure because I knew too little about sugar metabolism and about the complexity of brain function and structure. But above all I knew too little about biogenic amines, so-called, because they are normal and biologically important ingredients of our body. Among them are potent hormones such as dopamine, adrenalin, and serotonin. As we shall see, these biogenic amines regulate our emotions and alertness. Many psychiatrists now believe that a disturbance in the function of biogenic amines in the brain is a key feature in psychosis. Amphetamine and LSD are toxic amines believed to induce psychosis by interfering with the proper function of the natural biogenic amines.
When I immigrated to the United States in 1941,1 encountered no interest in either toxic or biogenic amines, but there were funds available through the March of Dimes for research in poliomyelitis. I was happy to get a job with a salary of 12,000 dimes per year to explore the effect of polio viruses on brain metabolism. I soon discovered a defect in the utilization of sugar in the brains of mice infected with polio virus. But once again I could not proceed logically with the problem because we were lacking fundamental information on sugar metabolism.
This was a turning point in my career, for I realized that without fundamental knowledge of the biochemical processes we cannot understand diseases of either the body or the mind; we cannot design a logical approach to either their treatment or their prevention. I therefore turned to the study of basic processes of carbohydrate and energy metabolism.
Diagnosis and Classification
During the first decades of this century, psychiatrists developed the diagnosis of mental diseases — an important contribution. To make a diagnosis we need a classification, and the most useful classifications are dependent on basic studies, either biological or psychological. If we have a patient with an insulin deficiency, we treat the patient with insulin. However, if we were to call every patient with sugar in the urine a diabetic, we would find many patients who would not be helped by insulin. The trouble with most mental diseases is that we do not know their basic causes and we diagnose by symptoms and signs only. Yet the symptoms are even more vague than sugar in the urine. It is therefore remarkable that the classification of psychoses into two major groups — schizophrenic and manic-depressive diseases — turned out to be valuable and consistent with later genetic studies. However, in 1911, Bleuler in Switzerland recognized the complexity of schizophrenia and referred to "groups of schizophrenia." In 1966, under the sponsorship of the World Health Organization, an international classification of mental diseases was adopted. It resembles other international disagreements. In the preface of the official booklet of the American Psychiatric Association on the classification of mental diseases, the following comment was made regarding schizophrenia and the deliberations of the international committee. "Even if it had tried, the committee could not establish agreement about what this disorder is; it could only agree on what to call it." In the international classification, schizophrenia has the number 295: 295.0 is the simple type; 295.2 is the catatonic type; 295.23 is schizophrenia, catatonic type, excited; 295.24 is schizophrenia, catatonic type, withdrawn; and 295.90 is schizophrenia, chronic undifferentiated type. As can be seen, the classification is based purely on signs and symptoms. What is badly needed in psychiatry is a more biologically oriented classification. If we could find out why some schizophrenics are catatonic and why some are not, why some patients are always depressed while others go through cycles of depression and excitement, we might be able to refine our classifications. Responsiveness to drugs may also help us in improving the classification we now have.
Genetic Factors in Mental Diseases
The important role of genetic factors in mental diseases is now widely accepted. Well-controlled studies with children of psychotic patients adopted shortly after birth established not only a genetic role in psychoses, but supported the psychiatric classification. Schizophrenics are more likely born to schizophrenics, and manic-depressives to manic-depressives. But it is not a simple problem, and the most favored view is that there are multiple genetic and environmental factors that influence susceptibility to these diseases. These various factors need to be elucidated, and we should avoid a fatalism often associated in the public mind with the verdict of a genetic disease. There are no diseases, including infections, that are not influenced by genetic factors. As I shall elaborate, even diseases caused directly by an altered gene are amenable to a therapeutic approach.
In this connection, the mental disease phenylpyruvic oligophrenia, or phenylketonuria (PKU), is particularly important because it has influenced psychiatric thinking and has removed some of the stigma of a "genetic" disease. Here is a biochemical disease with a known lesion. An enzyme which metabolizes phenylalanine, one of the natural amino acids in our body, is lacking, and PKU patients have high blood levels of phenylalanine. Since phenylalanine is metabolized to dopamine, the relation to the biogenic amines becomes obvious. What is the cause of the mental retardation of PKU patients? It appears from animal studies and recently also from clinical patients that high blood levels of phenylalanine are very toxic in early life but much less so in adulthood. Therefore, mental retardation can be prevented, or at least alleviated, in many cases by giving PKU babies a diet low in phenylalanine* This must be done early, and fortunately in many states testing of newborn babies for PKU is compulsory. There are now many cases of PKU adults who had been successfully treated with the diet shortly after birth.
PKU is a mental deficiency disease and not a psychosis. Another, much rarer, genetic disease that gives rise to psychotic symptoms is Hartnup disease, which is associated with the faulty metabolism of another natural amino acid called tryptophan. The biogenic amine serotonin is manufactured in the body from tryptophan. Thus we see another possible link between psychoses and biogenic amines. But tryptophan is also required for the production of the vitamin nicotinamide, a representative of the vitamin B group. A lack of nicotinamide gives rise to a disease called pellagra, which has, among its symptoms, lesions of the skin as well as psychotic manifestations. The faulty metabolism of tryptophan in Hartnup disease may lead to deficiency of a vitamin as well as of a biogenic amine. We are only beginning to learn about the complexity of interactions between such multiple factors. Moreover we now know that a deficiency in one biogenic amine or in one vitamin influences the functions of other amines and vitamins. We need to know more about these fine-tuning mechanisms in general and more about the specific changes in biogenic amines and vitamins in Hartnup disease before we can design a rational treatment.
An intriguing genetic disease was described by M. Lesch and W. L. Nyhan in the Journal of the American Medical Association (36, 1964). Children with this disease have symptoms of mental retardation, spasticity, strong tendencies of aggression, and compulsive self-mutilation. Unless strapped, they bite their hands and arms, severely wounding themselves. The genetics of this disease is well established. There is a defect in one gene which results in the lack of a single enzyme. How this single metabolic defect gives rise to a tendency of self-mutilation and aggression is completely unknown.
Biochemical Factors and Drug Therapy
What about the more frequent manic-depressive diseases and schizophrenia? Are they also biochemical diseases or are they environmental? Even though environmental factors play a role, I am convinced they are basically biochemical diseases because we can detect biochemical changes, because psychoses can be induced by chemicals, because of genetic studies, and because very specific drugs affect the disease. Although this kind of evidence is very circumstantial, I subscribe to this opinion because the biochemical hypothesis is the one which gives us hope for a cure.
Drugs such as chlorpromazine have radically changed both the clinical and sociological picture of schizophrenia. A few patients respond so well that they can leave the hospital without further treatment. Some have to be kept on the drug and some do not respond at all. In economic terms, the most important fact is that many patients become well enough to leave the hospital while remaining members of a therapeutic community.
The history of chlorpromazine is a fascinating story that should be known to every administrator responsible for the allocation of research funds, for it shows how completely unrelated research projects may profoundly influence another field. During the middle of the nineteenth century a chemist, while searching for a cure for malaria, accidentally prepared the first synthetic dye. This started the synthetic dye industry which is largely responsible for the colorful display of today's textiles, plastics, and paints. The dye industry more than once repaid their debt to medicine. Methylene blue was among the thousands of dyes that were synthesized. A curious cycle of discoveries was closed when, in 1891, Paul Ehrlich found that methylene blue is an effective drug in the treatment of malaria. Research in France during World War II led to the discovery that some compounds related to methylene blue were not only effective against malaria but counteracted certain allergic reactions. Again, by accident, it was discovered that some of these phenothiazine drugs, including chlorpromazine, made anesthetics more effective. It became an aid in the treatment of surgical shock and was found to have a calming effect on the behavior of patients. Chlorpromazine was finally tried on a mentally disturbed patient, and medical history was made. What a tortured road from malaria, via synthetic dyes, back to malaria, then to allergy, surgery, and schizophrenia!
Is there an administrator or scientist who could have stood up before a congressional committee and defended the study of methylene blue, anaphylaxis, the mode of action of histamine, or surgical shock as relevant for psychiatry? Yet the Evaluation Policy Committee of the National Institute of Mental Health has selected work on phenothiazine drugs as the most outstanding contribution in the past two decades in the treatment of schizophrenia.
How much do we know about the mode of action of chlorpromazine? Or shouldn't we care? Should we wait another hundred years for a scientist to synthesize a chemical compound that perhaps will be tried out as an anticancer drug and found to have behavioral action? Or perhaps someone will try this new chemical as a potential antipsychotic drug in a cancer patient and cure the cancer. Let us hope that such accidental discoveries will continue to bless us, but should we wait for them? Is it not more logical to find out how chlorpromazine works by supporting basic research on its mode of action? Unfortunately, the problem is not simple and may sound very confusing to a non-scientist.
