New Insight Into Mental Illness: Philosophical Implications

NEW INSIGHT into MENTAL ILLNESS:

by D. W. Woolley

THERE is a widespread belief that mental disease of the so-called functional kind arises from psychological rather than from organic abnormalities. Some recent biochemical discoveries, however, about a particular mental disease, namely phenylketonuria, may make us re-examine this common idea. The purpose of this paper is to explore the philosophical impact of this new concept of the causation of mental diseases and in particular to consider what it may mean for the understanding of the actions of normal minds.

Let us begin by mentioning why the idea of psychological cause has flourished in preference to others. It was primarily because no specific anatomical abnormality could be found in any particular mental disease of the functional kind. In schizophrenia or in manic-depressive psychosis there was no set of organic changes which marked the patients as being different from normal people, although, of course, they behaved abnormally. The belief arose that such mental diseases were the result of psychological damage perhaps suffered early in childhood, or according to some, even before birth. This way of looking at things has come to be known as the “Freudian” view. It is true that Freud said very little about schizophrenia and directed most of his discussions to neuroses, and to symptoms such as hysteria and anxiety, but his followers have taken his interpretations of mental abnormalities as fundamental to an understanding of the causes of the more severe mental diseases such as schizophrenia. His name has thus become attached to a widely held rationale for those mental diseases in which a distinctive anatomical or toxicological cause has not yet been found.

This “Freudian” concept of functional psychosis has been the prevailing one for quite some time. Its influence is prominent even in novels and plays and movies. Only within the past decade have dissenters become more outspoken because of the rather limited success its followers have had in controlling these mental diseases. Dissent has also increased because of the discovery of evidence to suggest that some specific biochemical abnormalities, particularly those involving the hormone serotonin, may be causally related to these psychoses. There has even been some success in the treatment of such diseases with therapeutic drugs based on these discoveries, and this, more than anything else, has increased dissent. Nevertheless, the Freudian philosophy is still dominant, especially in the large cities.

The importance of the lack of a distinctive and specific anatomical (that is, physical) sign cannot be overemphasized as a contributing factor in the thinking about causation of functional psychoses. If in all persons suffering from schizophrenia a characteristic anatomical abnormality were always present, the psychological hypothesis about causation would never have become so widely accepted. If, for example, one could always find that certain cells in schizophrenic brains were abnormal, one could easily believe that the malfunctioning of the mind was because of this anatomical lesion. In senile psychosis, for example, one can find these anatomical lesions, and therefore one does not need to go further to recognize why the mind of such a patient is sick.

So also in toxic psychoses, one does not need a psychological concept to understand why the mind has failed. Once the toxic agent has been recognized, there is a physical rationale for the disease. Thus, in the psychic changes arising from the use of alcohol or opium, there may be no anatomical lesion visible, but the cause of the mental failure is the taking of the drug.

In the case of functional psychoses, on the contrary, no characteristic physical or toxicological abnormality has been found, and largely for this reason the hypothesis about psychological trauma as the only cause has found favor. There have been numerous attempts to show that; schizophrenic persons have some special physical abnormality. Thus, they sometimes have a discoloration of the fingernails or a dryness of the skin, but these signs always turned out to be nonspecific. Some people who are not schizophrenic show the same signs, and there are schizophrenic people who do not show them.

LET US now consider the disease known as phenylketonuria, and particularly, let us examine some recent biochemical discoveries about its cause. Phenylketonuria is one of the inherited errors of metabolism. It is the inevitable result of the lack of a single recessive gene, the one having to do with The formation of the enzyme system which converts phenylalanine to tyrosine, the so-called hydroxylase. In persons who have this disease, the phenylalanine taken in their food is not metabolized to tyrosine and consequently accumulates in the tissues. Chemical analysis of the blood, for example, will show greatly increased concentrations of phenylalanine when compared to normal blood. Some of this excessive phenylalanine is deaminated to phenylpyruvic acid, and also converted to phenyllactic acid and phenylacetic acid, products which are present in the tissues and are excreted in the urine. A simple chemical test for phenylpyruvic acid in the urine (a green color when ferric chloride is added) is used to diagnose the disease. Normal people do not excrete a detectable amount of this acid.

Before the time in 1934 when Asbjörn Föiling, a Norwegian biochemist, first found a positive ferric chloride test in the urines of two brothers who were idiots, phenylketonuria was not recognized as a disease, and children suffering from it were often diagnosed as having childhood schizophrenia. Even in recent years this same misdiagnosis has been made, and patients have been committed to mental institutions as having childhood schizophrenia when in reality they have phenylketonuria, as shown by the ferric chloride test. It is well to bear this in mind because it shows how much like a functional psychosis the disease is.

The lack of characteristic physical signs in phenylketonuria is a most important fact. Patients with the disease are normal anatomically. They may be prone to epileptic attacks, but not all phenylketonurics have them, and most epileptics are not phenylketonurics. Similarly, phenylketonurics tend to have a blond complexion (which is understandable in view of their lack of the hydroxylase), but blondness is not a characteristic sign of phenylketonuria. In phenylketonuria, just as in schizophrenia and the other functional psychoses, there is no specific physical sign of the disease.

There is, however, a specific biochemical sign — namely, the presence of phenylpyruvic acid resulting from an excess of phenylalanine; and it is the one which is responsible for the mental failure. This specific biochemical sign is not reflected in characteristic anatomical abnormalities.

The mental failure in phenylketonuria is usually profound and begins early in life. Patients with the disease usually develop into morons or idiots. There is, however, a variation in the severity of the symptomatology among individuals. Most of the patients have intelligence quotients of about 30, but a few have been recorded with IQs of about 90, and one case of IQ 105 has been found. In general, however, a person with phenylketonuria, although he can learn the basic requirements of how to eat when food is provided, or how to put on clothes, is unable to function as a useful member of society.

The mental failure occurring in phenylketonuria can be prevented by reducing the amount of phenylalanine that the patient eats, a biochemical maneuver which establishes the biochemical cause of the mental defect. The reasoning behind this maneuver is that if the trouble in phenylketonuria is the failure to metabolize phenylalanine properly, the disease might be controlled by reduction of this amino acid in the food. The phenylalanine cannot be totally removed because it is one of the essential elements of food, but most of it can be removed, and a special diet low in phenylalanine is thus prepared.

When infants with phenylketonuria are raised on the phenylalanine-low diet, the profound mental defect seems not to develop. In order to succeed, it is absolutely essential that the special diet be started early in life, probably before two years of age. If it is started later in life, the idiocy is not prevented. Neither can it be cured once it has been established.

It is impossible to say at the present time whether the use of the phenylalanine-low diet will prevent all mental disease in phenylketonuric persons. The diet has been in use for only about twelve years, so that those who have been using it longest have still not grown to maturity. As will be pointed out below, there is a chance that these treated people may not entirely escape mental consequences, but it is plain at the present time that the characteristic idiocy of phenylketonuria does not develop when the special diet is used properly. When the phenylalanine intake is not restricted but is allowed to remain as it is in normal foods, the idiocy almost always develops.

Why should excess phenylalanine be harmful to the mind? The question is especially apt in view of the fact that phenylalanine is not only a normal constituent of animal tissues; it is also a dietary essential without which animals, including man, cannot survive. Why should it then be harmful in excess, and why should it harm the intellect without at the same time damaging many other organs?

DURING the past three years Theodore van der Hoeven and I have carried out experiments in laboratory animals which show that the cause of the mental defect is probably a deficiency of the hormone serotonin imposed early in infancy. In England C. M. B. Pare, M. Sandler, and R. S. Stacey had measured the content of serotonin in the blood of phenylketonuric patients and had found subnormal amounts. They made these measurements because in 1954 E. N. Shaw and I had done experiments to suggest that certain mental diseases, notably schizophrenia, probably arose from abnormalities in the metabolism of serotonin in the brain. Pare and the others therefore wanted to find out whether an abnormality with respect to serotonin also could be demonstrated in phenylketonuric idiots, and they were able to do so. H. Weil-Malherbe had shown earlier that the amounts of adrenaline in the blood were also subnormal. These findings were most suggestive because they showed some abnormality with respect to two hormones previously known to influence the functioning of nerves. They did not, however, show that the mental failure arose from these hormonal abnormalities. Nevertheless, my recent experiments with van der Hoeven in laboratory animals indicate that this may be the case with respect to serotonin.

The deficiencies of serotonin and of adrenaline probably arise in phenylketonuria in the following way. The excess phenylalanine, as we have seen earlier, is converted in the body to phenylpyruvic acid, phenyllactic acid, and phenylacetic acid. A. N. Davidson and M. Sandler showed that these acids inhibit the enzyme which forms both serotonin and a precursor of adrenaline. Although there is at the present time much discussion of whether this particular inhibition is the only one caused by these acids or by phenylalanine, the evidence is clear that it is an important contributor to the hormonal deficiency. When the excess of phenylalanine is prevented by suitable dietary measures, the deficiency of the hormones docs not occur.

In order to find out whether the deficiency of serotonin might be the cause of the mental failure in phenylketonuria, van der Hoeven and I produced phenylketonuria (the excretion of phenylpyruvic acid) in infant mice. We did this, as others had done previously with other species, by overloading normal mice with excess dietary phenylalanine. We found that it was necessary to begin the overloading at birth and to continue it to maturity. When the learning abilities of these animals were measured, they were found to be subnormal.

Other mice were raised on specific drugs which were known to cause serotonin deficiency in them by other mechanisms, and these mice also were found to be subnormal in learning ability. Finally, the defect in learning ability of phenylketonuric mice was prevented by administration of serotonin derivatives capable of penetration into the brain. These serotonin derivatives were administered from the time of birth in order to correct the serotonin deficiency in the brain early in life. They did not prevent the formation and excretion of phenylpyruvic acid, but they did seem to prevent the mental defect associated with the disease. They could not, of course, be expected to cure the mental defect once it was established.

One might object that the findings were made in animals and may have no relevance to the human disease and its cause. This objection is noteworthy. Nevertheless, we must not forget that the deficiency of serotonin has in fact been demonstrated by chemical analyses in the human disease. Since all phenylketonuric children are now, or at least should be, treated with the special diet, it is quite impossible to do the experiment with the serotonin derivatives in patients with the human form of the disease.

The philosophical implications of these discoveries about the mental failure of phenylketonuria neither arise from nor depend on any particular experimental detail. Instead, they arise from the realization that this disease, which for a long time was considered to be a typical functional psychosis, has, instead of a psychological cause, a biochemical one, which is manifested chemically in the tissues and psychologically in the behavior of the patient. It is now quite plain that if you are born with phenylketonuria — that is, if your genetic makeup is such that you lack the one particular gene (the hydroxylase gene) — you will develop into a mentally retarded, subnormal person, and this will take place no matter what your psychological background may be. The psychological environment can be changed until it approaches the ideal. All psychic trauma can be eliminated before and after birth, and you will still be a mental failure. The only thing which can make it otherwise is a specific biochemical interposition. You can avoid the trouble by restricting the intake of phenylalanine. You might also be able to avoid it by the intake of a suitable serotonin derivative. Always, however, unless something specific is done to correct the effects of the excess of phenylalanine, you will end up with severe mental failure, which you will then exhibit by all sorts of unacceptable behavior.

Phenylketonuria is no longer regarded as a functional psychosis. The discovery of phenylpyruvic acid in the urine of the patients removed it from that category. It may be that in like manner other functional psychoses will be found to have a chemical basis. Already there is considerable evidence to suggest that schizophrenia and manic-depressive psychosis may have their roots in abnormalities of the metabolism of serotonin. This evidence has been presented in detail in a book I published in 1952 (The Biochemical Bases of Psychoses, John Wiley & Sons, New York).

A more concrete connection between phenylketonuria and schizophrenia deserves some comment. In the book just mentioned, I suggested that when phenylketonuric persons who have been saved from idiocy by the phenylalanine-low diet grow to maturity, they can be expected to develop schizophrenia. The reasoning was as follows. The phenylalanine-low diet is expensive and distasteful in many ways. The pressure to escape a lifetime of it is therefore extreme. The evidence both clinically and from controlled experiments in laboratory animals suggests that it may not be necessary to use the special diet for a lifetime. It may be necessary to use it only during the first years of infancy and childhood, after which a return may be made to normal food for the remainder of the life-span. The economic and social and psychological pressures to do so have been so strong that the experiment of giving up the diet late in childhood is going on, already on a large scale, without anyone having planned it.

If the patient escapes idiocy by use of the diet and then at a “safe” age returns to normal foods, his serotonin deficiency will again be established, for reasons we have seen above. The enzyme which forms serotonin will be inhibited again by the phenylpyruvic and other acids arising from the excess phenylalanine.

Independent evidence has indicated that a serotonin deficiency imposed at the onset of maturity may be a prime factor in the causation of schizophrenia. The phenylketonuric person who has given up the special diet after the danger of the idiocy has passed may thus at maturity face a new mental disease. It is sad to reflect that this experiment on a large scale is being enacted quite unconsciously before our eyes. If the evidence now in our hands has validity, fifteen years from now a survey by any competent medical student may show that the incidence of schizophrenia is surprisingly high among those who in their infancy were treated successfully for phenylketonuria.

Already we have had a single case which bears on this point. We have knowledge of a young woman with typical schizophrenia who as a child gave positive tests for phenylpyruvic acid in her urine. The test was made because three other children in the same family were typical phenylketonurics with the characteristic mental failure. As a child, however, this young woman had been mentally normal, even though she had not been treated with the special diet. She may have been one of those rare phenylketonuric persons with a normal intelligence quotient. When she reached maturity, the test for phenylpyruvic acid became negative. Soon afterward, the schizophrenia became noticeable, and she now has been hospitalized for several years as a severe and typical case of this disease. There are some uncertainties in this case (for example, the disappearance of phenylpyruvic acid), but it may represent a forerunner of what we shall see on a large scale.

WITH these facts and deductions in mind, let us now consider some of their philosophical implications. These philosophical implications more than the medical ones are the subject of this discussion. The medical facts only give substance to the philosophy. Are we to assume that several aspects of the mind are controlled by a chemical substance called serotonin? Does it call the shots so that in infancy the developing brain depends on it for some of the control of those enzymatic processes which if activated in proper sequence result in a normal intellect? The idea that it does would seem to be a conclusion indicated by the findings in phenylketonuria. It would now seem that when the serotonin deficiency is imposed early in life, permanent damage to the intellect almost always results. When the deficiency is not imposed until later in life, at a time when the brain is fully developed, the mental effects may be somewhat different. Nevertheless, considerable evidence suggests that there are mental effects which may be rather profound.

If a deficiency of serotonin in infancy can have such deleterious effects on the mind as are found in most untreated phenylketonuric persons, we can wonder whether it might be possible to do the reverse and to cast some form of superintelligence in this same mold by suitable chemical intervention. It is conceivable that it might be possible to increase artificially the serotonin in the brains of normal infant animals or even men, and thereby to increase permanently the intelligence of the adults which they become. No experiment to test this idea has been done, but many probably will be, at least with laboratory animals. Grave philosophical questions would be raised if it were found possible artificially to change the mind permanently.

Does the explanation of the differences in mental powers of individuals have some connection with genetically determined small variations in the metabolism of serotonin in the developing brain? From the results in phenylketonuria it would seem that the answer in some special circumstances can be yes. The discoveries in phenylketonuria show us how profoundly some fundamental aspects of mind can be influenced biochemically. Of course, we always knew this as a result of the long experience with drugs such as ethyl alcohol and hashish and opium, but somehow the full implications of these pharmacological effects have not been assimilated into philosophy. The substances, because they were foreign to the body, were always regarded as poisons.

Now, however, we see that a normal constituent of the body can, by changes in concentration therein, bring about most far-reaching and permanent effects on the intellect. Whether all individual variations in the mental powers can be ascribed to individual differences with respect to serotonin seems very unlikely, but the findings in phenylketonuria show the sort of thing which can happen.

Does psychological stress cause the chemical changes which influence behavior, or rather, do the chemical changes themselves cause the psychological and behavioral changes? There can be no doubt that psychological stress can result in chemical changes. There is a long series of experiments to corroborate this. It is equally true that specific chemical substances — from ethyl alcohol on down to modern ones — can change behavior and some other aspects of intelligence. How are we then to put the horse before the cart, or decide which is cart and which is horse? In struggling with this ancient problem it may be helpful to remember that in phenylketonuria, if the chemical change in the body is not prevented, the change in intelligence and behavior will inevitably take place. No amount of psychological manipulation will prevent it. If the specific chemical change is prevented, the damage to the intellect will not arise, or in more precise words, the typical idiocy will not develop.

This is not to say that one cannot drive a man mad, or do other damage to the intellect by sufficient psychological stress. We all know many of the things which can be done, and we can believe that they may depend for their effects on specific chemical changes. The nervous system is a marvelously complex structure which cannot be seen completely from any single isolated point of view. Nevertheless, it may help in the understanding of such complicated matters to bear in mind what we can learn from phenylketonuria. It represents an extreme which may help in the understanding of normal properties and of less severe abnormalities of the mind.

To answer the question of whether psychological stress is the primary causative factor of mental diseases or whether, instead, these diseases may have a physical basis is now possible. The biochemical changes can cause the mental effects. The fact that psychological stress may also be accompanied by mental changes probably means only that the stress results in the biochemical changes, which are then the direct cause of the mental aberrations. Whether the chemical changes arise indirectly as the result of psychological stresses or whether they are caused directly by biochemical abnormalities (as they are in phenylketonuria) is only of secondary importance. We begin to see clearly that it is the chemical changes which are more intimately related to the mental results.

To understand the nature of being and of thinking is the goal of philosophy. There are recently some suggestions that a small part of this understanding may be possible through biochemical means.