Bull. Org. mond. Sante' 1959, 21, 397-410 Bull. Wid Hith Org. 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 of obviating them. CLINICAL CLASSIFICATION OF PHARMACEUTICALS INFLUENCING PSYCHOLOGICAL STATES Even the full-time worker in the field becomes confused at times by the plethora of names and descriptive terms used for drugs influencing psycho- logical states. The classifications of the drugs pro- posed by various authorities during the past four years are actually in quite close agreement ; difficulty arises because a variety of terms are employed to describe a single principle of drug action, and because at other times one and the same name is used to indicate quite different groups of pharmaceuticals. I list the common alternatives, with an indication of those which appear to me most suitable, and the reasons for such a choice. The entire group of drugs The most concise term designating all drugs which affect psychological function is PSYCHOPHARMA- CEUTICALS. " Tranquillizers " is obviously unsuitable, since stimulants are included in this group. The alternative, " psychochemicals," should be reserved for the even broader category of chemical substances, whether exogenous or endogenous, that are involved in psychological functioning. Psychopharmaceuticals are limited to substances of exogenous origin. As for the frequently used term " phrenotropic ", this literally means mind-influencing, and is perfectly acceptable. The alternative " neurotropic" (influenc- ing the nerves), although not particularly objec- tionable, introduces a theoretical assumption which may or may not be warranted. We should seek out words that make clear the actions of pharma- ceuticals in terms of their effect on psychological 'Director, Research Facility, Rockland State Hospital, Orangeburg, N.Y., USA; Assistant Clinical Professor of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, N.Y., USA behaviour; whether a drug does or does not alter brain function is irrelevant to this purpose. A term such as " neurotropic" also prejudges the case, by presuming that the sole or major site of action is the brain, whereas there is certainly a real possibi- lity that the endocrine glands, the liver, or other organs of the body may be of equal importance. There are three major categories of psycho- pharmaceuticals: (1) drugs which restrict, limit, restrain or depress either normal or abnormal psychological functioning, (2) drugs which increase, elevate, arouse or stimulate either normal or abnormal psychological functioning, and (3) compounds which produce abnormal psychological states of one kind or another. 1. The psycho-inhibitors. This term, which means that they restrict or restrain psychological activity, is selected because it describes the outstanding characteristic of the entire group and is itself a neutral word. The term " tranquillizers," originally used to designate a particular sub-category, is some- times assumed to refer to all the psycho-inhibitors. Another alternative, " depressants ", has a specific physiological meaning which implies a particular mode of action. It is also too closely associated with " depression ", as used in reference to the emotional state. Professor Delay has proposed the term " psycholeptic ", which is perfectly acceptable. It is only that the suffix "inhibitor" is a more familiar one to English readers. The psycho-inhibitors may be divided into the following sub-categories: (a) Hypnotics: drugs which induce sleep (what- ever other action they have). (b) Sedatives: compounds which reduce excite- ment, agitation and overactivity, whether physical or psychological. The ideal sedative would be one 828 -397-
Psychopharmaceuticals: Effects and Side EffectsNATHAN 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 oftheir principal side effects and the means of obviating them.
CLINICAL CLASSIFICATION OF PHARMACEUTICALS
INFLUENCING PSYCHOLOGICAL STATES
Even the full-time worker in the field becomesconfused at times by the plethora of names anddescriptive terms used for drugs influencing psycho-logical states. The classifications of the drugs pro-posed by various authorities during the past fouryears are actually in quite close agreement ; difficultyarises because a variety of terms are employed todescribe a single principle of drug action, andbecause at other times one and the same name is usedto indicate quite different groups of pharmaceuticals.I list the common alternatives, with an indication ofthose which appear to me most suitable, and thereasons for such a choice.
The entire group of drugsThe most concise term designating all drugs which
affect psychological function is PSYCHOPHARMA-CEUTICALS. " Tranquillizers " is obviously unsuitable,since stimulants are included in this group. Thealternative, " psychochemicals," should be reservedfor the even broader category of chemical substances,whether exogenous or endogenous, that are involvedin psychological functioning. Psychopharmaceuticalsare limited to substances of exogenous origin. Asfor the frequently used term " phrenotropic ", thisliterally means mind-influencing, and is perfectlyacceptable. The alternative " neurotropic" (influenc-ing the nerves), although not particularly objec-tionable, introduces a theoretical assumption whichmay or may not be warranted. We should seek outwords that make clear the actions of pharma-ceuticals in terms of their effect on psychological
'Director, Research Facility, Rockland State Hospital,Orangeburg, N.Y., USA; Assistant Clinical Professor ofPsychiatry, College of Physicians and Surgeons, ColumbiaUniversity, New York, N.Y., USA
behaviour; whether a drug does or does not alterbrain function is irrelevant to this purpose. A termsuch as " neurotropic" also prejudges the case,by presuming that the sole or major site of actionis the brain, whereas there is certainly a real possibi-lity that the endocrine glands, the liver, or otherorgans of the body may be of equal importance.There are three major categories of psycho-
pharmaceuticals: (1) drugs which restrict, limit,restrain or depress either normal or abnormalpsychological functioning, (2) drugs which increase,elevate, arouse or stimulate either normal or abnormalpsychological functioning, and (3) compounds whichproduce abnormal psychological states of one kindor another.
1. The psycho-inhibitors. This term, which meansthat they restrict or restrain psychological activity,is selected because it describes the outstandingcharacteristic of the entire group and is itself aneutral word. The term " tranquillizers," originallyused to designate a particular sub-category, is some-times assumed to refer to all the psycho-inhibitors.Another alternative, " depressants ", has a specificphysiological meaning which implies a particularmode of action. It is also too closely associatedwith " depression ", as used in reference to theemotional state. Professor Delay has proposed theterm " psycholeptic ", which is perfectly acceptable.It is only that the suffix "inhibitor" is a morefamiliar one to English readers.The psycho-inhibitors may be divided into the
following sub-categories:(a) Hypnotics: drugs which induce sleep (what-
ever other action they have).(b) Sedatives: compounds which reduce excite-
ment, agitation and overactivity, whether physicalor psychological. The ideal sedative would be one
828 -397-
N. S. KLINE
which, regardless of the magnitude of the dose,would not produce hypnosis.
(c) Muscle relaxants: pharmaceuticals which haveas their primary action the relaxation of musculartension. They apparently thereby break the feed-back chain of anxiety tension. The effects are notdissimilar to hydrotherapy. They may be said toconstitute " a Turkish bath in a tablet ".
(d) Ataraxics (noun: ataraxic; adjective: ata-ractic): This term means freeing from turmoil andconfusion. A great deal of stress has been laid onthe capacity of these drugs to reduce, restrain andrestrict hypermotility and emotional excitement. Ifthe drugs did only this there would be no reasonto classify them as other than super-sedatives.The one really unique property which they possess istheir capacity to remove, reverse, restrict or inhibitpsychopathological states, including hallucinationsand delusions-a property not possessed by the seda-tives or the hypnotics. A new term was needed todesignate this action; but since the modus operandiwas unknown it seemed sensible to avoid anyimplication as to whether it was biochemical,neurological, or something else.Although the term neuroleptic, as proposed by
Professor Delay, has had quite widespread acceptanceon the Continent of Europe, it implies a more or lessspecified mode of action, which may be quite correct,but for which sufficient evidence is not yet availableto be certain. Although the ataraxics are thesub-category (of the psycho-inhibiting drugs) towhich the term " tranquillizer" was originallyapplied, this word has been so abused that it haslost its original identity. To this might be added oneother legitimate objection-that the drugs do morethan merely tranquillize.Some objection to the term has been raised since
one drug firm unfortunately patented the wordAtarax as a trade name (and for a drug which is not anataraxic). This pharmaceutical house has recentlyintroduced the same compound under a differentname, with what they consider more adequaterecommendations on dosage, so perhaps the problemwill solve itself if the new trade name supplants theolder one.
(e) Undetermined: pharmaceuticals with whichsufficient experience has not yet been accumulatedto make a clear assignment as to where they belong.Rather than that they should be forced into aProcrustean bed, they are tentatively placed here untilevidence is available on which of the above categories
they belong to or on whether new sub-categoriesmust be created.
2. Psycho-activaztors. Professor Delay's term forthis group of drugs is psycho-analeptics, to whichwe would take no exception, merely preferring thesuffix " activator ", which is more familiar to someof us than " analeptic."
(a) Psychomotor stimulants: compounds whichstimulate both psychological and motor reactions.They tend to speed up mental activity, but also intro-duce distractibility and hyper-responsiveness toexternal stimuli. As a rule they will elevate the mood,often to the point of euphoria (i.e., a feeling of morethan normal elation). Blood pressure and heartrate are usually increased, although appetite islessened.
(b) Psycho-stimulants: compounds which arecapable of producing the same generalized psycho-logical stimulation (both mental and emotional)that is possessed by the psychomotor stimulants.The dosages of psychomotor stimulants are limitedin large part because of the motor side effects, whichare much reduced or absent in the present sub-category. If the psychomotor stimulants could begiven in sufficiently high doses the effect might bethe same as this group of drugs. In any case, thedecreased motor effects would place them in adifferent sub-category.
(c) Psychic energizers: compounds which tendto " fill the pump " rather than " speed it up ". Inthe treatment of depressed patients the mood israised to a normal base-line, producing a feeling ofwell-being (eudaemonia), rather than elevatedabove the base-line (euphoria). In contrast to thestimulants, blood pressure usually tends to dropslightly, and appetite increases rather than decreases.Although both the stimulants and the psychicenergizers will reduce the need for sleep, prolongedusage of the stimulants tends to produce hyper-irritability, whereas with the psychic energizers somepatients can go for a year or more on three or fourhours of sleep per night. Rather than distractibility,there is an increased capacity to concentrate.
3. Psychotomimetics. Professor Delay's category is"psycho-dysleptic ", which is also satisfactory.Although the term " hallucinogenic" might beapplicable to a specific sub-category, it is too limitedfor the major grouping, since these compounds mayproduce other types of psychotic manifestationsin addition to hallucinations. Although no effort
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PSYCHOPHARMACEUTICALS: EFFECTS AND SIDE EFFECTS 399
is made to be fully inclusive, some of the possiblesub-categories of this group would be:
(a) Hallucinogens: producers of hallucinations(auditory, visual, sensory, etc.).
(b) Cataplexogenics: producers of rigid or un-responsive conditions in which the subject doesnot respond to stimuli although he is fully consciousand in no sense comatose.
(c) Euphoriants: agents which elevate mood toan abnormal degree.
(d) Chronoleptogenics: drugs which distort thesense of time.
(e) Depressants: agents which lead to an abnor-mally " low " mood or emotional state.
(f) Disinhibitors: compounds which remove thenormal and customary inhibitions in respect ofspeech, fantasy, feeling and/or action.
(g) Confusants: preparations which induce inthe subject a state of perplexity and/or confusion.
CLINICAL CLASSIFICATION OF PHARMACEUTICALSINFLUENCING PSYCHOLOGICAL STATES
(d) Ataraxics (see table below)Unless there are reasons to the contrary it isrecommended that the intensive treatmentdose be reached by the end of the first week.Three months is the minimal period for anadequate clinical trial.
For severe depressions an initiating doseof 50 mg t.i.d. is recommended. This doseshould be halved weekly once improvementis established. A maintenance dose maynot be necessary, or may range from 5-10 mg a week to 50 mg or more a day.
III. Psychotomimetic Drugs.(doses not given)(a) Hallucinogens.
lysergic acid (LSD)mescalineharmine
(b) Cataplexogenic agents.bulbocapnine
(c) Euphoriants.cocainepsychomotor stimulants and psycho-stimu-
lants in large doses.(d) Chronoleptogenics
mescalineopiumLSD
(e) Depressants(f) Disinhibitors
Intravenous barbiturates(g) Confusants
bufoteninIV. Combinations of Psychopharmaceuticals.There are both advantages and disadvantages in
the simultaneous use ofseveral psychopharmaceuticalagents. Factors which should govern the decisionas to which drug or drugs should be used are:(1) the condition of the patient, (2) the response ofthe patient to previous psychopharmaceuticals,(3) the experience of the administering physician,(4) the closeness with which the patient can beobserved and supervised, and (5) the experienceof others as reported in the literature or recountedpersonally.Pharmacotherapy in the psychiatric field is
oriented toward " target" symptoms (which can bereadily observed or ascertained) rather than being
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PSYCHOPHARMACEUTICALS: EFFECTS AND SIDE EFFECTS
directed at etiological factors (which are unknown,uncertain, or non-responsive). A combination oftwo drugs with different actions would be indicatedif treatment with a single agent provided onlypartial relief and it was felt that further improvementcould be obtained. It should be emphasized, however,that "cure" is not always obtainable, and thatreduction of disability, as elsewhere in medicine,is a legitimate goal of treatment.
If the patient is restored to a state of beingreasonably happy and socially functional, furtherchanges in medication should be made only if thereis considerable certainty that they will lead tosignificantly greater improvement.The nature of psychiatric reactions is such that
it is often impossible to distinguish a primary froma secondary reaction, and alleviation of one symptommay lead to the clearing up of a number of others.In most circumstances, therefore, I would suggestthat the most disabling target symptom be selectedand the medication which the physician believesmost likely to modify or relieve the condition begiven. If no change is seen after the period when itcould have been anticipated (which varies from one
drug to another), the drug should be withdrawnand another substituted. If partial improvementdoes occur but then " plateaus " with insufficientremission, the addition of a second preparationthat is aimed at the residual symptoms should beconsidered.The doses of ataraxics when used in combination
are usually less than half of the dose of either prepara-tion used alone, with the consequence that those sideeffects which are related -to dosage can sometimesbe eliminated. At other times the side effects of one
drug may counteract those of the other and provideanother advantage. The opposite, of course, mayalso be true; some combinations produce more sideeffects of greater intensity. Of even greater import-ance is the fact that certain of the combinationsproduce therapeutic results that neither of the pre-
parations could produce alone.It is still my opinion that the combination of
Rauwolfia derivatives with a phenothiazine is thesingle most effective overall preparation in thetreatment of the disturbed schizophrenic patientof the chronic or semi-chronic variety. The utiliza-tion of a psychic energizer along with a pheno-thiazine derivative seems to open possibilities fortreatment of the agitated depressions, the withdrawnpsychotic and other syndromes for which neitherdrug alone seems to suffice.
Other combinations are too frequent to itemize.A distinction should be drawn between combinationscapable of producing therapeutic results that couldnot be obtained by either drug alone and adjunctivemedication that serves primarily to rectify theside effects of some other pharmaceutical.
SOME CONVENIENT RULES QF THUMB
Both in evaluating the clinical literature and injudging what to expect in terms of your own patients,there exist a number of indices which are usually sowell known by those in the field that they are nevermentioned and therefore occasionally come as aa valuable surprise. As a rule, the longer theduration of illness the more prolonged the treatmentmust be for an adequate clinical trial. This isparticularly true in respect of the ataractic drugs,and although initial sedation and some lesseningof the psychopathological state may be evidentwithin the first weeks the full benefits of treatmentare sometimes not achieved until after as long astwo years. In a case of long standing, certainlyanything under three to six months of treatmentcannot be regarded as sufficient.The incidence both of side effects and of favour-
able therapeutic responses, particularly with theataraxics, is markedly greater in females than inmales. Side effects of virtually every type occur twoto three times more frequently in females, so that inevaluating the relative usefulness of differentcompounds the sex of the patients must be considered.A study done with male subjects only will show alower incidence of side effects than one done withfemales. On the other hand the therapeutic responseis slightly better in females. There are a varietyof sociological, psychological, and biochemicalfactors which each enter to some degree into thecreation of this curious state of affairs. Anythingresembling a full discussion of this would easilyoccupy an entire article.As a rule (there are exceptions) within a specific
category of pharmaceuticals, the greater the potencyof the drug on a milligram for milligram basis thefewer the number of side effects, although occa-sionally those side effects which do occur tend to bemore marked than with less " concentrated " pre-parations. As elsewhere in medicine the real" pay-off" is the therapeutic index (i.e., the thera-peutically effective dose divided by the side effects),and one should not be led astray simply because
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compound A requires only half the number ofmilligrams of compound B.
Spontaneous remissions occur in all except theorganic psychoses, and even here compensatoryfactors sometimes bring about clinical improvement.Among first admissions to a mental hospital roughly50o% of those under 60 years of age are dischargedwithin the first year, even without treatment of aspecific type. After 21/2 years of hospitalization,however, the chances of a spontaneous remission areless than 1 in 100. Accurate figures for patients seenin practice are not available, but the figures forhospitalized patients provide a rough guide. Oneshould not be satisfied, nor too much impressed,by pharmaceuticals " proved " effective because the" average " duration of illness in the group ofpatients tested was 10.5 years and some patients hadbeen hospitalized for 20 years. This is insufficientinformation upon which to judge the true effective-ness of the preparation. Let us say that the range ofillness was from six months to twenty years. Oftwo hypothetical groups, the first might consist of100 patients with the following breakdown: 1 patienthospitalized for six months, 1 patient hospitalizedfor twenty years, with the remaining 98 all beinghospitalized (or ill) between ten and eleven years.The prognosis for spontaneous recovery in sucha group would be one or two patients at most.On the other hand, a second group (with the same"average duration of illness and the same range)might comprise 50 patients hospitalized for sixmonths and another 50 for twenty years, in whichcase the expected rate of spontaneous remissionwould be in the order of 250%. Data on durationof hospitalization or illness must be stratified interms of 1-year, 2-year, 5-year or other similargroupings for comparisons to be made betweenvarious drugs or between drugs and placebos.Similarly, when the sex of the patients, their age orother factors are also relevant, even stratificationis not sufficient at times, and an analysis of variantsor some other appropriate type of factor analysismay be required. Many clinicians have a strongaversion to statistical analysis, but a good sta-tistician, like a good physician, uses the simplesttechnique appropriate to the occasion. No onewould ask an internist or a surgeon to treatevery case of abdominal pain with cascara forthe sake of statistical simplicity, so that if one isunwilling to accept statistical analysis the obligationis to learn sufficient about it to be knowledgeablycritical.
SIDE EFFECTS AND THEIR MANAGEMENT
Drugs with any degree of potency almost inva-riably act at multiple sites, and therefore, in additionto accomplishing the specific therapeutic objectiveaimed at, they may produce other reactions. Theobvious ways in which these side effects can behandled are: (1) by reduction or elimination ofthe medication, (2) by providing adjunctive medica-tion to reduce or eliminate them, (3) by substitutionof other medication which has the same beneficialeffect but not the specific side effect in that particularindividual, or (4) by getting the patient to accept thefact that the specific side effect is inevitable and tolearn to live with it during the period of treatment.
Irreversible side effects (except in the case of therare fatalities) are virtually unknown. Thereforethe patient can safely be assured that whateverit is that is bothering him will almost certainly clearup at the termination of treatment, if not before.With the more potent preparations which are atpresent available, some of the side effects appearalmost inevitable. I believe it is a wise practiceto warn the patient of the probable occurrence ofthe most frequent and how they can be managed.If they do then occur, the patient is less alarmedthan would otherwise be the case, and if they do not,no great harm has been done. If the patient pressesfor details as to the degree of severity and discomfortthey may entail, it seems wise to indicate the actualrange but stress the high degree of individualvariability, indicating, as is the case, that in mostinstances they are more annoying than eitherpainful or serious. Unless one chooses to resort toa printed list, it is well to emphasize only the mostlikely of the side effects, since in addition one shouldunderscore those signs or symptoms which arepossible indicators of the serious side reactions andshould be reported immediately. Illustrations of thecommon side effects would be nasal stuffiness inthe Rauwolfia group, constipation and dryness ofthe mouth with the phenothiazines, and extra-pyramidal symptoms in both groups of drugs. Thedry and scratchy throat which may be indicativeof agranulocytosis or leukopenia (with some ofthe phenothiazines) should be emphasized, since thepatient may otherwise regard this as an unrelatedand not too uncomfortable occurrence unworthyof mention. The clinical evidences of jaundice areusually sufficiently dramatic, so that the patientneed not be specifically requested to bring them toattention. The general opinion of most clinicians
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PSYCHOPHARMACEUTICALS: EFFECTS AND SIDE EFFECTS
and investigators is that laboratory tests, unlessdone on a daily basis, are of relatively small value indetecting the prodromata of most of the side effects.The usual range of reactions, including nausea,
vertigo, skin manifestations, etc., may occur withalmost any of the preparations and should behandled, except in the case of the ataraxics and thepsychic energizers, by the customary procedure ofwithdrawal and substitution of some other com-pound. The side effects discussed in detail are thosecommonly seen with the ataraxics and psychicenergizers, and are not an indication for discontinu-ance or even reduction of medication (except asnoted). Once a specific course of treatment has beenstarted, it should not be interrupted short of aminimal three months trial, unless there are veryserious reasons for discontinuance, or therapeuticsuccess has been achieved.
Physiological side effects which may occur with anyataraxic.
Reduced resistance to intercurrent conditions.Although it is customary to list side effects in theorder either of their frequency or of their seriousness,I have felt it desirable to start with this importantside effect because it is so little known. We haveourselves pointed out that there is reduced resistanceto a large variety of intercurrent conditions. Infec-tions, whether local or systematic, require largerdoses of antibiotics, and there is some evidencethat susceptibility to infection is increased. Cardiacdecompensation, when it occurs, seems to proceedmore rapidly. Diabetic crises are usually more severe.In some patients there is rapid development oftrophic ulcers after only a few days in bed, with anunusual resistance to treatment. There is someevidence that glutethimide (Doriden) serves tocounteract some of the somatic as well as thepsychological side effects. We have had at leasta few patients whose cardiovascular reactions ledus to withdraw treatment, and who were sub-sequently able to complete ataractic treatmentsuccessfully after being placed on Doriden. Theremay be other preparations of this type, but we havenot systematically searched for them. The import-ant thing is that intercurrent conditions are aptto develop more rapidly and severely than underordinary circumstances, and require both unusuallyprompt and vigorous treatment.
Drowsiness. To some extent drowsiness may beinduced by any of the ataraxics, but it is particularly
characteristic of chlorpromazine and, to a lesserdegree, of reserpine. On the doses used for intensivetreatment lethargy occurs from time to time withalmost all the pharmaceuticals in this group. Theuse of a psychomotor stimulant as required is usuallyeffective.
Weakness or fatigue. As distinct from drowsiness,at times patients will complain of marked fatigueupon the slightest exertion. A fair percentage ofthese cases can be helped by the psychomotorstimulants, but at other times little relief is obtainableuntil the intensive treatment phase has been com-pleted and the dosage reduced.
Extra-pyramidal symptoms. To date, every drugthat has proved useful as an ataraxic has inducedextra-pyramidal symptoms in at least a percentageof the patients receiving it. In point of fact, extra-pyramidal symptoms are more marked among thenewer phenothiazines than in the " older drugs ",although other side effects are much less. Themanifestations cover an extremely wide range,which may extend from occasional mild generalizedtremulousness to the most extreme board-likerigidity of the well-advanced Parkinson syndrome.For a reason not yet clearly understood, some of thenewer phenothiazine derivatives seem selectively toproduce extra-pyramidal symptoms involving theneck and face muscles. Severe clenching of the jaw,protrusion of the tongue, torticollis and somesyndromes not previously described are not in-frequently seen. On occasion the muscular rigiditymay affect the abdominal muscles, and there havebeen cases of " typical board-like rigidity " whichon operation revealed nothing pathological inter-nally. It has been our strong conviction that,regardless of their degree of severity, extra-pyramidalsymptoms of themselves do not constitute a reasonfor discontinuing treatment. A number of anti-Parkinsonian agents have been reported as useful,and we ourselves (having observed what was pro-bably the first case of a drug-induced Parkinson-likesyndrome) were forced to extemporize and veryhappily obtained excellent results with methane-sulfonate (Cogentin). We have persisted with theuse of this compound, given in doses of 2 to 4 mgonce or twice a day. Because our programme ofpharmaceutical testing is so busy, we have not yethad an opportunity to do comparative studies withother products. We have, however, also notedsome relief of symptoms with glutethimide (Dori-
2
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den), when it was given as a corrective for otherside effects.
Disturbances of vision. Despite pharmacological"logic ", we have seen both myosis and mydriasisoccurring with either reserpine or the phenothiazinederivatives. The usual treatment is by the use ofpharmacological pupillary constrictors or dilators.In a number of patients where completely un-impaired vision was essential (for their work orother reasons) and pharmaceuticals were inadequate,the use of corrective glasses proved extremelysuccessful.
Oedema. Probably a good 20% of the patientsreceiving intensive treatment develop oedema ofthe face and/or extremities. At times this becomesa cosmetic problem, or it may produce acutediscomfort if the patient has to stand or walkexcessively. Some of the cases of facial oedemarespond to antihistamines, but at times such pre-parations as Diuril, Diamox, or even the mercurialdiuretics are necessary. " Concealed oedema" mayalso produce bloating on occasion.
Menstrual irregularities. Almost any menstrualirregularity may occur, although amenorrhea isby far the most frequent. We have not investigatedtechniques for correcting this condition, since it hasnot occasioned discomfort or concern once othercausative factors have been ruled out.
Convulsions. To a greater or lesser degree somedrugs induce convulsions in at least a percentage ofpatients treated. As a general rule this is a dosagefunction, and can be handled by either reductionin the amount of medication or, if the individual isunduly susceptible, anticonvulsive agents such asDilantin or phenobarbital, given concomitantly.
Lactation. Considerable embarrassment can beavoided if there is awareness that lactation accom-panied by engorgement of the mammary glands mayoccur. Occasionally a male patient will manifestgynaecomastia. In the main the condition is self-limited, but at times will persist until medication iswithdrawn.
Toxic syndrome. As with virtually any medication,over-dosage will produce typical symptoms of toxicpsychosis. The differential diagnosis is usually notdifficult, since the syndrome appears after prolongedadministration of substantial doses. There is reduc-tion of appetite, and the appearance of confusion
of the organic type. This is one of the few conditionscalling for reduction of dosage.
Mid-brain syndrome. Under unusual circum-stances most of these pharmaceuticals have on afew occasions produced a reaction which resemblesthat of a marked lesion of the mid-brain. There maybe hyperpyrexia, ocular palsy, decerebrate move-ment, or other signs such as opisthotonus. Twopoints worth noting are: (1) that individuals withprior brain injury or with mental deficiency seemmore prone than the usual patient; and (2) that thereaction occurs most frequently in unusually hotweather, which might indicate some disturbance ofthe heat-regulatory centre. The occurrence of amid-brain syndrome calls for immediate with-drawal of the medication and for symptomatictreatment. Pharmaceuticals of the same or relatednature may subsequently be re-introduced, butobviously great caution is indicated.
Weight changes. As a rule there is an appreciableweight gain, which does not appear to be primarilyrelated to the retention of fluids. This is true notonly in patients who were cachectic or mal-nourished, but also in those who appeared in goodphysical condition. In line with the " constantirregularity" of side-reactions, there are occasionalpatients who show weight loss, and in a few instancesanorexia develops, so that medication has to bereduced or discontinued.
Hypotension. Although the hypotensive effect isbetter known with the Rauwolfia derivatives, itcan also occur with the phenothiazines. As a rulethe blood pressure (although it may appear markedlyor even alarmingly low to the physician) does notfall below the level of physiological discomfort tothe patient. In some cases, however, there arereactions which may result in mild dizziness orvertigo. In other patients the effect is more marked,and either psychomotor stimulants or a combinationof 1/100 grain atropine and 3/8 grain of ephedrinet.i.d. is called for. In the very extreme cases, bedrest plus norepinephrine (Levophed) are required.
Psychological side effects which may occur with anyataraxic
Depression. The incidence of severe depressionwith Rauwolfia derivatives in the treatment ofneuropsychiatric conditions has, in my opinion,been vastly over-rated. Interestingly enough, thedepressive reaction is much more frequent in
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patients being treated for hypertension, and I haveelsewhere indicated that I believe the response is asecondary psychological one rather than a directdrug reaction. Many patients who develop hyper-tension have a psychological constitution whichdemands constant activity and proof of competency.Any agent or situation which immobilizes them isapt secondarily to produce depression. The pheno-thiazines may lead to the same depressive reaction,although at other times they may produce a mildelevation of mood. An interesting exception ismepazine (Pacatal), which rather consistently pro-duces a moderate mood elevation along with itsataractic effect. Occasionally one or two electro-shock treatments will relieve the depression, andmore recently we have had marked success incombining a psychic energizer with an ataraxic,although such combinations required markedlyreduced doses of the phenothiazines because ofpotentiation. The psycho-stimulants also appearuseful as a corrective. A recent paper has reportedthe success of glutethimide (Doriden) in handlingthis condition.
Anhedonia. The psychomotor stimulants, thepsycho-stimulants, or if necessary the psychicenergizers, are quite successful in relieving " lackof feeling ", which sometimes proves most disturbingto a patient. It is interesting to note that thiscondition occurs most frequently in psychoticpatients, once the abnormal mental content pro-duced by delusions and hallucinations has beenwiped out. Glutethimide (Doriden) has also beenreported useful in this situation.
Suicide. In our own very extensive series ofseveral thousand patients treated by ataraxics, wehave not found substantial evidence that the rate ofsuicide is appreciably increased. Care should betaken, as in the treatment of any depressed patient,and special caution should be observed at theperiod of transition, i.e. when the previously" immobilized" patient begins showing signs ofincreased activity but is not yet completely relievedof the depression. He has then sufficient energy toput suicidal thoughts into effect. A number ofrecent papers have stressed the fact that the over-whelming majority of suicidal patients eithervolunteer information as to their intention, orreadily admit it if questioned. The patient who isresponding to treatment but who goes through aphase of threatening suicide should be takenseriously and watched with extreme care, and there
should be no hesitation in using hospitalization ifit appears to be the only way protection can begiven through this phase.
Changes in sexual function. Both impotence andincreased eroticism have been noted. Increase ineroticism is somewhat more frequent with reserpine,and impotence more common with the phenothia-zine derivatives, although the data are too sparseto draw any statistically significant conclusions. Nospecific method of handling either of these con-ditions has been evaluated. Reassurance should begiven that the impotence is drug-induced, and iseither self-limited or will disappear upon reductionor withdrawal of the drug.
Dreams. Great vividness of dream life is notedby many of the patients undergoing treatment, andoccasionally they have difficulty in shaking free ofthese thoughts once awake. Increase in the " fre-quency" of dreams is common, although this maybe due to increased recall rather than to an actualquantitative change. Some patients are disturbedby nightmares, and others have commented on theexcitingly erotic nature of their night life.
Insomnia. Although as a rule most patientssleep more easily and with less disturbance, thereare occasional patients in whom insomnia develops.We have had very satisfactory results with glute-thimide (Doriden), although at times doses as highas 3 grams are needed. If the insomnia is associatedwith tension and restlessness, methanesulfonate(Cogentin) has proved useful.
Lethargy, retardation and withdrawal. In somecases the patient may pass from a state of reducedagitation to one in which he loses interest andconcern with his environment, sometimes to theextent of appearing somewhat dazed. At theextreme this may reach a point where he appearsmarkedly out of contact with his environment and" flat" in affect. The psychomotor stimulants orpsycho-stimulants, accompanied, if necessary, byreduction in the dosage of the ataraxic, are recom-mended as a way of handling this reaction.
Restlessness, agitation and turbulence. Eventhough a great many patients show lethargy, theymay at the same time give evidence of restlessness.With the Rauwolfia derivatives, and in almostequal frequency with the newer phenothiazinederivatives, the patient may pass through a stageof agitation and even turbulence, in which there is
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re-activation of disturbed behaviour which hadsubsided in the " sedative" phase (as originallydescribed by Barsa). During this period the patientsmay become extremely irritable, and at timeshypermotility as well as psychopathological mani-festations are greater than they were before treat-ment. Barbiturates are of practically no use, butoccasionally methanesulfonate (Cogentin), and more
frequently glutethimide (Doriden), are helpful. Inextreme cases hyoscine may also be necessary. Theexceptionally important point to be made is thatthis is a normal development in the course of treat-ment. It is very definitely not an indication foreither withdrawal of medication or reduction ofdosage if the patient is being given intensive treatment.The successful patients, after periods of from a fewhours to as long as six weeks, pass on to the re-
integrative phase, which is the therapeutic desider-atum. Only after at least three weeks of thisresponse should the dosage be reduced. It is not atall unusual to find that the patient then begins toimprove, since, as we have discussed elsewhere,there are cases characterized by a peculiar " thera-peutic lag ", which begins when intensive treatmentis discontinued. A low maintenance dose followinggradual withdrawal is recommended.
Side reactions peculiar to Rauwolfia derivatives
Flushing. If parenteral preparations of theRauwolfia derivatives are used, it is very frequentwith the initial doses to observe a marked flushingreaction, which usually does not recur after the firstfew treatments.
Nasal stuffiness. Apart from the direct discomfortresulting from oedema of the mucous membraneof the nares, this " stuffiness " sometimes requiresthe patient to breathe with open mouth, and producesa dry throat which interferes with sleep. Anti-histamines are not of much help. Nasal deconges-tants such as nephazoline (Privine) have provedmore useful, although the usual precautions accom-panying prolonged usage should be observed. OtherRauwolfia alkaloids such as deserpidine or recanes-cine are at times successful.
Bradycardia. There is no specific discomfortconnected with bradycardia per se, but it is importantto be aware of the likelihood of this response. Inpoint of fact, this side effect makes the preparationparticularly valuable in patients with tachycardiaor palpitations.
Gastro-intestinal symptoms. In contrast to thephenothiazines, not infrequently there may be mildcramps, diarrhoea, and even occasionally nauseaand vomiting, which are rapidly self-limiting.Methanesulfonate (Cogentin), which has an anti-cholinergic radical, usually alleviates these symptoms.If this is inadequate, a more direct anticholinergic pre-paration is almost invariably successful, whether itbe belladona, atropine, or one of the synthetics.
Ptyalism. Although excessive salivation and,occasionally, drooling are undoubtedly part of theextra-pyramidal syndrome, I believe that theydeserve separate mention because of the frequencywith which the condition occurs, particularly withthe Rauwolfia derivatives. Here again methane-sulfonate (Cogentin) is the treatment of choice inour experience.
Side effects peculiar to the phenothiazines
Gastro-intestinal reactions. Whereas the Rau-wolfia derivatives tend to produce hyper-activityof the gastro-intestinal tract, the phenothiazinesusually induce obstipation or constipation. Thesymptoms are particularly common in the older agegroups, and if not attended to promptly may producesevere distension and faecal impaction. Hagopianrecommends bi-weekly administration of one toone and a half ounces of equal parts of mineral oiland milk of magnesia.
Dryness of the mouth. In contrast to the ptyalismof the Rauwolfia derivatives, patients on pheno-thiazines are frequently disturbed by extremedryness of the mouth. Treatment is local, withpreparations such as lozenges or oil of lemon.
Dermatological reactions. A large range of reac-tions, including urticarial, macular, papular, ves-icular and even scarlatiniform, have been reported.At times antihistamines plus local antiprurients arehelpful, although in other cases the drug must bewithdrawn and an alternative substituted. Theoccurrence or exacerbation of seborrheic dermatitisis relatively frequent, and the use of seleniumsulfate (Selsun) or an equivalent should be usedpromptly to prevent spread of the condition.
It is extremely essential to keep in mind thephotosensitivity induced by some of the pheno-thiazines (particularly chlorpromazine), which isrelated both to dosage and duration of exposure.Lotions containing para-amino-benzoic acid seemto provide adequate protection, and it has been
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reported that gradual exposure may also reduceover-reaction. It should also be well noted thatnot only direct sunlight, but heat produced bydiathermy, by a beauty shop hair dryer, or byprolonged proximity to a kitchen oven, may alsoinduce this extremely painful reaction.
Jaundice. There are varying estimates of thefrequency of clinical jaundice, but the most probablefigure is 1.5% plus or minus 0.5%. The jaundiceis almost invariably of the obstructive type. In98% of cases it occurs during the first two monthsof treatment, so that after that length of time thepatient does not have to be followed nearly soclosely. The condition is definitely not related todosage and has been reported to occur in cases witha single dose of 25 mg and, in one case, 10 mg ofchlorpromazine. The very much lower incidenceor absence ofjaundice with the newer phenothiazinesis a distinct improvement. For research purposeswe have followed a variety of liver function testsover extended periods of time on a very large numberof patients, but in our opinion none of these hassufficient predictive value to be clinically useful.The yellow conjunctiva, the itching, and the othersigns of jaundice usually appear even prior to ab-normal elevations in the liver function tests or inthe alkaline phosphate. At the first clinical signthe drug should be promptly withdrawn andsupportive treatment administered. On occasionpatients have been re-started on the same medication,and patients have even been continued on chlor-promazine with disappearance of jaundice, but inview of the large number of phenothiazines nowavailable it is suggested that an alternative wouldbe preferable, since the occurrence of jaundice withone phenothiazine gives no indication that the samereaction will necessarily occur with a (chemically)closely related compound. Some interesting evidencehas been presented that if the patient is kept wellhydrated there is significantly less likelihood ofjaundice occurring. Many recommend for treatmentof jaundice diets of high protein, high carbohydrateand low fat content together with vitamin K (5 mgintramuscularly daily), Plebex (2 ml daily), a cortisonepreparation such as Cortef (50 mg eight-hourlyintramuscularly) and, if necessary, blood trans-fusion. Metacorten (10 mg six-hourly) has also beensuggested.
Care should be taken in the interpretation ofliver function tests in the absence of clinical symp-toms. We have routinely done four liver functiontests at weekly intervals in several thousand patients
for three weeks prior to starting medication, andfound at least one test to show abnormal results inover 80%.Leukopenia and leukocytosis. Some degree of
leukopenia is relatively common, occurring inperhaps 15 % of all patients on many of the pheno-thiazines. This reaches the point of agranulocytosisin 1-2% of the patients, and fatalities with chlor-promazine and some of the analogues should beconsidered as part of the therapeutic risk. Most ofthe newer phenothiazines have either no, or a muchlower occurrence of, leukopenia, and for this reasonare frequently preferable. The one therapeuticadvantage of chlorpromazine is that it induces acertain amount of somnolence and lethargy, whichat times is clinically desirable, but since this can beachieved in other ways it does not make chlor-promazine the most desirable of the phenothiazines.Proclorperazine (Compazine), triflupromazine (Ves-prin), perphenazine (Trilafon) and numbers ofothers appear to be much safer, and equally effective.The occurrence of marked leukopenia or agranulo-cytosis is an indication for immediate withdrawalof medication. With agranulocytosis, protective anti-biotics should be instituted at once in significantdoses, and a variety of adrenocortical preparationshave been recommended by various authors. Ifthe case is diagnosed early enough fatal terminationcan usually be avoided. It is therefore extremelyimportant to stress to the patient that the clinicalsigns of agranulocytosis, such as scratchy throat,extreme fatigue, etc., should be promptly reported. Itis also advisable to have a base-line haematologicalexamination to provide a standard against whichto judge subsequent laboratory data, should thisprove necessary.
Side effects ofpsychic energizersThe psychic energizers represent by far the most
potent group of pharmaceuticals in the psychiatricfield. They have frequently not been treated withthe respectful caution which is their due. This inpart has been due to the fact that even the ataraxicsare relatively " non-explosive" compounds. Sincedosage recommendations for most of the otherpsychopharmaceuticals definitely tend to lean tothe conservative side, many practitioners have foundit expedient to double or even triple recommendeddosages. In turn patients have had the sameventuresome spirit, and not infrequently doubled oreven tripled the prescribed dose. As a consequenceoccasional patients have taken, fairly regularly,
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five to ten times the dose suggested by the pharma-ceutical house. When iproniazid (Marsilid) wasintroduced, the practice was so well established that,despite the extremes of caution recommended, theoptimal dose was quite frequently exceeded. Sincethe pharmaceutical dose was a cumulative one,sometimes not reaching its onset of action for aslong as three weeks or more, there was a naturaltendency to keep on increasing the dosage in thehope of achieving a therapeutic response. Withthis type of loading, when the drug did begin to act,it was at levels far above the optimal. No sensiblephysician would either prescribe digitalis for apatient in cardiac decompensation, or suggest thata diabetic patient take insulin according to aninitial maximum recommended dose and return ina month or two. Unfortunately, because the otherpsychopharmaceuticals had such a large margin ofsafety this actually was done with iproniazid.Some of the psychic energizers now on clinical
trial (but not yet on the market) have a potencyranging up to roughly fifty times that of iproniazid,so that in the future even greater care will have tobe exercised.
Potentiation of other medications. The greatestcaution must be observed by keeping constantly inmind the ability of these drugs to potentiate manyother medications. To a small extent this is true ofsome of the phenothiazine derivatives, but comparedwith the psychic energizers other potentiating agentsare comparatively inert. On three or four occasionsI have failed to find the response I had anticipated,and only after close questioning did the patientsadmit that they were continuing their " small doseof barbiturate ", which they had been using regularlyfor from ten to twenty years. They had felt thatmy insistence that all other medications be dis-continued for the time being could not possiblyhave applied to their " sleeping pill ", even thoughit had been particularly mentioned. In effect,they had unknowingly raised their dose of barbitu-rate by five to ten times, and as a consequencebarely managed to stagger through the day. Thephenothiazine derivatives are also increased inpotency, and doses no more than a quarter of thecustomary should be used for initiation of treat-ment. As a result of failure to note this potentiation,I have been called in consultation to see a full-blown case of a Parkinson-like syndrome who wason long-term treatment with perphenazine (Trilafon).When a psychic energizer was added the extra-pyramidal symptoms developed in a few hours.
Since certain foods have a pharmacologicaeffect they should not be overlooked. It was apatient who brought to my attention the reasonfor her extreme jitteriness, which is not typical ofthese medications. She had sworn that she had nottouched any other medication-but finally askedme whether the fact that she drank ten or twelvecups of coffee a day might have any effect, addingthat under normal circumstances she had no reactionto this. When the coffee was reduced to two orthree cups a day excessive irritability disappeared.Subsequently I have observed the same reaction notonly with tea but also with some of the " cola "drinks, which contain caffeine. In one extreme case,a single cup of coffee taken in the morning keptthe patient not only jittery all day but up the entirenight. The reaction was repeated on three differentoccasions in the same patient, so that the effect wasprobably a real one.
Anaesthetics taken for dental work have alsooccasioned marked reactions. In part these appearrelated to the adrenaline present in most suchsolutions, but one would also suspect that anysubstance resembling cocaine might be anotherfactor. Therefore, dental work should be avoidedif possible. Similarly, if an operative procedurerequiring general anaesthesia is needed, the anaes-thetist should be warned of possible extremereactions. The patients themselves should be cau-tioned of this, since it might otherwise occurwithout the physician being given prior warning.As yet we do not know the exact degree to which
all other common medications are potentiated, sothat they should be administered circumspectlywith small initial doses if their use is indicated.
Liver toxicity. On April 1, 1958 (a few daysshort of a year after we had pointed out the specificpsychopharmacological action of iproniazid(Marsilid) on depression), the US Food and DrugAdministration estimated that 400000 to 500000patients had been treated with these drugs, with atotal of 33 fatalities associated with jaundice. Sinceboth clinically and pathologically the symptomato-logy cannot be distinguished from that of infectioushepatitis, it is almost certain that some of thesepatients died from the viral infection, and certainlyothers, for whom permission for an autopsy wasnot obtained, must also have died from othercauses. On the other hand there were almostcertainly more fatalities than reported, which wouldtend to increase the number of cases. The totalnumber of cases of jaundice (roughly 100) does not
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seem out of line with what might have been expectedfrom infectious hepatitis. The mortality rate doesseem unusual, if it is assumed that both figures areroughly accurate. I am therefore left with theimpression that, just as resistance to intercurrentconditions is lowered with the ataraxics, there ishere a similar weakening of resistance, which mayeven show some particular susceptibility in respectof specific virus conditions.The only near-effective alternative for many of
these patients was electroconvulsive therapy, wherethe generally accepted mortality rate is 1 in 1000.On the semi-official estimate of the number of casestreated with iproniazid (Marsilid), if the mortalitywere comparable to that of electro-shock therapy,one would anticipate four to five hundred deathsdirectly related to the drug. At the worst, therefore,on the basis of available data iproniazid is ten tofifteen times as safe as electro-shock therapy. Inview of the furore created about this jaundice amisquotation comes to mind: " Never has so muchbeen said so frequently about so little."
Various adrenocortical products have been sug-gested by way of treatment, but no definitiveevidence exists that they are consistently of help.Obviously withdrawal of the drug and supportivetreatment are mandatory.
Hypotension. Evidence would seem to indicatethat these drugs are even more regularly hypotensivein their action than the Rauwolfia derivatives,although here the drop below the limits of physio-logical functioning is more frequent. As a generalrule the drop in blood pressure is associated withpostural changes, and at times becomes so markedthat complete bed rest is required. These changesdisappear with reduction or withdrawal of medica-tion, although a number of clinicians have insistedthat administration of cortisone (12.5 mg twicedaily) or ACTH relieves the postural hypotensionand enables the patient to continue medicationwithout difficulty. My own experience has beenlimited to a number of patients who received a fewmilligrams of thyroid daily before or after treatmentwas begun with the psychic energizers. In each ofthe three cases seen the psychic energizer either failedto work, or it lost its therapeutic action after thethyroid was added. In view of the fewness of thecases one cannot draw conclusions as to incom-patibility, but I would certainly advise caution inthe use of endocrine products of any sort untilmore is known.
Neuralgias. On prolonged administration ofmoderate or high doses neuralgias may occur.These range from " earaches " to " arthritis ", and ifthe patient is not cautioned he or she may alsoend up with completely unnecessary dental extrac-tions. There has been no difficulty in managing thisreaction; this is usually done by a temporarylowering of dosage plus the administration of 25 to50 mg of pyridoxin (vitamin B6).
Changes in bowel habits. Obstipation or constipa-tion are very frequent to at least some degree, andoccur very markedly in the sensitive patient. Insome individuals faecal impaction or congestionseems to be associated with vasomotor instability,and it is therefore recommended that some methodof bowel evacuation be utilized approximatelytwice a week.
Changes in sexual function. The occurrence oftemporary impotence in the male is not at allinfrequent, although this may be more marked inattaining orgasm than in achieving erection. It isnot unusual to hear a patient complain that threehours of intercourse were required in order to reacha sexual climax, which proved to be a rather ex-hausting experience. Using this experience as abase, I have successfully treated a number of casesof ejaculatio praecox. On some of the newer psychicenergizers a number of female patients have com-mented on their increased sexual sensitivity. Alsoafter a period of reduced sensitivity while on thedrug, there have been cases of marked responsivenessupon withdrawal.
Weight changes. There is quite frequently anincrease in appetite, characterized by a positivenitrogen balance. After an early rise, the weightusually drops slightly. Since cosmetic or otherproblems may be involved, it is suggested that caloricintake be watched if there is reason for concern.
Oedema. As with ataraxics, the occurrence ofoedema is best handled by the use of Diuril, Diamox,or the mercurial diuretics, if the condition reachesthe point of cosmetic or physiological discomfort.
" Insomnia ". A reduced need for sleep is amongthe most characteristic of responses to the psychicenergizers. This is not true insomnia since there isno concomitant fatigue. Whether one chooses toregard this as a side effect, with the implication thatit is something undesirable, or it is looked upon asa bonanza, is in part dependent upon how thepossibility of this reaction is presented by the
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physician. Although meprobamate and other of thenon-barbiturate hypnotics can be used in lower thanusual doses without great danger, this to some extenttends to counteract the effect of the medication. Myown approach has been to point out that two orthree extra hours of waking life per day, if someoneis feeling in a good frame of mind, constitute aremarkable gift. The patients have been encouragedto organize their life around the fact that there will bereduced need for sleep, and discussion of what canbe done that is interesting and constructive duringthese periods has also proved helpful.We have elsewhere discussed the use of these
drugs for the treatment of drug addiction, and it hasbeen interesting to watch patients who have beenon nightly barbiturates for twenty or more yearsfind that they can get on perfectly well withoutthem. As might be anticipated, there is also a
paradoxical response in some patients who havepreviously suffered from marked insomnia. Theyfind that for the first time they are able to sleep wellwhen placed on these medications.
In summary then, rather than " treating" thisside effect in an effort to eliminate it, I would encou-rage its presence and help the patient make use of it.
Miscellaneous. A variety of other side effects havebeen reported occasionally. These include: hyper-aesthesia, paraesthesia, perspiration, altered depend-ent reflexes, reduced tolerance to cold, possible skinrashes, transient nausea and pyrosis.How regularly these are associated with the drug
is unknown, and we have had no particular ex-perience which would lead us to other than thenormal medical recommendations for handling suchreactions.
R1tSUM12
11 existe une telle abondance de noms et de termesdesignant les medicaments modifiant les fonctionspsychologiques que meme les specialistes peuvent sesentir par moment debordes. L'auteur donne une listedes d6signations usuelles en indiquant celles qui luiparaissent les plus appropriees et pourquoi.
En ce qui concerne l'ensemble des medicaments ayantune influence sur les 6tats psychologiques, le terme quepropose I'auteur est celui de medicaments # psycho-pharmaceutiques , le mot &(tranquillisants*) 6tantinacceptable puisque parmi ces medicaments il y a nonseulement des tranquillisants, mais egalement des
excitants. L'adjectif < phrenotropiques )) est parfaitementacceptable, celui de <'neurotropiques # trop limitatif.
Les trois categories principales de ( psychopharma-ceutiques > sont les psycho-inhibiteurs ou psycholeptiques,les psycho-activateurs ou psycho-analeptiques, les psycho-tomimetiques ou psycho-dysleptiques. L'auteur donneune liste des medicaments appartenant a chacune de cestrois categories, en les classant selon leur action principale,et en indiquant pour chacun d'eux les doses d'attaqueet les doses d'entretien. Cette classification est suivie deconseils sur leur utilisation, d'une etude detaill6e deseffets secondaires propres a chaque groupe de substanceset des differents moyens de combattre ces effets.
