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Psychopharmacological Procedures

HEINZ E. LEHMANN Douglas Hospital and McGill University, Montreal, Canada

Of all special fields in medicine, today has grown into a system of internal medicine and psychiatry empirical and rational procedures probably play the most important which can be studied and acquired roles in general medical practice. by anyone who is motivated to do This has always been so, but there so. To acquire knowledge and skill has also always been a gap be­ of psychopharmacological proce­ tween the clinical approach to the dures neither calls for particular medical aspects of the total treat­ assets of temperament or personal­ ment of a person, and to the psy­ ity nor dedicated immersion into chiatric aspects. This gap, which esoteric speculations and polysyl­ for many years has alienated psy­ labic terminology. chiatry from the other parts of medicine, has only been bridged in What is Psychopharmacology? the last two decades. Since the early 1950's psychiatric thinking Psychopharmacology is a new and practice has moved much closer scientific discipline which was born to general medical procedures, so in the first few years of the second that treatment of many psychiatric half of our century. It is a discipline patients has become more rational, which deals with psychotropic or more understandable and more psychoactive drugs, i.e., drugs practical for the non-specialist. which influence consciousness, If psychiatric treatment today is mood and behavior. Psychopharma­ a major concern of general medical cology, which has played such an practice, psychopharmacology has important role in bringing psychia­ been one of the most important fac­ try back into the fold of general tors in this development. New medicine, is concerned with four and effective pharmacological treat­ principal aspects of psychotropic ments of various psychiatric dis­ drugs: 1) indications for, and dos­ orders have made it possible for age of, psychotropic drugs; 2) side any physician to treat patients who effects and complications of these previously had to be hospitalized drugs and their management; 3) and could be treated only by psy­ understanding of the mechanisms of chiatrists. In making this claim for action of psychotropic drugs the pharmacotherapy of psychiat­ through the development of opera­ ric disorders, I do not wish to im­ tionally defined and measurable re­ ply that the fine arts of interview­ search procedures; 4) development ing, listening and psychological and screening of new substances in understanding are no longer needed this field. The first two of these as­ by the doctor; they still are and pects primarily concern the clini­ probably always will be among the cian; the latter two lie more within most important skills of any good the field of the researcher. physician. I simply want to make Following the discovery of chlor­ the point that psychopharmacology promazine, the first of a group of

MCV QUARTERLY 5(3): 151-160, 1969 151 PSYCHOPHARMACOLOGICAL PROCEDURES entirely new drugs for the treat­ psychiatry is less fortunate than acterized by aimless restlessness and ment of mental disorders, it became other branches of medicine, be­ autonomic signs of sympathomi­ clear within a few years that the cause (with very few exceptions) metic (adrenergic) arousal, e.g., new psychotropic drugs had made it lacks objective criteria for diag­ tachycardia, sweating, increased a tremendous impact on three nosis as well as knowledge about blood pressure, mydriasis. At the areas: 1 ) the public, for whom­ the etiology of most of the condi­ same time the patient feels uncom­ virtually overnight-tranquilizers tions for which a psychiatrist has fortable, unable to relax and­ became a household word and a to treat his patients. This does not when not only tension but also multimillion-dollar business; 2) re­ mean that psychiatric diagnosis is anxiety is present-apprehensive search, where the new discipline entirely subjective, but it does mean and threatened in some undefinable of psychopharmacology was estab­ that practically all psychiatric diag­ manner. Tense and anxious pa­ lished in the wake of these discov­ nosis is based primarily on the ob­ tients, as a rule, also suffer from eries; 3) treatment, where the new servation of behavioral deviations. insomnia. drugs made possible an almost rev­ The causes of the major psychoses Perceptual and cognitive disor­ olutionary new approach to the are still unknown, although a great ders occur mostly in psychotic con­ therapy for many psychiatric dis­ deal of promising research is going ditions and indicate impaired con­ orders. on in this area. The origin of tact with reality. Examples of A number of psychotropic drugs neurotic disturbances is better un­ symptoms occurring in this cate­ have, of course, been known and derstood but is also still subject to gory are: hallucinatory perceptions, used by man for a long time. Al­ controversy between proponents of in one or several sense modalities, cohol, caffeine and certain narcot­ psychoanalysis, learning theory and without any corresponding objec­ ics are the oldest psychotropic genetic or other somatic factors. In tive stimulation; delusional ideas, agents known. The discovery of spite of all these theoretical un­ i.e., false and persistent beliefs their properties has been lost in certainties, we now have a variety which cannot be corrected by ra­ the dawn of recorded history. But of effective pharmacological treat­ tional proof that they are un­ with the advent of scientific medi­ ments in psychiatry, and even if founded; a generalized thinking cine, systematic research during the their mechanisms of action are not disorder leading to irrational and past century led to the develop­ always clearly understood, many of bizarre forms of reasoning. ment of anaesthetic drugs and, these treatments have empirically Depression is behaviorally char­ later, to the introduction of a va­ proven their worth. acterized either by agitation or, riety of hypnotic and sedative Rather than involve you in the more typically, by psychomotor re­ agents. Thus, after the empirical problems of psychiatric diagnosis tardation, i.e., a general slowing discovery of intoxicants and stim­ and classification, I should like to down of all spontaneous and re­ ulants, medical research discovered discuss the four major symptomatic sponsive activity, an overall in­ remedies for some of the universal conditions which can be effectively crease of inhibition and reduction ills of mankind, i.e., pain, insomnia treated with psychotropic drugs. of energy output. Most important and anxiety. Effective drugs for These four conditions are: 1 ) psy­ is the core symptom, a subjective more specific uses in the treatment chomotor excitement; 2) tension background of an all pervasive of mental and emotional disorders and anxiety; 3) depression; 4) per­ feeling of dejection, pessimism and have been systematically developed ceptual and cognitive disorders hopelessness which not infrequently since two French psychiatrists, De­ (e.g., hallucinations and delusions). leads to attempted or completed lay and Deniker (1952), adminis­ Let me briefly define these well­ suicide. tered chlorpromazine (Thorazine) known behavioral deviations or for the first time to agitated psy­ mental symptoms. Classification of Psychotropic chotic patients and noted the Psychomotor excitement is char­ Drugs extraordinary tranquilizing effect of acterized by restless, overactive, this drug. agitated, noisy, boisterous and dis­ Having thus classified-though inhibited behavior; a feeling of be­ somewhat roughly-the four prin­ Pharmacotherapy in Psychiatric ing driven-being under pressure cipal psychiatric conditions which Disorders -with the mood being either one can be effectively treated with psy­ of aggressive anger or excessive chotropic drugs, let me now give Although the title of my paper elation. Usually, pronounced psy­ you the brief and simple classifica­ is "Psychopharmacological Proce­ chomotor excitement is associated tion of psychotropic drugs which dures," what I really intend to talk with insomnia and sometimes with has been proposed in the report, about is pharmacotherapeutics with clouded consciousness, i.e., confu­ "Research in Psychopharmacol­ psychiatric patients. At this point, sion and delirium. ogy," published by a World Health I would like to remind you that Tension and anxiety are char- Organization scientific group

152 H. E. LEHMANN

( 1967). The report distinguishes psychostimulant, he is often ren­ and affective processes, is still in five categories of drugs. The first dered more tense and sleepless and the experimental stage. category is Neuroleptics-often re­ may well become more depressed. ferred to as major tranquilizers or Sometimes, but rarely, an ampheta­ antipsychotics-which are repre­ mine or Ritalin may be helpful in Therapeutic Applications of sented by the phenothiazines, the the treatment of certain depressive Neuroleptics and Anxiolytic butyrophenones and the thioxan­ states, but only when the depres­ Sedatives (Tranquilizers) thenes, as well as by the reser­ sion is in its very beginning or pine derivatives. The second cat­ already fading out. During a full­ States of Excitement egory is Anxiolytic Sedatives­ blown depression, psychostimulants Effective agents in the treatment often referred to as minor tran­ are contraindicated. Because physi­ of acute excitement and acute or quilizers-which are represented cal tolerance of and psychological chronic states of tension and anxi­ by meprobamate and its derivatives, dependence on the amphetamine­ ety are the neuroleptics and the chlordiazepoxide (Librium) and its like psychostimulants develop rap­ anxiolytic sedatives. Both types of derivatives, and barbiturates. The idly, these drugs should only rarely drugs are often referred to as tran­ third category is Antidepressants, be prescribed. This is the conclu­ quilizers. However, if one chooses represented by monoamine oxidase sion reached in the report entitled to do so, he should make a clear (MAO) inhibitors or imipramine "Control of Amphetamine Prepara­ distinction between the major tran­ and other tricyclic compounds. The tions" prepared by a special com­ quilizers (neuroleptics) and the fourth category is Psychostimu­ mittee* which had been appointed minor tranquilizers ( anxiolytic sed­ lants, represented by the ampheta­ in Britain to study the place of atives). There are distinct clinical mines, methylphenidate (Ritalin) the amphetamines in clinical and pharmacological differences be­ and pipradrol (Meratran) and by medicine. tween the two types of tranquiliz­ caffeine. The fifth category is Psy­ The psychodysleptics, i.e., LSD ers. The only drugs which can ef­ chodysle pt ics (hallucinogens), and similar drugs which produce fectively reduce specific psyci;otic which are mainly represented by strange alterations of consciousness symptoms-hallucinations, delu­ lysergic acid diethylamide (LSD), -their current popularity notwith­ sions and psychotic thought disor­ mescaline, psilocybin, dimethyltryp­ standing-have no clearly estab­ der-are the major tranquilizers. tamine (DMT) and cannabis (mar­ lished therapeutic indications. Their But both the major and the minor ijuana, hashish .or bhang). use is mainly experimental, al­ tranquilizers will reduce psychomo­ though considerable literature exists tor excitement, tension and anxiety, on the use of LSD in neurotic con­ although the minor tranquilizers Clinical Applications ditions, behavior disorders and al­ will do it more effectively. Psychostimulants and coholism. Whether or not these Many of the anxiolytic sedatives are highly toxic and, thus, can be Psychodysleptics drugs are really effective in these disorders and, if so, in what dosage used for suicidal purposes. The Let us first look at the last two and under which conditions, will neuroleptics have a much higher categories of psychostimulants and be shown by the outcome of a margin of safety. Anxiolytic seda­ psychodysleptics, because they have number of controlled studies, the tives raise the convulsive threshold few clinical applications and we results of which will not be avail­ and, thus, have an anticonvulsant can rapidly dispose of them. Psy­ able for another three to five years. effect, whereas most of the neuro­ chostimulants are specifically indi­ There is also the possibility that leptics lower the convulsive thresh­ cated for the treatment of narco­ the recently isolated active princi­ old and, in high doses, may lepsy. Sometimes they are useful ple of marijuana-tetrahydrocan­ induce convulsions. Most of the in states of chronic lassitude, such nabinol (THC)-might find some anxiolytic sedatives can produce as may be seen following a pro­ clinical applications, perhaps in the tolerance and psychological de­ tracted disease, e.g., a virus infec­ treatment of depressions. At the pendence, and many drugs in this tion. The amphetamines may also present time, however, the applica­ category will produce physical de­ be helpful in programs of weight tion of the entire category of psy­ pendence when taken in high doses reduction because of their anorexo­ chodysleptic drugs, which manifest over long periods of time. The genic effect. In the treatment of their action mainly through disor­ neuroleptics produce neither toler­ depressive conditions, psychostim­ ganization of perceptual, cognitive ance nor psychological dependence. ulants play a very minor role, be­ Only anxiolytic sedatives will pro­ cause a severely depressed patient duce disinhibition of higher nerv­ requires more than a "lift" or * J. Chappell, W. W. Fulton, M. M. ous processes and, thus, like "boost." If a depressed patient's Glatt, W. L. Rees and C. W. M. alcohol, induce a phase of in­ state of arousal is increased by a Wilson. creased and uncontrolled behavioral

153 PSYCHOPHARMACOLOGICAL PROCEDURES

manifestations prior to their inhibi­ cular injection of 50 to 100 mg is psychotherapy, including the re­ tory action. Neuroleptics inhibit of chlorpromazine (Thorazine) or cent modifications of milieu ther­ only; they do not induce states of thioridazine (Mellaril). Once apy and behavior therapy. transient disinhibition. On the other calmed by these drugs, the pa­ As supportive therapy for a hand, only neuroleptic drugs can tients also tend to become more limited period of time, anxiolytic produce extrapyramidal side ef­ rational and cooperative rather sedatives, or the minor tranquil­ fects, e.g., parkinsonism-Iike rigid­ than confused or comatose, as with izers, are very effective in checking ity, tremor or muscular dystonia the anxiolytic sedatives. symptoms of anxiety and tension. and dyskinesia. Not every agitated patient can The neuroleptics or major tranquil­ Since both types of drugs, the be controlled with one injection of izers ("major," because they are minor or the major tranquilizers, a neuroleptic. The physician should capable of suppressing psychotic can be used for the management always consider a state of acute ex­ symptoms as well as anxiety sym­ of acute excitement or tension and citement as an acute emergency and toms) are less effective in reducing anxiety states, what factors should should no more abandon a patient anxiety than the minor tranquiliz­ determine our choice of drugs in before his excitement has been ers. However, the minor tranquiliz­ these conditions? The physician brought under control, than he ers tend to produce tolerance and who is faced with an extremely ex­ would abandon a patient before drug dependence and, thus, become cited patient is often inclined to shock or hemorrhage had been dangerous drugs if prescribed in choose what he thinks would be brought under control. The effects large doses for more than two or the most rapid way of subduing the of an intramuscularly administered three weeks. Tolerance and drug agitated patient, i.e., by intravenous neuroleptic manifest themselves dependence do not develop with the injection of a sedative drug. It is after about 15 to 20 minutes. If at neuroleptics, and for this reason not advisable to inject neuroleptic that time the patient is still excited, one may sometimes choose to pre­ drugs intravenously in a patient another dose of the neuroleptic, scribe a neuroleptic drug for a pa­ whose reactions one does not know either equal to the first dose or tient suffering from anxiety, even very well; there may be a sudden somewhat reduced, should be in­ though it is likely to be Jess effec­ marked drop of blood pressure or jected. After another 15 minutes a tive than an anxiolytic sedative. other undesirable complications. third injection might be given and, Such a choice would be indicated Therefore, the drugs chosen for sometimes, still a fourth 15 to 20 if, on the basis of the patient's pre­ intravenous administration should minutes later. By that time, how­ vious history or his personality be those belonging to the category ever, even the most excited patient structure, one has reason to believe of anxiolytic sedatives. Barbiturates, should be under control with this that he might rapidly develop psy­ e.g. , sodium amytal, in doses of cumulative intermittent or staggered chological and, also, physical de­ 250 to 500 mg; chlordiazepoxide sedation. pendence on an anxiolytic sedative. (Librium), in doses of 50 to 100 When faced with this hazard it is mg; or diazepam (Valium), in Tension and Anxiety often wiser to choose the second doses of 10 to 30 mg, are often best drug, e.g., a phenothiazine dramatically effective in terminat­ The treatment of anxiety and ten­ drug in small doses rather than a ing a state of acute excitement. sion states by drugs is only a symp­ minor tranquilizer for sedation. However, occasionally the patient tomatic approach to the underlying Of all psychiatric conditions does not calm down until very problem-a symptomatic approach which a physician is called upon to large doses have been administered, which should be limited to the treat, anxiety is undoubtedly the thus making the patient toxic and shortest possible period of time. most common. It is difficult to re­ comatose. This difficulty occurs The treatment of choice in all anx­ sist the urgent demands of an anx­ most frequently in states of hysteri­ iety states is psychotherapy, unless ious patient for immediate relief cal excitement. Because of these the tension and anxiety is due to from his symptoms. The doctor occasional complications with the physical causes, for instance, hyper­ mus.t learn to brace himself against intravenous administration of anx­ thyroidism or congestive failure. these demands and persuade his pa­ iolytic sedatives, and also because It is obvious that any physical tient to settle for less than complete this type of drugs in large doses causes of tension and anxiety relief, particularly if tranquilizing tends to make the patient confused, should receive specific treatment, drugs have to be prescribed for I feel that it is generally better but in the majority of cases, ten­ periods exceeding two or three practice to rely on the intramus­ sion and anxiety are due to psy­ weeks. Patients who present anxiety cular administration of neuroleptics chological causes, e.g., environmen­ symptoms are often highly sensitive for the management of acute ex­ tal stress, personality disorders or to side effects which may be asso­ citement. Most agitated patients intrapsychic conflicts. For these ciated with the use of major tran­ will settle down after an intramus- conditions the treatment of choice quilizers, and they will make every

154 H. E. LEHMANN

effort to convince the doctor that The only minor tranquilizer drug from the toxicity point of view they ought to receive a drug which which seems to be free of the po­ seems to be chlordiazepoxide; from does not cause them any discom­ tential hazard of inducing physical the point of view of physical de­ fort. However, patients should drug dependence is tybamate. With pendence, tybamate; and from the learn to accept the comparatively this drug it has been impossible to point of view of psychological de­ mild inconveniences of side effects, induce physical dependence in ani­ pendence, hydroxyzine. Pharma­ e.g., dry mouth, stuffy nose, even mals or humans under experimental cotherapy of anxiety and tension some drowsiness and lack of conditions, and dependence on the symptoms is always symptomatic energy. It is probable that major drug has not been reported under and should only be used as an ad­ tranquilizers produce less depen­ clinical conditions. This may be junct to other more specific ther­ dence, precisely because they tend due to the fact that tybamate has apy. One should avoid prescribing to produce more unpleasant side an unusually short half-life in the the same minor tranquilizer for effects than the minor tranquilizers. organism; its rapid degradation may more than two weeks, unless the When the dangers of drug toxicity, prevent the development of depend­ patient receives only small doses. It development of tolerance and de­ ence through the absence of any is advisable for a doctor to become pendency are threatening, the ther­ cumulative effects (Shelton and familiar with three or four minor apeutic "elegance" of prescribing Hollister, 1967). Looking for a tranquilizers at the most and to al­ a drug with no unpleasant side ef­ drug to be less likely to induce psy­ ternate their use if anxiety-relieving fects should definitely be disre­ chological dependence, we have drugs have to be prescribed for garded. noted that one of the new minor more than two weeks or if special Although barbiturates are the tranquilizers, hydroxyzine (Atarax), indications, e.g., danger of suicide principal offenders in producing is less likely than other sedatives or addiction are present. drug dependence and toxic symp­ to be taken in larger doses or for toms, it is a fact that almost every a longer time than prescribed­ Acute Psychotic States minor tranquilizer has these poten­ possibly because it causes euphoria tials. There is no pharmacological and disinhibition less frequently Acute psychotic episodes fre­ reason for making a distinction be­ than most of the other minor tran­ quently improve within a few days tween hypnotic drugs and anxioly­ quilizers. with the use of neuroleptic (anti­ tic sedatives. Every drug which is In summing up the salient fea­ psychotic) drugs. In previous years used primarily for sleep induction tures regarding clinical use of anxi­ these states usually lasted for can also be used in smaller doses olytic sedatives, we arrive at the months, and even with shock ther­ as a daytime sedative, and every following conclusions. Anxiolytic apy more time was required for daytime sedative (or minor tran­ sedatives, which are also called a successful resolution of symtoms quilizer) in larger doses will pro­ minor tranquilizers, differ from than is required today with pharma­ duce drowsiness and sleep. The dis­ hypnotic drugs only in dosage. cotherapy. tinction between hypnotics and Pharmacological and psychological The prototype of neuroleptic sedatives is, thus, only a question effects of all drugs in this category drugs is Thorazine, which still of dosage. Minor tranquilizers are very similar, regardless of the serves as a standard against which other than barbiturates, e.g., methy­ chemical nature of the drug. Many newer drugs in the neuroleptic cate­ prylon, or Noludar (Jensen, 1960; of the drugs in this category are gory are evaluated. Thorazine is a Peters, 1966), and glutethimide, or highly toxic; therefore, no patient phenothiazine derivative, as are Doriden (Ossenfort, 1957; Ling!, should be given a prescription for most of the other antipsychotic 1966), are just as likely to produce more than 15 doses of a barbiturate drugs on the market today. In re­ psychological and physical depen­ or meprobamate at one time. With cent years, the butyrophenones and dence with dangerous withdrawal very few exceptions, all anxiolytic thioxanthenes, derivatives of two symptoms as are the barbiturates. sedatives tend to produce tolerance other chemical structures, have To a lesser degree this is also true and psychological and physical de­ joined the phenothiazines as power­ for meprobamate (Equanil) and pendence. There is cross-tolerance ful neuroleptic agents. even chlordiazepoxide (Librium) between all drugs in this category, The neuroleptic drugs, which are and diazepam (Valium), although e.g., between alcohol and paralde­ mainly used in the treatment of physical dependence on the latter hyde, or alcohol and Librium, or psychotic conditions, may be di­ two drugs is rarely seen. Librium barbiturates and Librium. Once vided into two groups: 1) those has the best safety record of all physical dependence on a minor with side effects manifesting them­ minor tranquilizers; no death has tranquilizer has developed, abrupt selves mainly in disturbances of been reported with this drug, al­ withdrawal is potentially dangerous autonomic functions (hypertension, though, with large doses, a number and should always be undertaken miosis, tachycardia, dry mouth, of suicidal attempts have been made. in a hospital setting. The safest excessive perspiration and other

155 PSYCHOPHARMACOLOGICAL PROCEDURES

symptoms of adrenergic-cholinergic tion, constipation, obesity, menstrual be done in most cases without par­ imbalance); and 2) those with side irregularity and photosensitization. ticular risk because of the wide effects expressed mainly in the ex­ Skin rashes, edema, leucopenia and safety margin of all neuroleptic trapyramidal system (parkinson­ cholestatic jaundice may occur as drugs. ism, akathisia, muscular dystonia symptoms of idiosyncratic hyper­ Which of the many neuroleptics and dyskinesia). If the drug is a sensitivity. Rarely, agranulocytosis should one choose? Years of care­ phenothiazine derivative, the na­ and venous thrombosis are seen. ful clinical investigation have made ture of its side effects can usually With very large doses of neurolep­ it very clear that for all practical­ be predicted from the side chain tics-over I 000 mg of Thorazine i.e., clinical-purposes, no specific which is attached to the phenothia­ a day or its dose equivalent-con­ indications or specific therapeutic zine nucleus. Drugs containing a vulsions may occur. properties exist for any of the piperazine ring in the side chain are Mellaril, the neuroleptic with the neuroleptic drugs. Therefore, it is more potent, milligram for milli­ lowest incidence of extrapyramidal probably best for a physician to be­ gram and produce extrapyramidal side effects, should not be pre­ come thoroughly familiar with two symptoms more frequently than scribed in doses exceeding a daily or three neuroleptic drugs and then drugs with an aliphatic side chain maximum of 400 to 500 mg for restrict himself to their use. What which, in turn, are more likely to more than two or three weeks, is essential is that adequate doses produce changes in autonomic func­ since under those conditions it are given over an adequate period tions and sedation and must be might produce irreversible retinal of time. Such specific differences given in larger doses. Despite their changes or dangerous cardiac ar­ between the actions of various designation as major tranquilizers, rhythmias. Doses of the drug up to neuroleptic drugs as were found to not all neuroleptic drugs produce 400 mg/ day seem to be well toler­ exist were only of statistical sig­ sedation. Some of them have dis­ ated for an indefinite time. nificance and so slight that they tinctly stimulant effects and may The following is a list of the most probably have no importance for even increase tension in the pa­ frequently used neuroleptics: the clinician (Goldberg et al. , tient if one of their side effects 1) Phenothiazine derivatives with 1967). is akathisia, i.e., the inability of an aliphatic structure in the side What is an adequate dose? The the patient to remain still. The chain: chlorpromazine (Thora­ table on the opposite page shows hyperkinetic extrapyramidal symp­ zine) ; triflupromazine (Vesprin); approximate therapeutic equiva­ tom of akathisia, as well as the promazine ( Sparine) . lences of doses of various neuro­ hypokinetic symptom of rigidity, 2) Phenothiazine derivatives with leptic drugs in comparison to may be so disturbing to the patient a piperazine ring in the side chain: Thorazine. If I mg of Thorazine is that antiparkinsonism drugs must perphenazine (Trilafon) ; trifluo­ taken as 1 phenothiazine unit, the be employed to counteract these perazine (Stelazine); prochlorpera­ clinical approximations shown in symptoms. The most frequently zine (Compazine); thiopropazate the Table are obtained. For exam­ used drugs for this purpose are: (Dartal) ; fluphenazine (Prolixin; ple, the table indicates that 10 mg trihexyphenidyl hydrochloride (Ar­ Moditen). of Trilafon are equivalent to 100 tane), benzotropine methanesulfo­ 3) Phenothiazine derivatives with mg of Thorazine, and I mg of Hal­ nate (Cogentin) and procyclidine a piperidyl ring in the side chain: dol is equivalent to 70 mg of Thora­ hydrochloride (Kemadrin) . All of thioridazine (Mellaril). zine. these antiparkinsonism drugs have 4) Butyrophenone derivative: hal­ The therapeutic daily dose for a strong anticholinergic action. We operidol (Haldol). the treatment of an acute psychotic have found that they may produce 5) Thioxanthene derivatives: reaction is between 400 and 1000 toxic psychotic symptoms if they chlorprothixene (Taractan); thio­ phenothiazine units (mg of Thora­ are given in daily doses exceeding thixene (Navane). zine or the dosage equivalent of six or eight mg of Artane or Cogen­ This list is not complete, but re­ other neuroleptic drugs). Some­ tin, or 15 mg of Kemadrin. fers only to the more frequently times higher daily dose levels are Most neuroleptic drugs have re­ used drugs in the United States. required, e.g., 1000 to 2000 pheno­ markably low toxicity and an extra­ Specific doses for each drug can thiazine units and, occasionally, up ordinarily wide therapeutic margin, best be obtained from the informa­ to 3000 or 4000 units a day. But but they also have an unusually tion provided by the manufacturer, 400 to I 000 phenothiazine units a broad range of unpleasant side ef­ although dosage information given day will be effective in the treat­ fects, such as somnolence, apathy on the package inserts by the manu­ ment of most acute psychotic and restlessness, extrapyramidal facturer invariably tends to be on breakdowns. If the dose is ade­ symptoms, dryness of the mucous the conservative side and fre­ quate, the symptoms of restlessness membranes, tachycardia, hypoten­ quently has to be exceeded in in­ and insomnia should have subsided sion, disturbances of accommoda- dividual cases. Fortunately, this can after one week of pharmacother-

156 H. E. LEHMANN apy; after two weeks of treatment tenance therapy is interrupted, the It is true that probably 50% or the patient's anxiety, irritability, de­ risk of a relapse is between 30% 60% of former schizophrenic pa­ pression, suspiciousness and social and 50% . This risk can be reduced tients are today receiving neurolep­ withdrawal should be significantly to 5% or 10%, provided the patient tic drug therapy for months or reduced. Only after 8 to 12 weeks remains on regular follow-up ther­ years without needing it. The trou­ may one expect the disappearance apy. At times of increased stress, ble is that we cannot tell, by any of hallucinations, delusions and family conflicts, job changes and criterion, which of the patients are thought disorder. In some patients similar problems, the maintenance the 40% or 50% who will relapse resolution of all symptoms may, dose may have to be increased for a if they do not receive maintenance under adequate pharmacotherapy, short time; the same applies if the therapy. If we have seen once that be telescoped into a few days, par­ patient shows signs of increasing a patient who did not take any ticularly if the breakdown has been tension or instability. The clinical maintenance medication had a re­ very sudden in onset. On the other situation is similar to that of an lapse, we can assume with a high hand, if the above timetable indi­ epileptic patient on anticonvulsant degree of probability that this pa­ cates that the patient's symptoms treatment or of a diabetic on in­ tient will again relapse unless he are not subsiding within the ex­ sulin, i.e., the treatment is neither receives maintenance therapy. Usu­ pected periods of time, it may be merely symptomatic nor curative, ally, we do not have this infor­ necessary to increase the dose of but corrective or compensating in mation, because the patient is put the neuroleptic (Lehmann, 1965a). nature. on maintenance therapy after the An acute psychotic condition is A long-acting, injectable pheno­ first psychotic breakdown. In these treated preferably with intramuscu­ thiazine drug is now available in cases one should continue with lar injections, at least for the first the form of Fluphenazine Enan­ maintenance therapy for at least few days; then a change to oral ad­ thate. The usual dose is 1 cc, con­ six months and then carefully try ministration may be instituted. The taining 25 mg of the drug. For in­ to withdraw the maintenance medi­ risk of giving too much of a neuro­ dividual patients it is, of course, cation. Once it is known that an leptic drug is small if the general sometimes necessary to increase or individual patient requires main­ framework of the recommended decrease the dose, but the great ad­ tenance therapy, this treatment dosage is followed and one or two vantage of this preparation is that should have considerable priority test doses are given to observe the the effects of one injection in most over all other considerations. The patient's initial reaction to the drug. cases last for two weeks or longer, question one would have to ask of thus freeing the patient from the oneself is whether it is more ad­ Maintenance Therapy of responsibility to take medication vantageous for the patient to stop Schizophrenics in Remission himself every day. All he needs to taking his medication and be hos­ Chronic psychotic patients and do is return every two or three pitalized in a psychotic state or to schizophrenic patients in remission weeks for his injection. Since Flu­ continue taking his medication and frequently require maintenance phenazine has a piperazine struc­ remain a normally functioning therapy with neuroleptic drugs for ture in its side chain, the compound member of the community suffer­ many months-sometimes for years. is likely to induce extrapyramidal ing the inconvenience of certain The maintenance dose in most cases symptoms, and antiparkinsonism unpleasant side effects. is from one-sixth to one-fourth of drugs might be required to counter­ Serious complications, i.e., agran­ the acute treatment dose. If main- act these side effects. ulocytosis or jaundice, very rarely occur after the first two months of pharmacotherapy. Unfortunately, regular blood counts and biochemi­ Dose Equivalence of Various Neuroleptic Drugs cal tests have hardly more than legal value, unless they are re­ Neuroleptic Drugs Phenothiazine Units peated every two days. Skin pig­ Triflupromazine (Vesprin) 3 mentation and lens opacities (us­ Promazine (Sparine) t ually without effect on visual Perphenazine (Trilafon) 10 acuity) have been described after Trifluoperazine (Stelazine) 20 more than six months' medication Prochlorperazine (Compazine) 6 with high doses of Thorazine, and Fluphenazine (Prolixin; Moditen) 70 recently attention has been drawn Thioridazine (Mellaril) 1 to extrapyramidal symptoms, us­ Haloperidol (Haldol) 70 ually involving muscles of the Chlorprothixene (Taractan) 1 Thiothixene (Navane) 20 tongue and the mouth, which occur after long-term therapy with pipera-

157 PSYCHOPHARMACOLOGICAL PROCEDURES

zine derivatives of the phenothia­ However, it is still useful to at­ serotonin and noradrenaline at zines. (Unlike the extrapyramidal tempt an assessment of the varying neuronal synapses. This has been symptoms occurring under acute degrees to which each of these advanced as an explanation of treatment conditions, these late in­ two components is present in a their antidepressant action, since voluntary movements are usually given depression (Lehmann, 1965b, current neurochemical theories of irreversible. Fortunately, they oc­ 1968). depression propose that the under­ cur only in a comparatively small Once the decision to use antide­ lying physical substrate of a de­ percentage of patients, mostly in pressant drug therapy has been pressive state is a reduction of the the older age group, and only after made, the choice lies between drugs biogenic amines at the synapses of more than a year of continued drug belonging to the class of monoa­ the central nervous system. therapy.) mine oxidase inhibitors and drugs Some MAO inhibitors, e.g., which are often referred to as tricy­ tranylcypromine (Parnate), have an Therapeutics of Antidepressants clic antidepressants, because their immediate amphetamine-like stimu­ chemical structure is characterized lating and euphorizing effect in The physician who has diagnosed by a three-ring nucleus. Examples of addition to their principal antide­ his patient as being depressed and the first type are: phenelzine (Nar­ pressant action, which can be ob­ is considering the choice of treat­ dil); isocarboxazide (Marplan); served only after one to three ment must first determine how nialamide (Niamid); tranylcypro­ weeks. Such stimulation is often de­ threatening the patient's condition mine (Parnate) . Examples of the sirable, but in some cases it might is. Is the patient acutely suicidal? second group are: 1m1pramine be contraindicated. The side effects Does he refuse to take food or (Tofranil); amitriptyline (Elavil); of MAO inhibitors are more diffi­ medication? Is he psychotic and un­ desipramine (Pertofrane, Norpra­ cult to manage than those of the cooperative? These features may min); nortriptyline (Aventyl); tricyclic antidepressants, because determine whether the patient can protriptyline (Vivactil, Triptil). MAO inhibitors are incompatible be treated at home or must be hos­ The monoamine oxidase inhibitors with many other drugs and with pitalized; they may also indicate have approximately the same ther­ certain food substances, e.g., cheese, whether the patient should receive apeutic effectiveness as the tricyclic which may contain the pressor sub­ immediate electro-convulsive ther­ antidepressants, although there is stance tyramine. It is essential that apy or can be treated with an gradually increasing evidence that patients receiving a MAO inhibi­ antidepressant drug. In acutely sui­ the tricyclic antidepressants are tor abstain from these food items cidal patients electro-convulsive slightly more effective than the and from most other drugs, particu­ treatment is often indicated, since MAO inhibitors. On the average, larly adrenaline, amphetamines, most antidepressant drugs take about 60% to 65% of depressed thyroid and Demerol which, in from one to three weeks to produce patients show a satisfactory im­ combination with a MAO inhibi­ notable improvement. provement within two to three tor, may precipitate very alarming A differential diagnosis between weeks when treated with antide­ toxic complications. MAO inhibi­ endogenous and reactive depression pressant drugs. tors and tricyclic antidepressants is often helpful, because endoge­ The physician who prescribes a should not be administered simul­ nous depressions mainly require MAO inhibitor must remember taneously, and at least a week physical treatment, either electro­ that the effect of this enzyme in­ should elapse after discontinuation convulsive treatment or pharmaco­ hibitor is reaching farther than or­ of a MAO inhibitor before treat­ therapy, whereas reactive depres­ dinary drug action, because the in­ ment with a tricyclic antidepres­ sions, which may also respond to hibition of monoamine oxidase is sant is instituted. physical treatments, usually require not easily reversed. Monoamine Tricyclic antidepressants produce psychotherapy in addition to other oxidase is the enzyme that degrades mainly anticholinergic side effects; treatments. Today, the extent to serotonin and noradrenaline, and hence, care should be exercised which one can really distinguish when this enzyme is inhibited, the when ordering these drugs for pa­ between purely endogenous and biogenic amines are allowed to accu­ tients in whom urinary retention purely reactive depressions is be­ mulate. A similar effect is produced or glaucoma may be precipitated. coming more and more ques­ by the tricyclic antidepressants, A tricyclic antidepressant should tionable. The concept of "endo­ but through a different mecha­ never be administered concurrently reactive" depression, which is used nism; they prevent excessive nora­ with both an antiparkinsonism drug in the German psychiatric literature, drenaline, which has been freed at and a neuroleptic, since all three reflects the state of affairs which is the neuronal synapses, from being drugs-particularly the first two­ frequently encountered in depres­ reabsorbed into the cell body. Both have anticholinergic properties and sive states, i.e., one with endoge­ classes of antidepressant drugs, thus, may act synergistically to produce nous as well as reactive components. lead to an increase of available dangerous and even fatal complica-

158 H. E. LEHMANN tions, e.g., adynamic ileus (Warnes, sive states. Recently, Baastrup and patients. Treatment of the alco­ Lehmann and Ban, 1967). Some Schou ( 1967) have shown that holic is a complex problem and caution is also indicated in patients lithium carbonate, in doses of about involves the application of almost with myocardial damage in whom one-third or one-half of the thera­ every medical skill, but in the tricyclic antidepressants may pro­ peutic dose in manic conditions, framework of this discussion, I want duce reversible cardiac arrhythmias. can be given as successful main­ to draw your attention to one phar­ Some antidepressant drugs, e.g., tenance treatment to prevent the . macotherapeutic approach which is amitriptyline (Elavil), also have recurrence of both manic or de­ specifically applicable to the treat­ anxiety-reducing effects. Patients pressive episodes. This is a con­ ment of alcoholism. I am referring suffering from an anxious or agi­ siderable step forward, because to the use of disulfiram (Antabuse) tated type of depression often re­ maintenance treatment for affective as a maintenance treatment for al­ spond favorably to minor or major disorders previous to the introduc­ coholics who are motivated to give tranquilizers, e.g., Equanil, Librium tion of lithium treatment has by no up drinking. or Mellaril. Anxiety is very fre­ means been as effective as main­ Antabuse is an enzyme inhibitor quently associated with depression, tenance treatment of schizophrenic which blocks the breakdown of al­ and since the manifestations of patients in remission. However, be­ cohol in the organism at the acetal­ anxiety are far more conspicuous fore treatment with lithium carbon­ dehyde stage. Since acetaldehyde is than the manifestations of depres­ ate is instituted, a careful history a highly toxic substance, people sion, there is a danger that the les­ should be taken and the differ­ who have taken Antabuse and later sening of anxiety in response to a ential diagnosis should be well take alcohol become very ill within drug is mistaken for an overall im­ established, since this form of ther­ a matter of minutes. The alcoholic provement in the depressed pa­ apy does not seem to be effective who takes his Antabuse medication tient's condition. If this happens, in schizophrenic conditions and regularly will usually be deterred one may relax one's vigilance when would not be indicated for manic from taking alcohol by his knowl­ treating a patient who, in initial or depressive episodes which occur edge of the ordeal he would have response to therapy, may sleep bet­ only at long intervals. Since lithium to endure. The drug thus serves as ter, look better and display less may cause dangerous toxic compli­ a chemical straitjacket, a most val­ anxiety, but may still feel depressed cations which may be fatal, it is uable aid to those who are seri­ and hopeless and may also still be essential for patients on lithium ously motivated to give up drink­ suicidal. The core symptom of de­ therapy to have their lithium blood ing, but is not of much value to pression is a feeling of sadness, level monitored at regular intervals. those who simply stop taking Anta­ despair, pessimism and hopeless­ buse when they feel the desire to ness and the inability to get in­ Alcoholism and Antabuse drink. volved with things or people. Until Drugs are of no value in the these core symptoms have subsided, Summary a depressed patient's improvement treatment of most personality dis­ is far from complete. orders, for instance, antisocial be­ Psychopharmacology has opened After the depressed patient's havior and sexual deviation. Some the door to many previously blocked symptoms have disappeared, drug drugs can play an important role parts of psychiatric therapy. It has therapy should be continued for at in the rehabilitation of opiate ad­ been a welcome catalyst for a long least two to three months at the dicts, e.g., methadone, which, in the awaited rapprochement between same dosage; after this time the first few years of a large-scale trial psychiatry and the rest of medicine. dose of the antidepressant might in New York City, has shown re­ Even if psychopharmacological re­ be reduced to about one-half or markable results (Dole, Nyswander search is not likely to produce an­ one-third for another month or and Warner, 1968; Methadone other revolutionary "breakthrough" two. Maintenance Evaluation Commit­ type of drug in the near future, For patients with frequently re­ tee, 1968). However, the treatment there is good reason to expect many current depressions or patients who of addicts has not yet progressed to more useful therapeutic tools to is­ have many recurring manic or de­ the point where the non-specialist sue from such research in the years pressive episodes, lithium has re­ may be advised to undertake it. to come. cently been shown to offer valuable But there is one kind of addiction, prophylactic action. The therapeu­ i.e., alcoholism, which is so wide­ tic effects of lithium carbonate in spread-there are over two million References alcoholics in the United States­ states of manic excitement have BAASTRUP, P. C. AND M. SCHOU. been known for 20 years. However, that non-specialist physicians must Lithium as a prophylactic agent. Its the drug seems to have few, if accept a major part of the respon­ effect against recurrent depressions any, therapeutic effects in depres- sibility for treating this group of and manic-depressive psychosis.

159 PSYCHOPHARMACOLOGICAL PROCEDURES

Arch. Gen. Psychiat. 16 :162-172, Tranquilizer Proves Non-Addictive in 1967. Study, editorial. Medical World Control of amphetamine preparations. News 6:66, 1965. Brit. Med. J. 4: 572-573, 1968. WARNES, H., H. E. LEHMANN AND T. DELAY, J. AND P. DENIKER. Le traite­ A. BAN. Adynamic ileus during psy­ ment des psychoses par une meth­ choactive medication: A report of ode neurolytique derivee de l'hiber­ three fatal and five severe cases. notherapie. (Le 4560 RP utilise seul Can. Med. Assoc. J. 96: 1112-1113, en cure prolongee et continue.) 1967. Congres des Psychiatrie des Langues Franc;aise, Luxembourg, 22-26 July, 1952. DOLE, V. P., M. E. NYSWANDER AND A. WARNER. Successful treatment of 750 criminal addicts. JAMA 206:2708-2711, 1968. GOLDBERG, s. C., N . MATI'SSON, J. 0. COLE AND G. L. KLERMAN. Predic­ tion of improvement in schizophre­ nia under four phenothiazines. Arch. Gen. Psychiat. 16:107-117, 1967. JENSEN, G. R. Addiction to noludar. A report of two cases. New Zealand Med. J. 59:431-432, 1960. LEHMANN, H. E. Drug treatment of schizophrenia. In Psychopharmacol­ ogy. N. S. Kline and H. E. Lehmann (eds.). Boston: Little, Brown, l965a, pp. 717-751. ---. Problems of differential diag­ nosis and choice of therapy in depressive states. Psychosomatics 6:266-272, 1965b. ---. Clinical perspectives on anti­ depressant therapy. Am. J. Psychiat. 124 (Suppl.): 12-21, 1968. LINGL, F. A. Irreversible effects of glutethimide addiction. Am. J. Psychiat. 123: 349-351, 1966. Methadone Maintenance Evaluation Committee. Progress report of eval­ uation of methadone maintenance treatment program as of March 31, 1968. JAMA 206 :2712-2714, 1968. OSSENFORT, w. F . Drug addictions. Dallas M ed. J. 43:229-232, 1957. PETERS, U. H . Kombination von Nolu­ dar und Alkohol. Sucht und ein­ malige Vergiftungen. Med. Klin. (Munich) 61: 1455-1458, 1966. Research in psychopharmacology. Re­ port of a WHO scientific group. World Health Organ. Tech. Rep. Ser. 371:1-39, 1967. SHELTON, J. AND L. E. HOLLISTER. Simulated abuse of tybamate in man. Failure to demonstrate with­ drawal reactions. JAMA 199:338- 340, 1967.

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