T H E COLLOID CHEMISTRY OF INSANITY. I* BY WILDER D. BANCROFT ASD G . HOLMES RICHTER**
It is only natural that a subject as interesting as insanity should have attracted the thoughts of men from the earliest times and invited speculations concerning its cause. I n ancient times there was a difference of opinion even among the “wise men.” Western civilizations regarded the afflicted person as one possessed of the devil and treated him accordingly. On the other hand, Eastern religions reasoned that the supreme being had prematurely removed the patient’s soul as a special mark of favor. Neither of these explanations satisfy the intellect, nor are they acceptable to the medical science. However, the difference of opinion still exists. Medical research was not slow to realize that physical causes were often a t the base of the trouble. Indeed their studies of the subject showing the relation of diseases, growths, drugs, and in some cases the absence or underdevelopment of certain structures warranted the belief that all types of this affliction might be traced to some definite physical cause, Le., some abnormal variation in the structures of the nervous system. A Meyersonl expresses the idea thus: “JT7hen we speak about the causes of the major mental disorders, we must leave out of account the psychoanalytic and psychological points of view. Yeither Freud, Jung, or ddler, to mention the great triumvirate who, like their Roman predecessors, once were in amity and now hopelessly divided, have dealt in sufficient measure with the insanities to give their points of view a validity. Kor is what they have contributed on these matters a t all pragmatically recognized in the practical world which deals with the mentally sick. Nor is the psychological point of view, e.g., of Bernard Hart, that mental diseases are psychological situations which must be psychologically studied and treated, anything more than a philosophical pronunciamentio. When a patient has had his skull crushed in and develops a delirium (which is, of course, a mental disorder), neither psychiatrist nor surgeon is fundamentally psychological either in his understanding or his treatment of the case. Physical ir, its cause, they employ physical means.” It is indeed disappointing to admit that the above point of view has not withstood the criticisms, and that in a number of cases there have been found no definite physical variations in the nervous system that would justify that viewpoint. Meyerson again formulates this delicate situation thus: “The term ‘organic’ in medicine means that some organ is involved in its structure in a way which can be studied satisfactorily after death by the post-mortem * This work is part of the programme now being carried out a t Cornell University under a grant from the Heckscher Foundation for the Advancement of Research established by August Heckscher a t Cornell Cniversity. ** National Research Fellow in Chemistry. “The Psychology of Mental Disorders” (1927).
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examination, or which can be tested out chemically or microscopically in life. This term is in contrast with the term ‘functional’ which implies that no study during life or after death reveals changes in structure, though very evidently there is something wrong with the working (i.e. function) of a part.” It is not the intention of this paper to discuss either point of view and its relative virtues but rather to indicate the application of colloid chemistry to this problem. To some workers this may appear audacious, that colloid chemists should claim that some of the phenomena are colloid in nature. We do not insist that colloid chemistry will explain all of the phenomena or serve as an extensive basis; but it is not improbable that, when medical knowledge is supplemented with colloid chemistry, the medical research worker, in addition to enjoying the fruits of both medical and chemical knowledge, will be freed of some of the present difficulties in regard to the “functional” disorders. Colloid chemistry is still a very young science and indeed owes much to biological workers for its discovery and early development. Its close relationship to biology and medicine is shown in the universal regularity: that all living matter is colloidal in nature. The colloidal nature of the proteins, polysaccharides, fats, lipoids, enzymes, glycogen, etc., is the essence of their importance to the living cell. In fact everything in the cell is either colloidal in nature or can cause the colloids to undergo some change. Despite this clear-cut case it is a perpetual source of surprise to some that medical workers do not attempt the study of colloid chemistry and apply it to their investigations. This peculiar state of affairs is understandable however if one considers the nature of some of their problems. A large number of pathological conditions can be easily demonstrated and studied by “fixing” and staining sections of the tissue and examining them with an ordinary microscope Let us take a specific example that concerns the nature of this paper, the histology of the nervous system. In order to examine this tissue in the regular way it is “fixed” usually in alcohol or formaldehyde containing various chemicals such as: bichloride of mercury, nitric acid, zinc chloride, ammonium molybdate, gold salts, acetic anhydride, picric acid, iodine, iron alum, osmic acid, silver nitrate, oxalic acid, or chromium salts.‘ The material is dehydrated, by passage through absolute alcohol, then embedded in paraffin. The material can now be cut easily into thin sections and stained by various dyes after removing the paraffin with xylene. This is the normal procedure for all material requiring microscopical examination. Colloid chemists will immediately note that the above reagents are, without exception, violent coagulating agents. The material that has been treated with such violent agents has nothing in common with a normal cell except the name. The reason for this procedure lies in the fact that, when microscopes with bright-field condensers are used, naturally objects whose refractive index is close to that of the surrounding medium cannot be seen clearly unless they are stained. The normal protein colloids do not have any appreciable tendency to adsorb dyes and become stained as long as they are peptized. In order to Lee: “The Microtomist’s Vade-Mecum” (1928).
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‘TILDER D . BASCROFT A N D G . HOLMES RICHTER
induce them to stain it is necessary to coagulate the material; hence the “fixing” agents are merely coagulating agents. The appearance of the finished preparation depends upon what fixing agent was used; naturally different types of coagulating agents produce different types of coagulation. It is interesting to note that when normal living cells are studied under the ultramicroscope they present an appearance radically different from that observed in the fixed and stained preparations.’ Still, this method can demonstrate bacteria in the tissues, the presence of abnormal growths, the absence of other structures, the extent of injury or degeneration, the differentiation of tissues, etc., so it has found a definite and valuable place in medicine. But it is indeed irrational to take the position that only knowledge gained through such methods is of any value to medicine, and that colloid chemistry is overstepping the bounds of propriety in pointing out that conclusions drawn from such studies are emphatically incomplete in relation to the living cell. For by their very nature they exclude the most characteristic properties of living material, namely the colloidal variations of the cell. Insanity is a phenomenon exhibited by living beings and the fact that medicine has demonstrated only causative agents such as bacterial disease, presence of abnormal growths, the absence of other structures, and injury and degeneration causes no surprise to colloid chemists. I t is a certainty that a t least’ some types of mental disorders are due to the abormal variations of the colloids of the living nervous tissue. To what extent this may be generalized is not known at present but it cannot be excluded as a possible factor in any case not already explainable upon the basis of disease or organic disorders. Furthermore, since such variations are merely in degree of dispersion it will be impossible to observe these physical changes with modern histological methods because the basis of such technique depends upon complete coagulation before the material is ever examined. Xaturally, an interested worker would desire to know what would be the effects of a given variation in the degree of dispersion of the colloids of the nervous system, what variations are possible, and upon what evidence the conclusions have been based. The eminent pharmacologist, C. Binz,? and Claude Bernard3 “the father of physiology” pointed out that the reversible coagulation of the sensory nerves and brain would account for all of the phenomena of narcosis. This theory soon fell into disrepute for two reasons: the assumptions regarding the process of coagulation were regarded as improbable and secondly their contemporaries were unable to fully comprehend the colloidal nature of the theory. Recently the assumptions mere reinvestigated and found to be correct.‘ For the sake of clearness the reversible coagulation mentioned above does not mean the degree of coagulation observed in G. Marinesco: Kolloid-Z., 11, 209 (1912); S. DeiYitt Ludlurn, Taft and S u g e n t : Archiv. Neurol. Psychiat., 23, 1 1 2 1 (1930). * Deutsche Klinik, Nr. 29, 277 (1860). “L’AnesthBsie” Union Med., Paris, 8 , 109 (1869). Bancroft and Richter: J. Phys. Chern., 35, 2 1 5 (1931).
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eggs on boiling, or in milk on becoming acid, or in the clotting of blood. I t is true that it is similar to these cases but it differs markedly in degree, the coagulation is very light: it cannot be seen with the naked eye and cannot be observed with an ordinary microscope. The flocculation can often be seen with the aid of an ultramicroscope and can be demonstrated in general by certain changes in the viscosity of the cell protoplasm. By reversible coagulation is meant that the colloidal material returns to its normal state as soon as it is freed from the coagulating agent. This type of colloidal change in nervous tissue will inhibit its action and cause it to be in a state of narcosis. I t is the “semi-coagulation” of Claude Bernard and can be brought about by certain drugs, suffocation, heat, cold, electrical currents, a physical blow, or even by the injection of water in some cases.’ The first two agents are the most important from the biological point of view. T7arious other explanations have been advanced to explain the action of drugs such as their distribution coefficients, surface tension, etc.; but the action of a drug does not depend so much on the physical properties of the substance as on the physical changes it initiates in the tissues. These changes are variations in the degree of dispersion of the colloids and this is the reason why intangible agencies as heat, cold, electricity, etc., can cause similar effects. The physical properties of a drug merely determine the distribution of the substance within the organism. Suffocation can also bring about changes in the tissue colloids but in a roundabout, fashion. Both aerobic and anaerobic oxidations not only serve as a source of energy to the cell but are very efficient detoxicating mechanisms. \Then asphyxiation is brought about, it allows the toxic products to accumulate to such a degree that they will cause the coagulation of the cell colloids. The following illustration may clarify the idea somewhat: most workers are familiar with the fact that a part of the lactic acid formed in certain tissues is converted back into glycogen and a part is oxidized to carbon dioxide and water. In the absence of oxygen the lactic acid accumulates to a marked extent. I t is not so well known that lactic acid, or the lactates, can behave as narcotics. Xevertheless, it is an established fact.* The abilityof lactic acid to coagulate bio-colloids is a familiar household experience in the souring of milk. One must bear in mind that there are a large number of substances that will accumulate and behave as in the above example, although the specific lactic acid example is used in the sense of an analogy rather than of an identity. In connection with the phenomena of reversible coagulation it is interesting to note that the increasing instability of the colloids, before coagulation has taken place, is associated with the phenomena of stimulation. The stimulation is manifested in many forms depending upon the type of substrate which is affected, thus enzymes show greater activity, some cells show increased growth and activity, nerves an increased irritability, while in the brain tissue the stimulation is manifested by bizarre mental reactions as in Bancroft and Richter: J. Phys. Chem., 35, 2 1j ( 1 9 3 1 ) . Mendel: Deutsch. med. Wochenschr., Nr. 1 7 April 29, ( 1 8 7 5 ) ; Moskowski Wratschevni U‘estnik, 1876 N o . 7 .
* E.
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WILDER D. BANCROFT .4ND G. HOLMES RICHTER
drunkenness. Thus in passing into narcosis the tissue is first stimulated then narcotized ; on recovery the passage back through the phase of stimulation is again noted. The increased activity of biological systems in their reactions and responses when the colloidal systems within them are approaching coagulation is quite important. Another type of coagulation has been studied and its importance and application pointed out.‘ This type is the irreversible coagulation of the cell colloids. Whenever irreversible coagulation occurs within a cell the result is death, provided the coagulation is extensive. The reversibility depends to a large extent upon a time factor; as a rule the reversibility of the coagulation becomes increasingly difficult the longer it is allowed to stand. lF7ith disinfectants a dense, irreversible coagulation is produced and in a number of cases can be observed with the ultramicroscope. An antiseptic behaves towards bacteria as an anesthetic affects higher organisms. I t inhibits the activity of the organism but does not kill unless the coagulation, due to the high concentration of the substance or the great length of time it is acting, becomes irreversible. The facts are briefly this: a coagulating agent first stimulates, inhibits, and then becomes lethal; the corresponding colloidal variations are : instability, reversible coagulation, and irreversible coagulation. If the substrate happens to be bacteria the order is the same: stimulation, antisepsis, and then disinfection. The phenomena and the colloid chemistry are the same on all simple substrates although the medical names vary. If we start with the assumption, that insanity is due to an abnormal state of dispersion of the brain colloids, we can have two types of insanity, one when the brain colloids are over-coagulated, and the other when the brain colloids are overdispersed. The general changes on adding dispersing agents will be towards the left as given below, and towards the right on adding coagulating agents: Death, insanity, Dispersion
normal, e--+
insanity sleep or irritability anesthesia, Coagulation
death
Let us see what can be made of these facts and postulates in a few specific examples. Alcohol is credited with some 8 or IO% of the mental disorders that lead to hospital incarceration. Alcohol is variously described as: an intoxicant, stimulant, narcotic, antiseptic, disinfectant, hypnotic, astringent, etc. Actually it is only a coagulating agent, which defines all of the above terms as soon as the substrate upon which it acts is given. If we confine our attention to its action on the brain, it is agreed that alcohol first stimulates and then depresses, the depression passing into sleep, anesthesia, or death depending upon the amount taken. If taken repeatedly in appreciable amounts it will cause some interesting disturbances. The stimulation of the visual faculties will bring about “the snakes,” while stimulation of the auditory regions will bring about hallucinations of hearing, and stimulation of other regions of 1
Bancroft and Richter: J. Phys. Chem., 35, 511 (1931).
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the brain will bring about general mental confusion. The combination of these effects in various degrees will mark the person as temporarily insane. These effects are due to the initial decrease in dispersion of the colloids of the nervous system and are entirely physical in nature. Since the initial phases of coagulation are easily reversible, it is not surprising to find that these cases recover in a short time. There is another type of reaction obtained after excessive and long-continued use of alcohol, marked by a demented state of long duration with pronounced disturbances of the intelligence, memory, and judgment. It is frequently associated with actual damage to the nervous system (Korsakoff’s Disease). This slow or incomplete recovery with damage to the nerves is clearly a case of coagulation that is difficultly reversible. The ability of alcohol to bring about alterations in the degree of dispersion of the colloids of the cell protoplasm is not hypothetical. Heilbrunn’ has shown by means of his viscosity studies that this effect of alcohol is quite common. hlarinesco,2using higher concentrations, was able to produce coagulations in the nerves of such density that he was able to photograph the colloidal change in the ultramicroscope. The mechanism of the coagulation with low concentrations of the material has been considered in another paper.3 Examples of damage to the nervous system, with the corresponding psychical changes, by means of known coagulating agents are very numerous. The action of lead on the nervous system is interesting. It is well known that lead salts can behave as coagulating agents towards bio-colloids. In fact their use in medicine as astringents and haemostatics depends upon this property. The effects of lead upon the brain are well known; it is found that there are but two phases of a ~ t i o n . In ~ low concentrations or in the initial stage of poisoning, stimulation of the brain and of the optic nerves causes hallucinations of sight and mental disturbances which resemble those of delirium tremens. The second phase is exactly what one would expect of a coagulating agent. The stage of stimulation passes into depression, during which the early symptoms of paresis appear. I n more advanced stages there is actual paralysis and damage to the nervous tissue. Lead is not alone in these effects; mercury, copper, and arsenic, which are coagulating agents, will cause disturbances of this type.5 Iodoform, an innocent coagulating agent, has a variety of actions that are understood best from a colloid point of view. The following quotation from “Useful Drugs” (1917) gives a good description of its effects. “Iodoform is a mild local analgesic, antiseptic, and stimulant. When adsorbed through the skin or from denuded surfaces, i t produces intoxication which is not evident until after the lapse of some time. When swallowed, it is partially decomposed with the production of iodides which produce their ordinary effects. Part of the drug is adsorbed, however, in a form of combination not yet under“The Colloid Chemistry of Protoplasm” (1928). 2Kolloid-Z, 11, 209 (1912). 3 Bancroft and Richter: J. Phys. Chem., 35, 215 (1931). J. F. Goodheart: J. Nervous and Mental Disease, 9,435 (1882). Dana: “Textbook of Nervous Diseases” (1915). 1
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stood, and produces sympt,oms that are different from those ordinarily caused by iodine. Iodoform is sxcreted slowly, iodine compounds appearing in the urine for several days after a single dose. “The symptoms are restlessness, anesthesia, sometimes unconsciousness, occasiona! convulsions, hallucinations, and delusions of persecution, rapid pulse and elevated temperature; in many cases collapse, coma, and death may follow.” Here is a case where local anesthetic, stimulant, intoxicant, hypnotic, antiseptic, and disinfectant are combined in one and the same substance. This action can be best explained on a colloid basis as outlined in the first part of this paper. The stimulation both locally and mentally being associated with the initial destabilization of the tissue colloids, which is later followed by reversible Coagulation producing the anesthetic effect, hypnosis, or antiseptic action. Disinfection and deat,h are due to the irreversible coagulation. Schede’ discusses a number of cases of insanity due to iodoform. He describes cases where the use of iodoform has been attended wit’h marked psychical symptoms. One type noted among children was a marked dullness of special senses. In adults he has seen great mental confusion produced by the external use of iodoform. In one case there was loss of personal identity, general mental confusion, loud singing, and violence. The substances mentioned above are in no manner exceptional. There are a host OF other coagulating agents that cause identically the same thing, to name but a few: morphine, henbane, cocaine, hashish, atropine, hyoscyamine, hyoscine, carbon bisulphide, tea, coffee, tobacco, and the interesting case of a mechanical blow upon the head. When one is struck upon the head, the preliminary stage of stimulation is passed through so rapidly that the effect seems only to be anesthesia or death. On recovery from such mechanical anesthesia the stage of stimulation can be seen as symptoms similar to those of intoxication. The case for the mechanical coagulation of the colloids of nerves has been discussed in another paper.? Indirect narcotics, such as carbon monoxide, have been known to produce insanity. A more interesting type is that produced by lowering the pressure of oxygen in a medium that is breathed by the subject. The exclusion of oxygen will lead to an asphyxiation narcosis; but, if the oxygen pressure is not decreased that far, an interesting series of mental reactions is observed. Such cases are important, because it is recognized that aviators in flying to high altitudes become temporarily incompetent.3 There is a height for each aviator above which it is not safe for him to go, This is termed his “flying ceiling.” The symptoms of the disturbance produced by tensions of oxygen lower than this value are mental confusion, leading to errors of performance: sometimes hallucinations of sight and hearing were found; in some men an uncontrollable desire to sing and whistle were manifested.
’ Centr. Chirurgit., S r . 3 (1882).
* Bancroft and
Richter: d . Phys. Chem., 35, 2 1j (1931). Sheep: The Flight Sur eon, Air Service Information Circular. July, 1921; Bagby: Psychopathology under l o a 8xygen Tension, ibid. May, 1920.
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I n conclusion, we may sum up the effects of both the direct and indirect coagulating agents by pointing out that when they are acting upon a given substrate, the increasing instability of the colloids followed by a reversible coagulation, which may later become irreversible, is associated with t’he stimulation, depression or narcosis, and actual damage observed in that tissue. The stimulation in particular is important because it is believed to be the source from which some of the mental phenomena of insanity originate. The important point is that not just any degree of dispersion of the cell colloids will satisfy the needs of the cell. There must be some normal and definite state of dispersion of the nerve colloids and any alteration from this normal state will bring about the same type of mental disturbance as is observed in cases with organic disorders. There are at least two major alterations that are possible; first a decrease in dispersion (coagulation) and second, an increase in dispersion (peptization). It has been shown that those coagulating agents that have a preferential adsorption for the higher nervous centers and bring about the alteration of the colloids of that tissue to a lower state of dispersion will reproduce phenomena that are associated with certain types of insanity. The alteration of the cell colloids in the opposite direction, towards an increase of dispersion, are also of an interesting character. Such an alteration can be accomplished by the preferential adsorption of an ion that will increase the potential difference between the colloid and the surrounding medium, or by the adsorption of another colloid, and thirdly by the adsorption of water. These are the three methods commonly employed in the laboratory to bring about peptization. If something were known of the chemistry of nerve cytoplasm it would be possible to discuss clearly the possibilities of peptization. Dana’ gives the necessary data. The reaction of the tissue is alkaline, water is the dispersing medium, the important thing being that “the albuminous substances, called also proteins by Halliburt,on, have lit,tle or no phosphorus and make up the most of the cell-body or the cytoplasm.” Peptizing salts for protein material in an alkaline medium have already received the attention of chemistry; from the Hofmeister series it is known that bromides, iodides, and thiocyanates will show this property in an alkaline medium. Deliberate studies of the physiological or psychological effects of peptizing agents on the nervous system do not exist. However, since the bromides, iodides, and thiocyanates have been extensively used without realizing that they were potent peptizing agents, the literature on these substances will furnish the necessary data if properly interpreted. Before considering the data it is well to point out that, since the increasing instability of the nerve colloids are associated with stimulation, stabilization would be expected to bring about the opposite effect, a t least up to a certain point. Also, it must not be overlooked that while the bromides, iodides, and thiocyanates are peptizing agents in an alkaline medium, they are just as potent coagulating agents in acid medium. This point will be emphasized later. “Textbook of Nervous Diseases" (1915).
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Krosd gives a good description of the effects of the bromides and a summary of the earlier literature. The bromides lower the reflex irritability, this is noticeable in the throat where the base of the tongue, palate, and pharynx are involved, making swallowing difficult and a perceptible slowing of speech. Mentally there is a feeling of exhaustion and confusion combined with a dimness of vision and a slight deafness. The heart action is slowed. Albertoni2 showed directly that the bromides lowered the irritability of the brain. He exposed the brains of dogs and by means of electrical stimulation found areas that when stimulated would produce convulsions in the animals. The animals were then fed upon bromides and the experiment repeated; it was found that in consequence of the bromide ion there was an enormous reduction in this irritability. Similar results were obtained by Bickels and Zbys~ewski.~ Although bromides are frequently referred t o as hypnotics, they differ in that bromides produce restfulness through lowering of the reflex irritability, thus permitting a normal uninterrupted sleep to be realized. It is for this reason that they are so effective in combination with a true hypnotic such as chloral. Peptization, unlike coagulation, is not very rapid; hence the administration of small amounts over long periods of time shows some effects that are different from those of a single dose. When administered over long periods of time there is no great tendency to sleep and the motor regions lose their irritability to such an extent that paralysis results and continued administration a t this stage produces death. The effect of the iodides have been studied by M. Sgalitzer.' The decrease in respiration frequency, lowering of the temperature, slowing of the pulse, etc., are similar to that produced by the bromides. I n high concentrations there is the decreased irritability of the motor regions which will pass into paralysis. It was noted that narcosis was not produced by the iodides. Death is due to the paralysis of the breathing center. The ready decomposition of the iodides in the body with the liberation of iodine and the additional effect of iodine upon the thyroid complicate the pure peptizing action somewhat. The literature on the action of the thiocyanates upon the nervous system is not very extensive. As to be expected, their effects are not unlike those of the bromides and iodides in lowering the irritability of the motor region^.^ The ability of the thiocyanates to cause mental disturbance has been noted. J. F. Bo& describes the condition: "Toxic psychoses developed in four patients, with disorientation, hallucinations of sight and hearing, mania, confusion, and ideas of persecution, singly or in combination. They lasted only from five to seven days after the drug was stopped. They were all in patients to whom it had been necessary to give large doses to obtain a desirable reduc'Archiv. exp. Path. Pharmakol., 6, I (1877). Archiv. exp. Path. Pharmakol., 15, 251 (1882). a Neurol. Zentr.. 17, 1081;Zentr. Physiol., 34, 366. Archiv. intern. Pharmacodynamie, 18, 284. Munch. med. Wochenschr., 50, 153 (1903); Centr. ges. Ther., 22, 19 (1904); Med. Klinik, 8,234 (1912);Wiener klin. Wochenschr., 25, 794 (1912). Minn. Med., 13, 281 (1930).
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tion [of blood pressure].” The thiocyanates have been the least studied of all the peptizing agents, although it is probable that they will show this property t o a greater degree than any other ion. Throughout this series of bromides, iodides, and thiocyanates two interesting side effects are always noticeable, namely, irritation of the stomach and the skin. It will be recalled that in acid media these ions are strong coagulating agents, Naturally the coagulating effect in the stomach is due to the acidity of the gastric juices and will lead to the nausea and vomiting that are frequently observed. The effect on the skin is also intelligible if it is remembered that in most cases the perspiration is acid in reaction,l naturally the effect of coagulation would be irritation. The conclusions that can be drawn from the study of the influence of coagulating and peptizing agents on the nervous centers are evident. h variation in the degree of dispersion of the colloids of such tissue from the normal state will bring forth abnormal mental reactions that are found to be not unlike the phenomena of insanity. Hence it is not improbable that in mental disorders not directly traceable to any organic disturbances, the cause may be due to some variation from the normal state of the brain colloids. Such a point of view is of great service because it can explain the effects of drugs on cases of insanity, give a simple classification of the types of disorders, and a t the same time suggest substances that would alter favorably the course of the disorder. A few specific examples will clarify this position somewhat. If a case of mental disorder could be found that was due to the over-peptization of the brain colloids such a state would be favorably altered by coagulating agents, provided enough of the drug were given to decrease the dispersion to the normal state. Such cases that respond to treatment by coagulating agents are known and the following experiments make it seem highly probable that the abnormally high dispersion of the brain colloids are responsible for the condition. I n 1916 Loevenhart, Lorenz, Martin, and Malone2 were conducting experiments on stimulating the respiratory center with sodium cyanide. A very interesting observation was made in the case of a patient with dementia praecox. This patient had been mute for several months, but following the injection of sodium cyanide there was a short period in which “the patient made a few coherent and relevant responses to simple questions.” This peculiar property of sodium cyanide is not very marked and the substance is unsatisfactory. Later carbon dioxide was employed as a stimulant with very striking results.3 The results of this significant piece of work are best given in the authors’ own words: “The most favorable and striking reactions occurred in those patients who had been mute and mentally inaccessible for long period of time. I n these cases, after a short period of respiratory stimulation, this inaccessibility disappeared and the catatonia passed off. A 1
Hammaraten: “Text Book of Physiological Chemistry.” Archiv. Int. Med., 21, 10g (1918). Loevenhart, Lorens, and Waters: J. Am. Med. Assoc., 92, 880 (1929).
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number of patients have carried on conversation. .A few mentioned depressive thoughts. One patient was markedly facetious, making responses typical of talkative hebephrenic dementia praecox. Another patient, the least reactive of those so far observed, showed only a disappearance of muscular tension and a voluntary looking about the room and at those standing near. “A number of patients appeared frightened when the cerebral stimulation developed; they looked about apprehensively but became calm and a t ease quite promptly when efforts were made to reassure them. In other words, they seemed to comprehend the situation correctly, and, following this almost immediately, they made coherent and relevant replies to questions. In one patient who had been mute for more than six years, the efforts a t speech for about two minutes resulted in a jumble of unintelligible but speech-like sounds, after which the words became distinct and a successful conversation was held. “The cerebral stimulation, as evidenced by free muscular movements, animated features, and ability to carry on conversation and to comply with requests has lasted from two to t’wenty-five minutes.” “During the period of cerebral stimulation, the inhalation of carbon dioxide and oxygen was stopped. If no more gaseous mixture is given, the patient gradually returns to his former condition. This return is as striking as is the development of increased psychic activity. Gradually the patient’s attention can no longer be held; he ceases to respond to questions; muscular tensions redevelop, if previously present, and quite like the drawing of a curtain on psychic function, the patient returns to his former stuporous condition. In some cases, during the period of stimulated mental function, the patient responded quite like a talkative psychotic person, expressing many bizarre delusions and resembling in every way rather typical psychotic patients. In one notable case there was a prolonged period of from two to twelve minutes during which the patient maintained a comprehensive conversation without any evidence of psychosis; then quite suddenly the patient seemed to become frightened and began to express many delusions in a loud voice.!’ Since this manuscript was sent to the printer, there has appeared in the X e w York Times of March 29, an account of experiments by Dr. Karl Langenstrass on catatonic stupor a t St. Elizabeth’s Hospital in JVashington. “Several years ago it had been observed that, by making the patient inhale a mixture of carbon dioxide and oxygen, it was possible to bring him back to consciousness for a period no longer than thirty minutes, during which he would behave in a normal manner. With this as a clue experiments were begun a t St. Elizabeth’s Hospital two years ago under the direction of Dr. Karl Langenstrass, who today described the results [at the annual clinical session of the American College of Physicians]. “Various ways of prolonging the period of recovery have been tried out. Beginning with a mixture of five percent carbon dioxide and ninety-five percent oxygen, the proportions were shifted gradually until it was found that a mixture of twenty-five percent carbon dioxide and the rest oxygen was the most advantageous. In addition to the inhalation treatment, Dr. Langen-
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strass told further that suggestion therapy, a mild form of hypnosis, was tried on the patient as soon as the gas mask was removed from his face after about half an hour of inhaling the mixture. Typhoid vaccine and coli fluid were also administered for the purpose of producing a rise in temperfture. “The net result, Dr. Langenstrass stated, is that one patient who had been in a mental stupor for over ten years has now been perfectly normal for the last two years. One woman is now supporting a drunken husband and three or four children. In all, three cases have been sent out into the world again functioning normally without any need of further treatment. The original treatment lasted for about a month.’’ Both sodium cyanide and carbon dioxide are known to be narcotic or coagulating agents, the carbon dioxide acting directly’ while the sodium cyanide is an indirect narcotic.? It is t o be noted that the reactions were observed before narcosis, or reversible coagulation was reached. It was also found that it was possible to narcotize a patient and observe the interesting phenomena after narcosis. W. F. Lorenz3 describes the observations: “It, was found that cases of catatonic stupor responded to this narcotic [sodium amytal] quite like a normal individual. That is, within 4 or 5 minutes, and before a total of I O to 14 C.C.of the solution are injected they sink into deep sleep. The muscular rigidity disappears; the reflexes are abolished; breathing becomes slow and quite shallow; the systolic blood pressure falls 30 to 40 millimeters of mercury. After an hour the blood pressure returns to its former level; the patient can then be aroused and will respond to painful stimuli. Then follows a period of what appears to be normal sleep, the duration of which is largely determined by noises or other disturbing environmental influences. “In the stuporous, catatonic cases we have seen prolonged periods of mental clearness following the state of deep narcosis. A brief account of one such case will serve to illustrate the striking change in mental condition, which is being presented. Case-T.1T. (female) ; age z j ; married and the mother of two children. She had been in a state of catatonic stupor for a period of four months when she was admitted to our service and sodium amytal administered. At this time the patient showed rather extreme muscular rigidity; active negativism; her limbs, head and body in a flexed position resembling the fetal posture. She had been tube-fed for over four months and voided involuntarily. Furthermore, she was in a state of extreme emaciation, weighing 66 pounds. “This patient was given I / Z gm. of sodium amytal dissolved in I O C.C.of distilled water by intravenous route. Within 5 minutes she was in a state of deep narcosis. The muscular rigidity had disappeared; all reflexes, including the corneal, were absent. She continued in this state of deep narcosis for about an hour and then continued a t a level of unconsciousness which could be influenced by slight painful stimuli. She remained in this condition
’ Heilbrunn: “The Colloid Chemistry of
Protoplasm” (1928). Bancroft and Richter: J. Phys. Chem., 35, 2 1 5 (1931). Psychiatric Quarterly, 4, 95 (1930).
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another three hours, or a total of 7 hours, after the time of the injection. She was then aroused by speech and she responded to conversation, asked for food and drink. She continued in this aroused mental state for a period of four hours, when no further efforts were made to keep her awake and she dropped into what appeared to be a natural sleep for a period of five hours, when the mutism, muscular rigidity, and active negativism slowly redeveloped. ” Looney‘ studied the blood analysis of catatonic patients and found that there was an abnormally low amount of calcium present and an increase in creatine. He raised the calcium content slightly, but there was no change noted in the clinical condition of the patients. His investigation is being continued in the hope “that it will be possible to raise the calcium values up to about 15 mg. and keep it there for a period of a t least a week so that definite conclusions may be drawn as to whether such a change results in any diminution of the muscle tension.” English2 has employed an interesting coagulating agent, manganese chloride, in the treatment of nervous disorders. The following case is quoted from his study as indicative of the effects of treatment: ‘‘W.G.H.-18 years; single. Catatonic schizophrenia. Yutritive condition poor and inferior muscular development. Was defective as a student. Symptoms exhibited three weeks previous to admission. Dull, stupid state changing to one of impulsiveness and he became sleepless, stubborn and negativistic. He lay in bed markedly indifferent and refused food, and, if up, would stand for a considerable time even if placed in an uncomfortable position. “He was given a course of manganese chloride and his weight, which was 88 pounds before treatment, increased to 146 pounds. There was also a marked change in his mental condition-he is now bright in manner, tidy in habits and thoroughly mischievous and over active.” The original work should be consulted for other interesting cases. Berger3 has also had an interesting experience with the effect of coagulating drugs and catatonic stupor. He injected eleven patients with small amounts of cocaine hydrochloride and noted that the majority became suddenly active after the first injection. Like some of the above cases, the improvement did not last more than an hour or two. His observations lead him to regard the basis of catatonic stupor as a diminution of the processes of dissimilation and of the cortical functions generally. He does not regard the theory of psychic origin of catatonic stupor with favor. Such striking responses as the above cases to known colloidal coagulating agents cannot help but impress one that the stuporous catatonic state is associated with an over-peptization of the colloids; and that the gradual decrease in dispersion produced by the narcotics must pass through the normal degree of dispersion before the other extreme of reversible coagulation is reached. Conversely, if the brain colloids of such cases are coagulated re‘ A m . J. Psychiatry, 5 , 213 (192j). Am. J. Psychiatry, 9, 569 (1929). 3 Munch. med. Wochenschr., No. I j (1921)
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versibly and then allowed to pass slowly to the state of abnormally high dispersion, the system would again have to pass through the intermediate normal colloidal and mental state, as was found in the case that became normal anesthesia. The truth of this view is justified and strengthened in the fact that cases of mental disorders due to the opposite effect, i.e. decreased dispersion, can be materially relieved by peptizing agents. This statement will be made more convincing by illustration of facts. Substances that so decrease the dispersion of the colloids of the central nervous system that it is ina state of stimulation can be antagonized bypeptizing agents. Januschke’ investigated a number of such cases. He was able to produce epileptoid convulsions in guinea pigs by means of camphor; running movements and clonic twitching of the muscles were marked. This condition would be maintained for several hours and in most cases would end with the death of the animal. Large doses of bromides would suppress these effects and even small doses would cause a marked diminution in intensity. Also the clonic contractions of the muscles of rabbits produced by cocaine, which are caused by the stimulation of the higher centers of the cerebrum, can be antagonized by bromides. The effects of picrotoxin can also be diminished by the bromides. He also found that the tonic reflex convulsions produced by strychnine could be abolished by means of the bromides. Since the bromides had no influence on physostigmine, which does not affect the cerebrum, he concluded that the primary effect of the bromide ion was on this and other centers of the spinal cord. The effects of bromides on epilepsy afford a very interesting study. The actual cause, or causes, of epilepsy are not known, so it is a functional disorder; some of the external symptoms are produced by a host of toxic agents such as alcohol, lead, camphor, etc., and even by mechanical injury to the head. It does not seem improbable that in some cases a decrease in dispersion of the colloids is associated with the disorder. Dana* in speaking of the pathology sags: “It is probable that in true epilepsy there is an instability of certain cell layers of the cortex cerebri and a tendency to degenerate”. Degeneration from a colloidal viewpoint is nothing more than the coagulation and subsequent digestion of the involved structures, as it is impossible to digest peptized substrates. As already indicated, the phenomena of epilepsy are similar to those produced by stimulants, so it is no surprise to find that in many cases the phenomena can be antagonized by peptizing agents such as the bromides. An unbiased account of the effects of bromides on epilepsy can be found in “iModern Medicine” by Osler and McCrae. They point out that “in view of the fact that the number of individual attacks is usually so speedily reduced by the exhibition of bromides, even to the entire suppression of them, the hope that the drug is a real curative agent in the disease has been and still is widely held. So great has been the reliance upon the bromides that real scientific therapy has actually been delayed by this erroneous empiricism. ‘Z. ges. exp. Med., 8, 1 7 ; Med. Klinik, 10, 389 ( 1 9 1 3 ) . *Text Book of Nervous Diseases” (1915).
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Until a few years ago the almost wholesale use of the drug made i t possible for a public clinic to count the cases showing bromide poisoning as the rule rather than the exception. Happily the recognition that there is an acquired art in the use of bromides is removing this reproach. “The whole plan of treatment including the bromides should be continued for years even though the attacks should cease. Some authorities regard the plan of successful routine a necessary plan of life henceforth; its long continuance after attacks have ceased (for several years a t least) seems to upbuild and make for permanency of the restored normal psyche.” Wright’ has recently studied the use of the bromides in functional disorders. He noted that the conditions which best respond to the bromide treatment were cases in which there was some degree of tension. Most of the cases in which the bromide treatment failed were found to occur in states of apathy. If the disorders in epilepsy are due to an instability of the colloids with a tendency to decrease in dispersion, there should be two methods of relieving the symptoms. The first of which has already been discussed, i.e. peptizing effect of the bromides. It has already been indicated in the first part of this paper that a coagulating agent affects a normal tissue by first stimulating, then depressing the tissue. The depression passes slowly into sleep, narcosis, or death, depending upon the concentration of the drug and reversibility of the coagulation. If the tissue is in the stage of stimulation, as in epilepsy, then small amounts of narcotics will relieve the hypertension, because it will merely push it into the initial phases of the depression preceding narcosis. It is to this fact that the barbituric acid derivatives owe their popularity in the treatment of epilepsy. The bromides have other interesting properties that would justify a more intensive investigation. In a recent paper we pointed out from theoretical reasons that peptizing agents might have a favorable effect in the treatment of drug addicts.2 Since then our attention has been drawn to several interesting cases of this type. MacLeod? in 1897, treated a patient, suffering from migraine and a highly nervous state, with bromides. The patient was also a confirmed morphine addict. The course of the treatment was such that the patient was in a deep stupor for several days such as that produced by the bromides. Upon recovery from the effects of the bromide he noted: “TOher own astonishment and that of the sisters (she had been in their charge previously) she had no desire for morphine from the time she entered the hospital, and I am glad to say it has not yet returned. “This case was, so to speak, cured by mistake and is all the more interesting that the patient had no desire to be cured, as she had informed me on several occasions. Naturally desirous of being certain how far the bromidism conAm. J. Psychiatry, 5, 365 (1926). Nat. Acad. Sci., 16, 573 (1930). *Brit. Med. J., 1897, 76.
* Bancroft and Richter: Roc.
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tributed to the result, I determined to test the question by excluding other conditions.” His next case was that of a pilot on a boat who was a confirmed morphine habitu6. The patient underwent a heroic treatment with the bromides and upon recovery was rejoiced over his deliverance from the craving for the morphine. An interesting side-light of this case was that he also lost the desire for liquor. These are not isolated cases; the treatment was tried on several other drug habitues with favorable results in all except one case, which succumbed due to an error of the nurse in giving an overdose of the bromide.’ Among these MacLeod says: “It is noteworthy that the loss of alcoholic craving in the second case was pointed out by the astonished patient himself.” Xaturally, such interesting observations did not wait long before they were confirmed by other workers. Church2 in America discussed the dangers of the treatment and apparently the whole matter was dropped. The unfavorable results were never due to lack of care, but more to the excessive doses of bromides. It should not be forgotten that it has never been shown that such large doses of bromides are necessary. 44s already mentioned, peptization is not rapid; hence the giving of bromides until toxic symptoms appear is dangerous, because the full toxic effect is somewhat delayed. The bromides should never be given to a patient with acidosis. We do not wish to give the impression that drug addiction and its cure is all a purely colloidal problem. It is very important in treating addicts to hasten the elimination of the drugs from their system. I n fact all the present-day treatments employ this as a preliminary measure; the next important thing is to restore the nerve colloids to their normal state, and this is best done only by colloidal means, such as peptization. The purging, education, hospital care, etc., of the patient are just as important but are not colloidal in nature and so have found no treatment in this paper. Quite aside from this, the mere fact that a plausible explanation has been given to the action of the bromides, it would seem that medical interest would be centered in other peptizing drugs. Both the iodides and thiocyanates have this property to a greater degree than the bromides. The iodides cannot be employed very well due to their unfavorable effect on the thyroid. However, the thiocyanates offer many interesting possibilities both in the treatment of epilepsy and drug addiction that would justify a very careful and comprehensive study. The bro-mides do not stand alone as examples of peptizing agents employed in medicine. The iodides have a limited application in the treatment of certain metallic poisonings, notably lead, mercury, and arsenic. As has already been indicated, the mental disturbances brought about by some poisons are similar to those shown in insanity. Clevenger3 observed a case of lead MacLeod: Brit. Med. J., April I j (1899).
ZN.Y. Med. J., 71, 904 (1900). Servous and Mental Disease, 11, 308 (1884).
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poisoning in which the symptoms of mute depression, observable in ordinary melancholia and epileptiform convulsions were present. He treated the patient with potassium iodide and in a short time the patient was discharged as fully recovered. He points out that “had the cause of this attack been unascertained, the patient would have died insane.’’ Oslerl gives a short summary of the use of the iodides in the treatment of cases of lead, arsenic and mercury poisoning. Naturally the manner in which the iodides relieve the symptoms of such cases is an interesting topic. On first thought i t might seem that the iodides form insoluble iodides with the metals and thus antagonize their action. This cannot be the complete story however, for the iodide of lead, for example, is soluble to the extent of 0.0442 gms. per IOO C.C. while lead chromate is soluble to the extent of 0.000007 gms. per IOO C.C. Yet lead chromate can easily bring about lead poisoning. While the amount of lead required to bring about poisoning is not known with great exactness, Brouardel considers that I mg. daily is sufficient. The treatment requires 0.3 gm of potassium iodide three times daily so that i t seems quite necessary that an excess of iodide be present. This excess iodide undoubtedly behaves in the body as it does in the laboratory and merely serves as a powerful peptizing agent to the coagulated colloids of the nervous tissue. This is by no means an exhaustive treatment of the subject dealing with the effects of colloidal reagents on the nervous system; the examples may be multiplied many fold, but the basic causes always come back to the alteration from the normal state of dispersion of the cell colloids. All of the work has been carried out by medical research workers who do not take into consideration that the materials they are dealing with are the best-known colloidal systems and that the drugs they use are potent reagents that will bring about colloidal changes in the tissues. Such a state of affairs is not conducive to a rapid advancement in knowledge concerning functional disorders. It is the hope of the authors that this paper may, in a small way, stimulate such workers to recognize that there is no sharp boundary between medicine and colloid chemistry, and that their researches are incomplete if they have not either included or excluded the variations of the tissue colloids in the pathological conditions. S-arY
Medicine regards the major mental disorders as organic or functional disturbances. The causes and ideas of functional abnormalities are very hazy and incomplete. It is shown that while modern histological methods are well adapted (2) to show the usual type of organic troubles they are absolutely inadequate to demonstrate the most characteristic property of living matter, i.e. the colloidal state, and its variations. (3) The suggestion is made that many of the “functional disorders” may be nothing more than an abnormal degree of dispersion of the nerve col(I)
“Modern Medicine” (1915).
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loids and have erroneously been classified as functional due to the inability of the histological technique to reveal the colloidal abnormalities. (4) A study of the effects of known coagulating agents on the normal nervous system reveals that such colloidal reagents will produce symptoms that are not unlike many of those of insanity. ( 5 ) The effects of peptizing agents are similar in many respects to other disorders. (6) This is definite proof of the view that there is a normal state of dispersion of the nerve colloids and that any alteration from this state will bring about abnormal mental reactions. (7) It is suggested that disorders of over-dispersion may be benefited by coagulating agents, and disorders of decreased dispersion would be improved by peptizing agents. ( 8 ) Some physiological symptoms of catatonia are similar to the effects produced by peptizing agents. The striking results obtained in treating catatonic patients with coagulating agents indicates that this disorder may be due to the over-peptization of the colloids. ( 9 ) Some of the symptoms of epilepsy can be reproduced by known chemical and physical coagulating agents. Both the symptoms produced by these agents and that of epilepsy are antagonized by peptizing agents such as sodium bromide. (IO) Other disorders, due to the use of coagulating agents, such as are found in drug addiction can be relieved by means of peptizing agents. The beneficial effects of potassium iodide in lead, arsenic, and mer(11) cury poisoning is another example of disorders of decreased dispersion being improved by peptizing agents. (12) Coagulating agents cause changes in the brain colloids from normal through irritability and insanity to sleep or anesthesia, and death. Dispersing agents cause changes in the brain colloids from normal through insanity to death. Our thanks are given to Dr. Seymour DeWitt Ludlum’of Philadelphia, who is primarily responsible for our starting on this investigation. Cornel2 Unaaersity.
* S. Dew. Ludlum and 4 . E. T a f t : Trans. Am. Neurological Ass., 1927); Alexander’s “Colloid Chemistry,” 2, 695 (1928).
