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Home , Alseroxylon, Oxanamide, Psycholeptic

Bull. Org. mond. Sante' 1959, Bull. Wid Hith Org. 21, 397-410

Psychopharmaceuticals: Effects and Side Effects

NATHAN S. KLINE, M.D, F.A.C.P.1

Drugs which affect psychological behaviour are being used in vast amounts nowadays, with, in all too many cases, but scant regard for their exact uses or possible side effects. This article contains a clinical classification of these drugs, followed by an account of their principal side effects and the means ofobviating them.

CLINICAL CLASSIFICATION OF PHARMACEUTICALS behaviour; whether a drug does or does not alter INFLUENCING PSYCHOLOGICAL STATES brain function is irrelevant to this purpose. A term such as " neurotropic" also prejudges the case, Even the full-time worker in the field becomes by presuming that the sole or major site of action confused at times by the plethora of names and is the brain, whereas there is certainly a real possibi- descriptive terms used for drugs influencing psycho- lity that the endocrine glands, the liver, or other logical states. The classifications of the drugs pro- organs of the body may be of equal importance. posed by various authorities during the past four There are three major categories of psycho- years are actually in quite close agreement ; difficulty pharmaceuticals: (1) drugs which restrict, limit, arises because a variety of terms are employed to restrain or depress either normal or abnormal describe a single principle of drug action, and psychological functioning, (2) drugs which increase, because at other times one and the same name is used elevate, arouse or stimulate either normal or abnormal to indicate quite different groups of pharmaceuticals. psychological functioning, and (3) compounds which I list the common alternatives, with an indication of produce abnormal psychological states of one kind those which appear to me most suitable, and the or another. reasons for such a choice. 1. The psycho-inhibitors. This term, which means The entire group of drugs that they restrict or restrain psychological activity, The most concise term designating all drugs which is selected because it describes the outstanding affect psychological function is PSYCHOPHARMA- characteristic of the entire group and is itself a CEUTICALS. " Tranquillizers " is obviously unsuitable, neutral word. The term " tranquillizers," originally since are included in this group. The used to designate a particular sub-category, is some- alternative, " psychochemicals," should be reserved times assumed to refer to all the psycho-inhibitors. for the even broader category of chemical substances, Another alternative, " ", has a specific whether exogenous or endogenous, that are involved physiological meaning which implies a particular in psychological functioning. Psychopharmaceuticals mode of action. It is also too closely associated are limited to substances of exogenous origin. As with " depression ", as used in reference to the for the frequently used term " phrenotropic ", this emotional state. Professor Delay has proposed the literally means mind-influencing, and is perfectly term " psycholeptic ", which is perfectly acceptable. acceptable. The alternative " neurotropic" (influenc- It is only that the suffix "inhibitor" is a more ing the nerves), although not particularly objec- familiar one to English readers. tionable, introduces a theoretical assumption which The psycho-inhibitors may be divided into the may or may not be warranted. We should seek out following sub-categories: words that make clear the actions of pharma- (a) : drugs which induce sleep (what- ceuticals in terms of their effect on psychological ever other action they have). 'Director, Research Facility, Rockland State Hospital, (b) : compounds which reduce excite- Orangeburg, N.Y., USA; Assistant Clinical Professor of Psychiatry, College of Physicians and Surgeons, Columbia ment, agitation and overactivity, whether physical University, New York, N.Y., USA or psychological. The ideal would be one

828 -397- 398 N. S. KLINE which, regardless of the magnitude of the dose, they belong to or on whether new sub-categories would not produce hypnosis. must be created. (c) Muscle relaxants: pharmaceuticals which have 2. Psycho-activaztors. Professor Delay's term for as their primary action the relaxation of muscular this group of drugs is psycho-, to which tension. They apparently thereby break the feed- we would take no exception, merely preferring the back chain of anxiety tension. The effects are not suffix " activator ", which is more familiar to some dissimilar to hydrotherapy. They may be said to of us than " ." constitute " a Turkish bath in a tablet ". (a) Psychomotor stimulants: compounds which (d) Ataraxics (noun: ataraxic; adjective: ata- stimulate both psychological and motor reactions. ractic): This term means freeing from turmoil and They tend to speed up mental activity, but also intro- confusion. A great deal of stress has been laid on duce distractibility and hyper-responsiveness to the capacity of these drugs to reduce, restrain and external stimuli. As a rule they will elevate the mood, restrict hypermotility and emotional excitement. If often to the point of (i.e., a feeling of more the drugs did only this there would be no reason than normal elation). pressure and heart to classify them as other than super-sedatives. rate are usually increased, although appetite is The one really unique property which they possess is lessened. their capacity to remove, reverse, restrict or inhibit hallucinations (b) Psycho-stimulants: compounds which are psychopathological states, including capable of producing the same generalized psycho- and delusions-a property not possessed by the seda- logical stimulation (both mental and emotional) tives or the hypnotics. A new term was needed to that is possessed by the psychomotor stimulants. designate this action; but since the modus operandi The dosages of psychomotor stimulants are limited was unknown it seemed sensible to avoid any in large part because of the motor side effects, which implication as to whether it was biochemical, are much reduced or absent in the present sub- neurological, or something else. category. If the psychomotor stimulants could be Although the term neuroleptic, as proposed by given in sufficiently high doses the effect might be Professor Delay, has had quite widespread acceptance the same as this group of drugs. In any case, the on the Continent of Europe, it implies a more or less decreased motor effects would place them in a specified mode of action, which may be quite correct, different sub-category. but for which sufficient evidence is not yet available to be certain. Although the ataraxics are the (c) Psychic energizers: compounds which tend sub-category (of the psycho-inhibiting drugs) to to " fill the pump " rather than " speed it up ". In which the term " tranquillizer" was originally the treatment of depressed patients the mood is applied, this word has been so abused that it has raised to a normal base-line, producing a feeling of lost its original identity. To this might be added one well-being (eudaemonia), rather than elevated other legitimate objection-that the drugs do more above the base-line (euphoria). In contrast to the than merely tranquillize. stimulants, blood pressure usually tends to drop Some objection to the term has been raised since slightly, and appetite increases rather than decreases. one drug firm unfortunately patented the word Although both the stimulants and the psychic Atarax as a trade name (and for a drug which is not an energizers will reduce the need for sleep, prolonged ataraxic). This pharmaceutical house has recently usage of the stimulants tends to produce hyper- introduced the same compound under a different irritability, whereas with the psychic energizers some name, with what they consider more adequate patients can go for a year or more on three or four recommendations on dosage, so perhaps the problem hours of sleep per night. Rather than distractibility, will solve itself if the new trade name supplants the there is an increased capacity to concentrate. older one. 3. Psychotomimetics. Professor Delay's category is (e) Undetermined: pharmaceuticals with which "psycho-dysleptic ", which is also satisfactory. sufficient experience has not yet been accumulated Although the term " hallucinogenic" might be to make a clear assignment as to where they belong. applicable to a specific sub-category, it is too limited Rather than that they should be forced into a for the major grouping, since these compounds may Procrustean bed, they are tentatively placed here until produce other types of psychotic manifestations evidence is available on which of the above categories in addition to hallucinations. Although no effort PSYCHOPHARMACEUTICALS: EFFECTS AND SIDE EFFECTS 399 is made to be fully inclusive, some of the possible * (Miltown, Equanil, Oasil) 400- sub-categories of this group would be: 1200 mg (a) : producers of hallucinations * (Thorazine, Megaphen, Lar- (auditory, visual, sensory, etc.). gactil) 50-100 mg * (b) Cataplexogenics: producers of rigid or un- (Doriden) 0.5-1.0 Gm responsive conditions in which the subject does methylparafynol (Dormison) 500-1000 mg not respond to stimuli although he is fully conscious * (Noludar) 200-500 mg and in no comatose. * (Valmid) 0.5-1.0 Gm ethychlorvynol (Placidyl) 0.5-1.0 Gm (c) Euphoriants: agents which elevate mood to * 300-600 an abnormal degree. ectylurea (Nostyn) mg (t.i.d.) (d) Chronoleptogenics: drugs which distort the (b) Sedatives-(All dosages are thrice a day (t.i.d.) sense of time. as required, unless otherwise stipulated) * chlorpromazine (Thorazine, Megaphen, Ami- (e) Depressants: agents which lead to an abnor- nazine, Largactil) 10-50 mg " " mally low mood or emotional state. * (Harmonyl) 0.1-1.0 mg (f) Disinhibitors: compounds which remove the * ectylurea (Nostyn) 150-300 mg normal and customary inhibitions in respect of ethychlorvynol (Placidyl) 100-200 mg speech, fantasy, feeling and/or action. * glutethimide (Doriden) .25-.50 Gm (g) Confusants: preparations which induce in * (Atarax, Vistaril) 25-100 mg the subject a state of perplexity and/or confusion. mepazine (Pacatal) 25-50 mg * methyprylon (Noludar) 50-100 mg CLINICAL CLASSIFICATION OF PHARMACEUTICALS * oxanamide (Quiactin) 150-300 mg INFLUENCING PSYCHOLOGICAL STATES * (Trilafon) 2-4 mg Psychopharmaceuticals (Phrenotropics) * proclorperazine (Compazine, Stemetil) 5-15mg * (Sparine) 10-50 mg 1. Psycho-inhibitors (Psycholeptics) * (a) Hypnotics (Phenergan, Lergigan, Atosil) (b) Sedatives 25-50 mg (c) Muscle relaxants rauwolfia root (Raudixin) 50-200 mg (d) Ataraxics (neuroleptics) Rauwolfia serpentina, alseroxylon fraction (e) Unclassified (Rauwiloid) 2.0 mg * rescinnamine (Moderil) 0.1-1.0 mg 2. Psycho-activators (Psycho-analeptics) * (Serpasil, Rau-Sed, Sandril, Eska- (a) Psychomotor stimulants serp, etc.) 0.1-1.0 mg (b) Psycho-stimulants * (Dartal) 2-5 mg (c) Psychic energizers * (Vesprin) 10-25 mg 3. Psychotomimetics (Psycho-dysleptics) (c) Muscle relaxants-(Dosages t.i.d.) (a) Hallucinogens * (b) Cataplexogenics meprobamate (Miltown, Equanil) 200-400 mg (c) Euphoriants phenoglycodol (Ultran) 300 mg (d) Chronoleptogenics (d) Ataraxics (see table below) (e) Depressants Unless there are reasons to the contrary it is (f) Disinhibitors recommended that the intensive treatment (g) Confusants dose be reached by the end of the first week. Three months is the minimal period for an CLASSIFICATION OF SPECIFIC DRUGS1 adequate clinical trial. Psychopharmaceuticals (e) Undetermined-(Dosages t.i.d.) * I. Psycho-inhibitors (Psycholeptics) (Frenquel) 20-100 mg * benactyzine (Suavitil, Parason, Suvren) 1.0- (a) Hypnotics. Only recently introduced pre- 3.0 mg parations are listed. * phenyltoloxamine (PRN) 200-400 mg An asterisk denotes a proposed international non-pro- acetylpromazine/*acepromazine (Notensil, prietary name (Prop. I. N. N.). Plegicil) 400 N. S. KLINE

TABLE RECOMMENDED DOSES OF ATARAXICS

Name of Namedrugdrugof | Intensive~~~~dosetreatment Maintenance dose

* reserpine (Serpasil, Rau-Sed, Sandril, Eskaserp, etc.); *deserpidine (Harmonyl); *rescinnamine (Moderil) ...... 8.0-15.0 mg daily 3-5 mg daily * . chlorpromazine (Thorazine) . . . 150-500 mg t.i.d. 50-100 mg t.i.d. mepazine (Pacatal) .100-150 mg t.i.d. 50-100 mg t.i.d. * perphenazine (Trilafon) .2-16 mg t.i.d. 2-8 mg twice a day (b.i.d.) or t.i.d. * (Compazine) .50-150 mg t.i.d. 25-50 proclorperazine mg .. go * promazine (Sparine) .200-600 mg 50-100 t.i.d. mg . .I (Dartal) .20-30 mg 5-15 mg thiopropazate t.i.d. ,. .. it

trifluperazine (Stellazine) .10-20 mg t.i.d. 1-10 mg ,. .. it * 50-200 d. triflupromazine (Vesprin) ...... mg t.i 25-50 mg of it

II. Psycho-activating Drugs-(Dosages t.i.d. except (b) Cataplexogenic agents. as noted) bulbocapnine (a) Psychomotor stimulants. (c) Euphoriants. * dextro- (Dexedrine) 5-15 mg * (Methedrine, Desoxyn, psychomotor stimulants and psycho-stimu- etc.) 5-15 mg lants in large doses. * (Ritalin) 5-10 mg (d) Chronoleptogenics * (Meratran) 1.0-2.5 mg mescaline (b) Psycho-stimulants. opium * (Tofranil) 10-75 mg LSD (c) Psychic energizers. (e) Depressants * iproniazid (Marsilid) 10-150 mg/day (f) Disinhibitors For severe depressions an initiating dose Intravenous of 50 mg t.i.d. is recommended. This dose (g) Confusants should be halved weekly once improvement bufotenin is established. A maintenance dose may not be necessary, or may range from 5- IV. Combinations of Psychopharmaceuticals. 10 mg a week to 50 mg or more a day. There are both advantages and disadvantages in JB516 (Catron) 3-24 mg (initial dose 12-24 mg) the simultaneous use ofseveral psychopharmaceutical phenaline (Nardil) 10-120 mg (initial dose agents. Factors which should govern the decision 60-120 mg) as to which drug or drugs should be used are: nialamid (Niamid) 25-300 mg (initial dose (1) the condition of the patient, (2) the response of 75-300 mg) the patient to previous psychopharmaceuticals, RO 50831 (Marplan) 10-20 mg t.i.d. (3) the experience of the administering physician, (4) the closeness with which the patient can be III. Psychotomimetic Drugs. observed and supervised, and (5) the experience (doses not given) of others as reported in the literature or recounted (a) Hallucinogens. personally. lysergic acid (LSD) Pharmacotherapy in the psychiatric field is mescaline oriented toward " target" symptoms (which can be harmine readily observed or ascertained) rather than being PSYCHOPHARMACEUTICALS: EFFECTS AND SIDE EFFECTS 401 directed at etiological factors (which are unknown, Other combinations are too frequent to itemize. uncertain, or non-responsive). A combination of A distinction should be drawn between combinations two drugs with different actions would be indicated capable of producing therapeutic results that could if treatment with a single agent provided only not be obtained by either drug alone and adjunctive partial relief and it was felt that further improvement that serves primarily to rectify the could be obtained. It should be emphasized, however, side effects of some other pharmaceutical. that "cure" is not always obtainable, and that reduction of disability, as elsewhere in medicine, is a legitimate goal of treatment. SOME CONVENIENT RULES QF THUMB If the patient is restored to a state of being reasonably happy and socially functional, further Both in evaluating the clinical literature and in changes in medication should be made only if there judging what to expect in terms of your own patients, is considerable certainty that they will lead to there exist a number of indices which are usually so significantly greater improvement. well known by those in the field that they are never The nature of psychiatric reactions is such that mentioned and therefore occasionally come as a it is often impossible to distinguish a primary from a valuable surprise. As a rule, the longer the a secondary reaction, and alleviation of one symptom duration of illness the more prolonged the treatment may lead to the clearing up of a number of others. must be for an adequate clinical trial. This is In most circumstances, therefore, I would suggest particularly true in respect of the ataractic drugs, that the most disabling target symptom be selected and although initial sedation and some lessening and the medication which the physician believes of the psychopathological state may be evident most likely to modify or relieve the condition be within the first weeks the full benefits of treatment given. If no change is seen after the period when it are sometimes not achieved until after as long as could have been anticipated (which varies from one two years. In a case of long standing, certainly drug to another), the drug should be withdrawn anything under three to six months of treatment and another substituted. If partial improvement cannot be regarded as sufficient. does occur but then " plateaus " with insufficient The incidence both of side effects and of favour- remission, the addition of a second preparation able therapeutic responses, particularly with the that is aimed at the residual symptoms should be ataraxics, is markedly greater in females than in considered. males. Side effects of virtually every type occur two The doses of ataraxics when used in combination to three times more frequently in females, so that in are usually less than half of the dose ofeither prepara- evaluating the relative usefulness of different tion used alone, with the consequence that those side compounds the sex ofthe patients must be considered. effects which are related -to dosage can sometimes A study done with male subjects only will show a be eliminated. At other times the side effects of one lower incidence of side effects than one done with drug may counteract those of the other and provide females. On the other hand the therapeutic response another advantage. The opposite, of course, may is slightly better in females. There are a variety also be true; some combinations produce more side of sociological, psychological, and biochemical effects of greater intensity. Of even greater import- factors which each enter to some degree into the ance is the fact that certain of the combinations creation of this curious state of affairs. Anything produce therapeutic results that neither of the pre- resembling a full discussion of this would easily parations could produce alone. occupy an entire article. It is still my opinion that the combination of As a rule (there are exceptions) within a specific Rauwolfia derivatives with a is the category of pharmaceuticals, the greater the potency single most effective overall preparation in the of the drug on a milligram for milligram basis the treatment of the disturbed schizophrenic patient fewer the number of side effects, although occa- of the chronic or semi-chronic variety. The utiliza- sionally those side effects which do occur tend to be tion of a psychic energizer along with a pheno- more marked than with less " concentrated " pre- thiazine derivative seems to open possibilities for parations. As elsewhere in medicine the real treatment of the agitated depressions, the withdrawn " pay-off" is the therapeutic index (i.e., the thera- psychotic and other syndromes for which neither peutically effective dose divided by the side effects), drug alone seems to suffice. and one should not be led astray simply because 402 N. S. KLINE compound A requires only half the number of SIDE EFFECTS AND THEIR MANAGEMENT milligrams of compound B. Spontaneous remissions occur in all except the Drugs with any degree of potency almost inva- organic psychoses, and even here compensatory riably act at multiple sites, and therefore, in addition factors sometimes bring about clinical improvement. to accomplishing the specific therapeutic objective Among first admissions to a mental hospital roughly aimed at, they may produce other reactions. The 50o% of those under 60 years of age are discharged obvious ways in which these side effects can be within the first year, even without treatment of a handled are: (1) by reduction or elimination of specific type. After 21/2 years of hospitalization, the medication, (2) by providing adjunctive medica- however, the chances of a spontaneous remission are tion to reduce or eliminate them, (3) by substitution less than 1 in 100. Accurate figures for patients seen of other medication which has the same beneficial in practice are not available, but the figures for effect but not the specific side effect in that particular hospitalized patients provide a rough guide. One individual, or (4) by getting the patient to accept the should not be satisfied, nor too much impressed, fact that the specific side effect is inevitable and to by pharmaceuticals " proved " effective because the learn to live with it during the period of treatment. " average " duration of illness in the group of Irreversible side effects (except in the case of the patients tested was 10.5 years and some patients had rare fatalities) are virtually unknown. Therefore been hospitalized for 20 years. This is insufficient the patient can safely be assured that whatever information upon which to judge the true effective- it is that is bothering him will almost certainly clear ness of the preparation. Let us say that the range of up at the termination of treatment, if not before. illness was from six months to twenty years. Of With the more potent preparations which are at two hypothetical groups, the first might consist of present available, some of the side effects appear 100 patients with the following breakdown: 1 patient almost inevitable. I believe it is a wise practice hospitalized for six months, 1 patient hospitalized to warn the patient of the probable occurrence of for twenty years, with the remaining 98 all being the most frequent and how they can be managed. hospitalized (or ill) between ten and eleven years. If they do then occur, the patient is less alarmed The prognosis for spontaneous recovery in such than would otherwise be the case, and if they do not, a group would be one or two patients at most. no great harm has been done. If the patient presses On the other hand, a second group (with the same for details as to the degree of severity and discomfort "average duration of illness and the same range) they may entail, it seems wise to indicate the actual might comprise 50 patients hospitalized for six range but stress the high degree of individual months and another 50 for twenty years, in which variability, indicating, as is the case, that in most case the expected rate of spontaneous remission instances they are more annoying than either would be in the order of 250%. Data on duration painful or serious. Unless one chooses to resort to of hospitalization or illness must be stratified in a printed list, it is well to emphasize only the most terms of 1-year, 2-year, 5-year or other similar likely of the side effects, since in addition one should groupings for comparisons to be made between underscore those signs or symptoms which are various drugs or between drugs and placebos. possible indicators of the serious side reactions and Similarly, when the sex of the patients, their age or should be reported immediately. Illustrations of the other factors are also relevant, even stratification common side effects would be nasal stuffiness in is not sufficient at times, and an analysis of variants the Rauwolfia group, constipation and dryness of or some other appropriate type of factor analysis the mouth with the , and extra- may be required. Many clinicians have a strong pyramidal symptoms in both groups of drugs. The aversion to statistical analysis, but a good sta- dry and scratchy throat which may be indicative tistician, like a good physician, uses the simplest of agranulocytosis or leukopenia (with some of technique appropriate to the occasion. No one the phenothiazines) should be emphasized, since the would ask an internist or a surgeon to treat patient may otherwise regard this as an unrelated every case of abdominal pain with cascara for and not too uncomfortable occurrence unworthy the sake of statistical simplicity, so that if one is of mention. The clinical evidences of jaundice are unwilling to accept statistical analysis the obligation usually sufficiently dramatic, so that the patient is to learn sufficient about it to be knowledgeably need not be specifically requested to bring them to critical. attention. The general opinion of most clinicians PSYCHOPHARMACEUTICALS: EFFECTS AND SIDE EFFECTS 403 and investigators is that laboratory tests, unless characteristic of chlorpromazine and, to a lesser done on a daily basis, are of relatively small value in degree, of reserpine. On the doses used for intensive detecting the prodromata of most of the side effects. treatment lethargy occurs from time to time with The usual range of reactions, including nausea, almost all the pharmaceuticals in this group. The vertigo, skin manifestations, etc., may occur with use of a psychomotor as required is usually almost any of the preparations and should be effective. handled, except in the case of the ataraxics and the psychic energizers, by the customary procedure of Weakness orfatigue. As distinct from drowsiness, withdrawal and substitution of some other com- at times patients will complain of marked fatigue pound. The side effects discussed in detail are those upon the slightest exertion. A fair percentage of commonly seen with the ataraxics and psychic these cases can be helped by the psychomotor energizers, and are not an indication for discontinu- stimulants, but at other times little relief is obtainable ance or even reduction of medication (except as until the intensive treatment phase has been com- noted). Once a specific course of treatment has been pleted and the dosage reduced. started, it should not be interrupted short of a minimal three months trial, unless there are very Extra-pyramidal symptoms. To date, every drug serious reasons for discontinuance, or therapeutic that has proved useful as an ataraxic has induced success has been achieved. extra-pyramidal symptoms in at least a percentage of the patients receiving it. In point of fact, extra- Physiological side effects which may occur with any pyramidal symptoms are more marked among the ataraxic. newer phenothiazines than in the " older drugs ", Reduced resistance to intercurrent conditions. although other side effects are much less. The Although it is customary to list side effects in the manifestations cover an extremely wide range, order either of their frequency or of their seriousness, which may extend from occasional mild generalized I have felt it desirable to start with this important tremulousness to the most extreme board-like side effect because it is so little known. We have rigidity of the well-advanced Parkinson syndrome. ourselves pointed out that there is reduced resistance For a reason not yet clearly understood, some of the to a large variety of intercurrent conditions. Infec- newer phenothiazine derivatives seem selectively to tions, whether local or systematic, require larger produce extra-pyramidal symptoms involving the doses of , and there is some evidence neck and face muscles. Severe clenching of the jaw, that susceptibility to is increased. Cardiac protrusion of the tongue, torticollis and some decompensation, when it occurs, seems to proceed syndromes not previously described are not in- more rapidly. Diabetic crises are usually more severe. frequently seen. On occasion the muscular rigidity In some patients there is rapid development of may affect the abdominal muscles, and there have trophic ulcers after only a few days in bed, with an been cases of " typical board-like rigidity " which unusual resistance to treatment. There is some on operation revealed nothing pathological inter- evidence that glutethimide (Doriden) serves to nally. It has been our strong conviction that, counteract some of the somatic as well as the regardless of their degree of severity, extra-pyramidal psychological side effects. We have had at least symptoms of themselves do not constitute a reason a few patients whose cardiovascular reactions led for discontinuing treatment. A number of anti- us to withdraw treatment, and who were sub- Parkinsonian agents have been reported as useful, sequently able to complete ataractic treatment and we ourselves (having observed what was pro- successfully after being placed on Doriden. There bably the first case of a drug-induced Parkinson-like may be other preparations of this type, but we have syndrome) were forced to extemporize and very not systematically searched for them. The import- happily obtained excellent results with methane- ant thing is that intercurrent conditions are apt sulfonate (Cogentin). We have persisted with the to develop more rapidly and severely than under use of this compound, given in doses of 2 to 4 mg ordinary circumstances, and require both unusually once or twice a day. Because our programme of prompt and vigorous treatment. pharmaceutical testing is so busy, we have not yet had an opportunity to do comparative studies with Drowsiness. To some extent drowsiness may be other products. We have, however, also noted induced by any of the ataraxics, but it is particularly some relief of symptoms with glutethimide (Dori-

2 404 N. S. KLINE den), when it was given as a corrective for other of the organic type. This is one of the few conditions side effects. calling for reduction of dosage. Disturbances of vision. Despite pharmacological Mid-brain syndrome. Under unusual circum- "logic ", we have seen both myosis and mydriasis stances most of these pharmaceuticals have on a occurring with either reserpine or the phenothiazine few occasions produced a reaction which resembles derivatives. The usual treatment is by the use of that of a marked lesion of the mid-brain. There may pharmacological pupillary constrictors or dilators. be hyperpyrexia, ocular palsy, decerebrate move- In a number of patients where completely un- ment, or other signs such as opisthotonus. Two impaired vision was essential (for their work or points worth noting are: (1) that individuals with other reasons) and pharmaceuticals were inadequate, prior brain injury or with mental deficiency seem the use of corrective glasses proved extremely more prone than the usual patient; and (2) that the successful. reaction occurs most frequently in unusually hot weather, which might indicate some disturbance of Oedema. Probably a good 20% of the patients the heat-regulatory centre. The occurrence of a receiving intensive treatment develop oedema of mid-brain syndrome calls for immediate with- the face and/or extremities. At times this becomes drawal of the medication and for symptomatic a cosmetic problem, or it may produce acute treatment. Pharmaceuticals of the same or related discomfort if the patient has to stand or walk nature may subsequently be re-introduced, but excessively. Some of the cases of facial oedema obviously great caution is indicated. respond to , but at times such pre- parations as Diuril, Diamox, or even the mercurial Weight changes. As a rule there is an appreciable are necessary. " Concealed oedema" may weight gain, which does not appear to be primarily also produce bloating on occasion. related to the retention of fluids. This is true not only in patients who were cachectic or mal- Menstrual irregularities. Almost any menstrual nourished, but also in those who appeared in good irregularity may occur, although amenorrhea is physical condition. In line with the " constant by far the most frequent. We have not investigated irregularity" of side-reactions, there are occasional techniques for correcting this condition, since it has patients who show weight loss, and in a few instances not occasioned discomfort or concern once other anorexia develops, so that medication has to be causative factors have been ruled out. reduced or discontinued. Convulsions. To a greater or lesser degree some Hypotension. Although the hypotensive effect is drugs induce convulsions in at least a percentage of better known with the Rauwolfia derivatives, it patients treated. As a general rule this is a dosage can also occur with the phenothiazines. As a rule function, and can be handled by either reduction the blood pressure (although it may appear markedly in the amount of medication or, if the individual is or even alarmingly low to the physician) does not unduly susceptible, anticonvulsive agents such as fall below the level of physiological discomfort to Dilantin or , given concomitantly. the patient. In some cases, however, there are reactions which may result in mild dizziness or Lactation. Considerable embarrassment can be vertigo. In other patients the effect is more marked, avoided if there is awareness that lactation accom- and either psychomotor stimulants or a combination panied by engorgement of the mammary glands may of 1/100 grain atropine and 3/8 grain of ephedrine occur. Occasionally a male patient will manifest t.i.d. is called for. In the very extreme cases, bed gynaecomastia. In the main the condition is self- rest plus norepinephrine (Levophed) are required. limited, but at times will persist until medication is withdrawn. Psychological side effects which may occur with any Toxic syndrome. As with virtually any medication, ataraxic over-dosage will produce typical symptoms of toxic Depression. The incidence of severe depression . The differential diagnosis is usually not with Rauwolfia derivatives in the treatment of difficult, since the syndrome appears after prolonged neuropsychiatric conditions has, in my opinion, administration of substantial doses. There is reduc- been vastly over-rated. Interestingly enough, the tion of appetite, and the appearance of confusion depressive reaction is much more frequent in PSYCHOPHARMACEUTICALS: EFFECTS AND SIDE EFFECTS 405 patients being treated for hypertension, and I have should be no hesitation in using hospitalization if elsewhere indicated that I believe the response is a it appears to be the only way protection can be secondary psychological one rather than a direct given through this phase. drug reaction. Many patients who develop hyper- tension have a psychological constitution which Changes in sexual function. Both impotence and demands constant activity and proof of competency. increased eroticism have been noted. Increase in Any agent or situation which immobilizes them is eroticism is somewhat more frequent with reserpine, apt secondarily to produce depression. The pheno- and impotence more common with the phenothia- thiazines may lead to the same depressive reaction, zine derivatives, although the data are too sparse although at other times they may produce a mild to draw any statistically significant conclusions. No elevation of mood. An interesting exception is specific method of handling either of these con- mepazine (Pacatal), which rather consistently pro- ditions has been evaluated. Reassurance should be duces a moderate mood elevation along with its given that the impotence is drug-induced, and is ataractic effect. Occasionally one or two electro- either self-limited or will disappear upon reduction shock treatments will relieve the depression, and or withdrawal of the drug. more recently we have had marked success in Dreams. Great vividness of dream life is noted combining a psychic energizer with an ataraxic, by many of the patients undergoing treatment, and although such combinations required markedly occasionally they have difficulty in shaking free of reduced doses of the phenothiazines because of these thoughts once awake. Increase in the " fre- potentiation. The psycho-stimulants also appear quency" of dreams is common, although this may useful as a corrective. A recent paper has reported be due to increased recall rather than to an actual the success of glutethimide (Doriden) in handling quantitative change. Some patients are disturbed this condition. by nightmares, and others have commented on the Anhedonia. The psychomotor stimulants, the excitingly erotic nature of their night life. psycho-stimulants, or if necessary the psychic Insomnia. Although as a rule most patients energizers, are quite successful in relieving " lack sleep more easily and with less disturbance, there of feeling ", which sometimes proves most disturbing are occasional patients in whom insomnia develops. to a patient. It is interesting to note that this We have had very satisfactory results with glute- condition occurs most frequently in psychotic thimide (Doriden), although at times doses as high patients, once the abnormal mental content pro- as 3 grams are needed. If the insomnia is associated duced by delusions and hallucinations has been with tension and restlessness, methanesulfonate wiped out. Glutethimide (Doriden) has also been (Cogentin) has proved useful. reported useful in this situation. Lethargy, retardation and withdrawal. In some Suicide. In our own very extensive series of cases the patient may pass from a state of reduced several thousand patients treated by ataraxics, we agitation to one in which he loses interest and have not found substantial evidence that the rate of concern with his environment, sometimes to the suicide is appreciably increased. Care should be extent of appearing somewhat dazed. At the taken, as in the treatment of any depressed patient, extreme this may reach a point where he appears and special caution should be observed at the markedly out of contact with his environment and period of transition, i.e. when the previously " flat" in affect. The psychomotor stimulants or " immobilized" patient begins showing signs of psycho-stimulants, accompanied, if necessary, by increased activity but is not yet completely relieved reduction in the dosage of the ataraxic, are recom- of the depression. He has then sufficient energy to mended as a way of handling this reaction. put suicidal thoughts into effect. A number of recent papers have stressed the fact that the over- Restlessness, agitation and turbulence. Even whelming majority of suicidal patients either though a great many patients show lethargy, they volunteer information as to their intention, or may at the same time give evidence of restlessness. readily admit it if questioned. The patient who is With the Rauwolfia derivatives, and in almost responding to treatment but who goes through a equal frequency with the newer phenothiazine phase of threatening suicide should be taken derivatives, the patient may pass through a stage seriously and watched with extreme care, and there of agitation and even turbulence, in which there is 406 N. S. KLINE re-activation of disturbed behaviour which had Gastro-intestinal symptoms. In contrast to the subsided in the " sedative" phase (as originally phenothiazines, not infrequently there may be mild described by Barsa). During this period the patients cramps, diarrhoea, and even occasionally nausea may become extremely irritable, and at times and vomiting, which are rapidly self-limiting. hypermotility as well as psychopathological mani- Methanesulfonate (Cogentin), which has an anti- festations are greater than they were before treat- cholinergic radical, usually alleviates these symptoms. ment. Barbiturates are of practically no use, but Ifthis is inadequate, a more direct pre- occasionally methanesulfonate (Cogentin), and more paration is almost invariably successful, whether it frequently glutethimide (Doriden), are helpful. In be belladona, atropine, or one of the synthetics. extreme cases hyoscine may also be necessary. The Ptyalism. Although excessive salivation and, exceptionally important point to be made is that occasionally, drooling are undoubtedly part of the this is a normal development in the course of treat- extra-pyramidal syndrome, I believe that they ment. It is very definitely not an indication for deserve separate mention because of the frequency either withdrawal of medication or reduction of with which the condition occurs, particularly with dosage ifthe patient is being given intensive treatment. the Rauwolfia derivatives. Here again methane- The successful a patients, after periods of from few sulfonate (Cogentin) is the treatment of choice in hours to as long as six weeks, pass on to the re- our experience. integrative phase, which is the therapeutic desider- atum. Only after at least three weeks of this response should the dosage be reduced. It is not at Side effects peculiar to the phenothiazines all unusual to find that the patient then begins to Gastro-intestinal reactions. Whereas the Rau- improve, since, as we have discussed elsewhere, wolfia derivatives tend to produce hyper-activity there are cases characterized by a peculiar " thera- of the gastro-intestinal tract, the phenothiazines peutic lag ", which begins when intensive treatment usually induce obstipation or constipation. The is discontinued. A low maintenance dose following symptoms are particularly common in the older age gradual withdrawal is recommended. groups, and if not attended to promptly may produce severe distension and faecal impaction. Hagopian Side reactions peculiar to Rauwolfia derivatives recommends bi-weekly administration of one to one and a half ounces of equal parts of oil Flushing. If parenteral preparations of the and milk of magnesia. Rauwolfia derivatives are used, it is very frequent with the initial doses to observe a marked flushing Dryness of the mouth. In contrast to the ptyalism reaction, which usually does not recur after the first of the Rauwolfia derivatives, patients on pheno- few treatments. thiazines are frequently disturbed by extreme dryness of the mouth. Treatment is local, with Nasal stuffiness. Apart from the direct discomfort preparations such as lozenges or oil of lemon. resulting from oedema of the mucous membrane of the nares, this " stuffiness " sometimes requires Dermatological reactions. A large range of reac- the patient to breathe with open mouth, and produces tions, including urticarial, macular, papular, ves- icular and even a dry throat which interferes with sleep. Anti- scarlatiniform, have been reported. At times histamines are not of much help. Nasal deconges- antihistamines plus local antiprurients are tants such as nephazoline (Privine) have proved helpful, although in other cases the drug must be more useful, although the usual precautions accom- withdrawn and an alternative substituted. The panying prolonged usage should be observed. Other occurrence or exacerbation of seborrheic dermatitis is Rauwolfia such as deserpidine or recanes- relatively frequent, and the use of selenium cine are at times successful. sulfate (Selsun) or an equivalent should be used promptly to prevent spread of the condition. Bradycardia. There is no specific discomfort It is extremely essential to keep in mind the connected with bradycardia per se, but it is important photosensitivity induced by some of the pheno- to be aware of the likelihood of this response. In thiazines (particularly chlorpromazine), which is point of fact, this side effect makes the preparation related both to dosage and duration of exposure. particularly valuable in patients with tachycardia Lotions containing para-amino-benzoic acid seem or palpitations. to provide adequate protection, and it has been PSYCHOPHARMACEUTICALS: EFFECTS AND SIDE EFFECTS 407 reported that gradual exposure may also reduce for three weeks prior to starting medication, and over-reaction. It should also be well noted that found at least one test to show abnormal results in not only direct sunlight, but heat produced by over 80%. diathermy, by a beauty shop hair dryer, or by Leukopenia and leukocytosis. Some degree of prolonged proximity to a kitchen oven, may also leukopenia is relatively common, occurring in induce this extremely painful reaction. perhaps 15 % of all patients on many of the pheno- Jaundice. There are varying estimates of the thiazines. This reaches the point of agranulocytosis frequency of clinical jaundice, but the most probable in 1-2% of the patients, and fatalities with chlor- figure is 1.5% plus or minus 0.5%. The jaundice promazine and some of the analogues should be is almost invariably of the obstructive type. In considered as part of the therapeutic risk. Most of 98 % of cases it occurs during the first two months the newer phenothiazines have either no, or a much of treatment, so that after that length of time the lower occurrence of, leukopenia, and for this reason patient does not have to be followed nearly so are frequently preferable. The one therapeutic closely. The condition is definitely not related to advantage of chlorpromazine is that it induces a dosage and has been reported to occur in cases with certain amount of somnolence and lethargy, which a single dose of 25 mg and, in one case, 10 mg of at times is clinically desirable, but since this can be chlorpromazine. The very much lower incidence achieved in other ways it does not make chlor- or absence ofjaundice with the newer phenothiazines promazine the most desirable of the phenothiazines. is a distinct improvement. For research purposes Proclorperazine (Compazine), triflupromazine (Ves- we have followed a variety of liver function tests prin), perphenazine (Trilafon) and numbers of over extended periods of time on a very large number others appear to be much safer, and equally effective. of patients, but in our opinion none of these has The occurrence of marked leukopenia or agranulo- sufficient predictive value to be clinically useful. cytosis is an indication for immediate withdrawal The yellow conjunctiva, the itching, and the other of medication. With agranulocytosis, protective anti- signs of jaundice usually appear even prior to ab- biotics should be instituted at once in significant normal elevations in the liver function tests or in doses, and a variety of adrenocortical preparations the alkaline phosphate. At the first clinical sign have been recommended by various authors. If the drug should be promptly withdrawn and the case is diagnosed early enough fatal termination supportive treatment administered. On occasion can usually be avoided. It is therefore extremely patients have been re-started on the same medication, important to stress to the patient that the clinical and patients have even been continued on chlor- signs of agranulocytosis, such as scratchy throat, promazine with disappearance of jaundice, but in extreme fatigue, etc., should be promptly reported. It view of the large number of phenothiazines now is also advisable to have a base-line haematological available it is suggested that an alternative would examination to provide a standard against which be preferable, since the occurrence of jaundice with to judge subsequent laboratory data, should this one phenothiazine gives no indication that the same prove necessary. reaction will necessarily occur with a (chemically) closely related compound. Some interesting evidence Side effects ofpsychic energizers has been presented that if the patient is kept well The psychic energizers represent by far the most hydrated there is significantly less likelihood of potent group of pharmaceuticals in the psychiatric jaundice occurring. Many recommend for treatment field. They have frequently not been treated with of jaundice diets of high protein, high carbohydrate the respectful caution which is their due. This in and low fat content together with K (5 mg part has been due to the fact that even the ataraxics intramuscularly daily), Plebex (2 ml daily), a cortisone are relatively " non-explosive" compounds. Since preparation such as Cortef (50 mg eight-hourly dosage recommendations for most of the other intramuscularly) and, if necessary, blood trans- psychopharmaceuticals definitely tend to lean to fusion. Metacorten (10 mg six-hourly) has also been the conservative side, many practitioners have found suggested. it expedient to double or even triple recommended Care should be taken in the interpretation of dosages. In turn patients have had the same liver function tests in the absence of clinical symp- venturesome spirit, and not infrequently doubled or toms. We have routinely done four liver function even tripled the prescribed dose. As a consequence tests at weekly intervals in several thousand patients occasional patients have taken, fairly regularly, 408 N. S. KLINE five to ten times the dose suggested by the pharma- Since certain foods have a pharmacologica ceutical house. When iproniazid (Marsilid) was effect they should not be overlooked. It was a introduced, the practice was so well established that, patient who brought to my attention the reason despite the extremes of caution recommended, the for her extreme jitteriness, which is not typical of optimal dose was quite frequently exceeded. Since these . She had sworn that she had not the pharmaceutical dose was a cumulative one, touched any other medication-but finally asked sometimes not reaching its onset of action for as me whether the fact that she drank ten or twelve long as three weeks or more, there was a natural cups of coffee a day might have any effect, adding tendency to keep on increasing the dosage in the that under normal circumstances she had no reaction hope of achieving a therapeutic response. With to this. When the coffee was reduced to two or this type of loading, when the drug did begin to act, three cups a day excessive irritability disappeared. it was at levels far above the optimal. No sensible Subsequently I have observed the same reaction not physician would either prescribe digitalis for a only with tea but also with some of the " cola " patient in cardiac decompensation, or suggest that drinks, which contain caffeine. In one extreme case, a diabetic patient take insulin according to an a single cup of coffee taken in the morning kept initial maximum recommended dose and return in the patient not only jittery all day but up the entire a month or two. Unfortunately, because the other night. The reaction was repeated on three different psychopharmaceuticals had such a large margin of occasions in the same patient, so that the effect was safety this actually was done with iproniazid. probably a real one. Some of the psychic energizers now on clinical Anaesthetics taken for dental work have also trial (but not yet on the market) have a potency occasioned marked reactions. In part these appear ranging up to roughly fifty times that of iproniazid, related to the adrenaline present in most such so that in the future even greater care will have to solutions, but one would also suspect that any be exercised. substance resembling cocaine might be another Potentiation of other medications. The greatest factor. Therefore, dental work should be avoided caution must be observed by keeping constantly in if possible. Similarly, if an operative procedure mind the ability of these drugs to potentiate many requiring general anaesthesia is needed, the anaes- other medications. To a small extent this is true of thetist should be warned of possible extreme some of the phenothiazine derivatives, but compared reactions. The patients themselves should be cau- with the psychic energizers other potentiating agents tioned of this, since it might otherwise occur are comparatively inert. On three or four occasions without the physician being given prior warning. I have failed to find the response I had anticipated, As yet we do not know the exact degree to which and only after close questioning did the patients all other common medications are potentiated, so admit that they were continuing their " small dose that they should be administered circumspectly of ", which they had been using regularly with small initial doses if their use is indicated. for from ten to twenty years. They had felt that Liver toxicity. On April 1, 1958 (a few days my insistence that all other medications be dis- short of a year after we had pointed out the specific continued for the time being could not possibly psychopharmacological action of iproniazid have applied to their " sleeping pill ", even though (Marsilid) on depression), the US Food and Drug it had been particularly mentioned. In effect, Administration estimated that 400000 to 500000 they had unknowingly raised their dose of barbitu- patients had been treated with these drugs, with a rate by five to ten times, and as a consequence total of 33 fatalities associated with jaundice. Since barely managed to stagger through the day. The both clinically and pathologically the symptomato- phenothiazine derivatives are also increased in logy cannot be distinguished from that of infectious potency, and doses no more than a quarter of the hepatitis, it is almost certain that some of these customary should be used for initiation of treat- patients died from the viral infection, and certainly ment. As a result of failure to note this potentiation, others, for whom permission for an autopsy was I have been called in consultation to see a full- not obtained, must also have died from other blown case of a Parkinson-like syndrome who was causes. On the other hand there were almost on long-term treatment with perphenazine (Trilafon). certainly more fatalities than reported, which would When a psychic energizer was added the extra- tend to increase the number of cases. The total pyramidal symptoms developed in a few hours. number of cases of jaundice (roughly 100) does not PSYCHOPHARMACEUTICALS: EFFECTS AND SIDE EFFECTS 409 seem out of line with what might have been expected Neuralgias. On prolonged administration of from infectious hepatitis. The mortality rate does moderate or high doses neuralgias may occur. seem unusual, if it is assumed that both figures are These range from " earaches " to " arthritis ", and if roughly accurate. I am therefore left with the the patient is not cautioned he or she may also impression that, just as resistance to intercurrent end up with completely unnecessary dental extrac- conditions is lowered with the ataraxics, there is tions. There has been no difficulty in managing this here a similar weakening of resistance, which may reaction; this is usually done by a temporary even show some particular susceptibility in respect lowering of dosage plus the administration of 25 to of specific virus conditions. 50 mg of pyridoxin (vitamin B6). The only near-effective alternative for many of Changes in bowel habits. Obstipation or constipa- these patients was electroconvulsive therapy, where tion are very frequent to at least some degree, and the generally accepted mortality rate is 1 in 1000. occur very markedly in the sensitive patient. In On the semi-official estimate of the number of cases some individuals faecal impaction or congestion treated with iproniazid (Marsilid), if the mortality seems to be associated with vasomotor instability, were comparable to that of electro-shock therapy, and it is therefore recommended that some method one would anticipate four to five hundred deaths of bowel evacuation be utilized approximately directly related to the drug. At the worst, therefore, twice a week. on the basis of available data iproniazid is ten to fifteen times as safe as electro-shock therapy. In Changes in sexual function. The occurrence of view of the furore created about this jaundice a temporary impotence in the male is not at all misquotation comes to mind: " Never has so much infrequent, although this may be more marked in been said so frequently about so little." attaining orgasm than in achieving erection. It is not unusual to hear a patient complain that three Various adrenocortical products have been sug- hours of intercourse were required in order to reach gested by way of treatment, but no definitive a sexual climax, which proved to be a rather ex- evidence exists that they are consistently of help. hausting experience. Using this experience as a Obviously withdrawal of the drug and supportive base, I have successfully treated a number of cases treatment are mandatory. of ejaculatio praecox. On some of the newer psychic Hypotension. Evidence would seem to indicate energizers a number of female patients have com- that these drugs are even more regularly hypotensive mented on their increased sexual sensitivity. Also in their action than the Rauwolfia derivatives, after a period of reduced sensitivity while on the although here the drop below the limits of physio- drug, there have been cases of marked responsiveness logical functioning is more frequent. As a general upon withdrawal. rule the drop in blood pressure is associated with Weight changes. There is quite frequently an postural changes, and at times becomes so marked increase in appetite, characterized by a positive that complete bed rest is required. These changes nitrogen balance. After an early rise, the weight disappear with reduction or withdrawal of medica- usually drops slightly. Since cosmetic or other tion, although a number of clinicians have insisted problems may be involved, it is suggested that caloric that administration of cortisone (12.5 mg twice intake be watched if there is reason for concern. daily) or ACTH relieves the postural hypotension and enables the patient to continue medication Oedema. As with ataraxics, the occurrence of without difficulty. My own experience has been oedema is best handled by the use of Diuril, Diamox, limited to a number of patients who received a few or the mercurial diuretics, if the condition reaches milligrams of thyroid daily before or after treatment the point of cosmetic or physiological discomfort. was begun with the psychic energizers. In each of " Insomnia ". A reduced need for sleep is among the three cases seen the psychic energizer either failed the most characteristic of responses to the psychic to work, or it lost its therapeutic action after the energizers. This is not true insomnia since there is thyroid was added. In view of the fewness of the no concomitant fatigue. Whether one chooses to cases one cannot draw conclusions as to incom- regard this as a side effect, with the implication that patibility, but I would certainly advise caution in it is something undesirable, or it is looked upon as the use of endocrine products of any sort until a bonanza, is in part dependent upon how the more is known. possibility of this reaction is presented by the 410 N. S. KLINE physician. Although meprobamate and other of the paradoxical response in some patients who have non-barbiturate hypnotics can be used in lower than previously suffered from marked insomnia. They usual doses without great danger, this to some extent find that for the first time they are able to sleep well tends to counteract the effect of the medication. My when placed on these medications. own approach has been to point out that two or In summary then, rather than " treating" this three extra hours of waking life per day, if someone side effect in an effort to eliminate it, I would encou- is feeling in a good frame of mind, constitute a rage its presence and help the patient make use of it. remarkable gift. The patients have been encouraged to organize their life around the fact that there will be Miscellaneous. A variety of other side effects have reduced need for sleep, and discussion of what can been reported occasionally. These include: hyper- be done that is interesting and constructive during aesthesia, paraesthesia, perspiration, altered depend- these periods has also proved helpful. ent reflexes, reduced tolerance to cold, possible skin We have elsewhere discussed the use of these rashes, transient nausea and pyrosis. drugs for the treatment of drug addiction, and it has How regularly these are associated with the drug been interesting to watch patients who have been is unknown, and we have had no particular ex- on nightly barbiturates for twenty or more years perience which would lead us to other than the find that they can get on perfectly well without normal medical recommendations for handling such them. As might be anticipated, there is also a reactions.

R1tSUM12

11 existe une telle abondance de noms et de termes excitants. L'adjectif < phrenotropiques )) est parfaitement designant les medicaments modifiant les fonctions acceptable, celui de <'neurotropiques # trop limitatif. psychologiques que meme les specialistes peuvent se Les trois categories principales de ( psychopharma- sentir par moment debordes. L'auteur donne une liste ceutiques > sont les psycho-inhibiteurs ou psycholeptiques, des d6signations usuelles en indiquant celles qui lui les psycho-activateurs ou psycho-analeptiques, les psycho- paraissent les plus appropriees et pourquoi. tomimetiques ou psycho-dysleptiques. L'auteur donne une liste des medicaments appartenant a chacune de ces En ce qui concerne l'ensemble des medicaments ayant trois categories, en les classant selon leur action principale, une influence sur les 6tats psychologiques, le terme que et en indiquant pour chacun d'eux les doses d'attaque propose I'auteur est celui de medicaments # psycho- et les doses d'entretien. Cette classification est suivie de pharmaceutiques , le mot &(tranquillisants*) 6tant conseils sur leur utilisation, d'une etude detaill6e des inacceptable puisque parmi ces medicaments il y a non effets secondaires propres a chaque groupe de substances seulement des tranquillisants, mais egalement des et des differents moyens de combattre ces effets.