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The Newer Analeptic Drugs
The Newer Analeptic Drugs HOWARD D. FABING, M.D.*
DRUGS which stimulate the central nervous system have interested the pharmacologist and clinician alike throughout the period of modern therapeutics in medicine. Agents which have this property are known as analeptics, a term of difficult derivation from the Greek, which may be translated loosely as "compounds which lift up those who have been cast down." Perhaps the oldest of these compounds in general use are those of the strychnine family.! Nux vomica was widely used in former times for the relief of chronic lassitude, excessive sense of fatigue and that stubborn syndrome which has been so vividly labeled as neurasthenia. Another compound in wide use for the same indications was caffeine, but its effects were less reliable. A group of compounds which exhibited a central stimulating action plus sympathomimetic effects came under study in 1940. 2 These phenylisopropylamines include especially amphetamine and d-desoxyephedrine. The addition of this amphetamine group of compounds enlarged the spectrum of the oral analeptics greatly, and these drugs continue to enjoy wide use at the present time. They not only stimulate the central nervous system, increasing the sense of alertness and elevating mood, but they also act on peripheral adrenergic (sympathetic) receptors. Both the central and peripheral effects vary widely from patient to patient, so that dosage is variable as are their side effects. Anorexia, insomnia, a sense of inward "jitteriness," muscular tension or increase in peripheral blood pressure and heart rate may be of such magnitude that both patient and physician may become discouraged from continuing their use in some cases. This can be circumvented in part on occasion when central stimulant action is needed by adding small doses of barbiturates to the amphetamine compound. In addition to this sympathomimetic group of stimulants, other rapidly and dramatically acting compounds, designed especially for parenteral use, have been added to the analeptics in recent times. These are picrotoxin, cardiazol (Metrazol) and nikethamide (Coramine). They are indicated where massive central stimulation is needed quickly to counteract states of profound neural depression, such as deep barbiturate narcosis. * Chairman of Neurology, Christ Hospital, Cincinnati, Ohio.
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H o1Dard D. F abing
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The Piperidyl Group Sinee 195;-~ t\VO separate groups of investigators have found that eonlpounds containing a piperidine nueleus Inay also have analeptie qualities without concomitant peripheral sYlnpathomimetic side effects. l-'he piperidine nucleus is a six-sided ring having one nitrogen atom and five carbon atoms vvithin its confines: /N~ C c I I
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The tvvo cOlnpounds containing thisnueleus which have undergone clinical study recently are alpha (2-piperidyl) benzhydrol hydrochloride (Meratran)* and phenyl-piperidyl-2-aeetic acid rnethylester (ltitalin).t
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* Meratran is the trade name of the WIn. S. Merrell Company for pipradrol, or
al pha-(2-piperidyl) benzhydrol hydrochloride.
t Ritalin is the trade name of Ciba Pharmaceutical Products, Inc., for phenidylate. or phenyl-piperidyl-2-acetic acid methylester.
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apparently important in producing analeptic action. In the case of Mcratran, for instance, if the nitrogen atom is placed else\vhere in the ring, such as the 4-positioll, azocyclonol, or Frenquel,3 results. 1'he latter compound has quite different pharmacologic propcrties,4 and belongs in the ataractic 5 or tranquilizing group of drugs rather than among the analeptics clinically. MERATRAN
Pharlllacology
The pharmacology of this conlpound was studied by Brown and Werner. 6 Milligram for milligram it is less toxic than dl-amphetamine sulfate orally and subcutaneously in the rat, and of similar toxicity intravenously. Convulsions do not occur until the LD[)o dose is reached and then only \vhen given parenterally. Doses which are quite small in relation to the I--ID. o dose induce prolonged periods of purposeful hyperaetivity in the rat and in the dog. As the dose is increased hyperactivity increases until forced circling nlovements may occur. Dogs remain friendly and eat avidly during these periods of drug-induced overactivity. One-half to one J.JD 50 dose of the drug intravenously rouses rabbits from light barbiturate narcosis, but it is ineffective as an antidote against lethal barbiturate depression. Doses of the conlpound whieh cause motor hyperactivity in the experiluental aninlal have little or no effect on blood pressure, pulse rate or respiratory rate. 1'hese findings indicate that Meratran has central stimulating action without overt convulsant qualities in the experimental animal and that there i,s a \vide margin of safety between the CNS stimulating dose and the lethal dose. In addition, the increased activity of the experimental animals appeared well organized and is not associated with irritability and hostility, since they can be handled and petted and fed throughout the experilnental period. 'rhe absence of sympathomimetic effects indicate that it is a member of a ne\v group of analeptic drugs. Clinical Indications
Meratran has been used therapeutically ill narcolepsy, selected motor tics, mild reactive depressions, the apathy of the senium, the lassitude \vhich may be associated vvith chronic disease, in occasional alcoholics, in enuresis and in hyperkinetic syndron1es in children, and in druginduced sedation. In narcolepsy7 the dose of Meratran lnust be quite high to obtain effects comparable with those of amphetanline. '1'his poorly understood condition appears to defy all dosage schedules for analeptic drugs, since the need for drugs of the arnphetalnine series is also enorlnous on occasion if clinical results are to be obtained. In our experienee the dose must be \vorked out by trial and error. One rniddle-agcd wonlan has reeeived consistent benefit on 5 Illg. Meratran, t.i.d., for more than three years,
H oward D. Fabing but at the other end of the dosage scale another woman requires the unbelievable quantity of 100 mg. daily in divided doses, and even supplements this at times with amphetamine. The narcoleptic sleep attacks and the cataleptic trance states respond best to the drug, whereas the cataplectic attacks of sudden loss of muscular tone with collapse and fall to the floor often continue, but usually with less frequency. Sometimes the cataplectic attacks may be reduced in severity with the drug; instead of the patient falling in a heap, the attack may be limited to the head falling to the chest. This stubborn resistance of the cataplectic feature of the narcolepsy syndrome is common to all therapies for the disorder. It is worth the clinician's effort to attempt to administer Meratran in the treatment of some of the motor tics. 7, 8 Again, the dose required is usually relatively high, and patients fail to get benefit if they cannot tolerate large doses of the drug without side effects. Bilateral eye blinking, or blepharospasm, will often be relieved by 10 to 20 mg. daily in divided doses. Talley 9 has reported favorably on a number of these cases and finds that when he switches the patient to a placebo surreptitiously, the blepharospasm returns fully within the next day. In our experience unilateral facial tics involving the muscles innervated by the seventh nerve do not respond to the drug. Meratran therapy may also be attempted in spasmodic torticollis. To be of any degree of help, the effective dosage range must be from 20 to 40 mg. daily in divided doses. We have not seen any cases of complete relief of torticollis with this drug but have seen partial amelioration on occasion, especially if the patient can tolerate high doses of the drug. If the wryneck is fixed rather than spasmodic, the drug is of no benefit. The greatest area of usefulness of Meratran is in mild to moderately severe mood disorders of the reactive depressive type. 10 Situations of emotional stress which produce tearfulness, psychomotor retardation, anorexia, attention defect, loss of interest in one's ordinary pursuits and withdrawal from social intercourse may often be helped by small doses of the drug, along with support therapy by the physician. Among the most common are prolonged bereavements, ill-starred love affairs, domestic and vocational stresses and business reverses. In such cases it is well to begin with 1 mg. of the drug t.i.d., and to advance the dose to as much as 2.5 mg. t.i.d. if necessary. The final dose should be given at the time of the evening meal, and if any disturbance of sleep results, the final dose should be lessened or omitted. It should be borne in mind that these reactive depressions are often associated with anxiety. If the anxiety element is large, and the depressive element small, the drug will not be of value. In such cases it may relieve the depressive element of the patient's illness, but its tendency to increase the anxiety features may be such that all the beneficial effects may be cancelled out by the unpleasantness of the side reactions. The only guide to the selection of patients in this category is the skill and artfulness of the clinician. When
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he is able to assess the depressive and anxiety features accurately, and ,vhen he confines the use of Meratran to those cases in which the depressive element is the major one, the drug is beneficial when the dose is properly regulated. It is more difficult to use Meratran successfully in true melancholia, or depressive reactions of psychotic proportions. I-Iere the doses required are higher, extending from 10 to 15 and perhaps more milligrams daily in divided doses. If the psychotic depression is of the agitated type, the drug is contraindicated because agitation becomes worse with it. In selected cases of simple severe depression with marked psychomotor retardation the drug has been helpful. It is our clinical impression that it not only ameliorates the depressive symptoms but apparently shortens the attack as well. For the majority of psychotic depressions, however, no analeptic drug appears to be able to supplant electroconvulsive therapy at this time. Andrenll has reported that the combination of Meratran plus electroshock therapy (EST) may be worthy of trial in psychotic depressions. One-half hour before EST he injects 1 mg. Meratran intramuscularly, and on alternate days ,vhen electrical treatment is not given, he continues the same regimen of Meratran intramuscularly. He finds the results better than might be expected from EST alone, a lessening of confusion and amnesia attendant upon EST, and a more rapid elevating of mood and dissolution of suicidal urges. Schut and Himwich 12 found Meratran of value in improving the behavior and hygiene of a group of chronic psychotic patients in a state hospital. A useful place for Meratran has been in the treatment of old folks. I3 As senescence steals upon many people they lose their lust for living, and activities which were pleasurable in earlier days often become a bore and a burden. With this comes an attitude of pessimism, concern over security, fretfulness, insomnia, anorexia and morbid preoccupation with the thought of death-the clinical picture of the unhappy and poorly adapted geriatric patient whose life is difficult for both himself and those around him. l'his state often occurs at the time of retirement from active work, as Pomeranze I4 has noted. In these cases Meratran has often proved of value. The dosage is often as little as 1 mg. each morning, or 1 mg. morning and midafternoon, or 1 mg. t.i.d. Kleemeier et. al. 15 made a controlled study of the effect of 2 mg. daily on a group of men varying in age from 66 to 85 years in a brotherhood home, using a double-blind technique of Meratran and placebo, and noted significant results with the drug. In fatigue states which follow organic disease, small doses of Meratran have been advocated for "tonic" purposes. AntosI 6 finds small doses, usually 1 to 3 mg. daily, occasionally going to 6 mg. in divided doses, of value following hepatitis, anemia, cholecystitis, allergic diseases and the like. Hypertensives who experience fatigue may also benefit from small
doses of the drug, as do vvomen with lnild 111enopausal reactions and dysmenorrhea. 17 Convalescents and postoperative patients lnay also be given the drug. Diabetics vvho fatigue easily may have Meratran added to their therapeutic regimen in slnall doses without disturbing sugar chemistry. 'I'he drug has also been advocated in alcoholic problems 18 and in the relief of fatigue brought on by loss of sleep. An example of the last therapeutic indication lnay be taken from personal experience. Some t\VO years ago I found myself in a situation which required me to live on four to five hours sleep for three consecutive days. By noon of the fourth day I was cornpletely \veary, and as I looked at the list of patients I was to see that afternoon I felt that I could not possibly get through the day. I took 2 mg. Meratran and ,vent to work in my office. About 4 P.M. I became aware of the fact that I was not exhilarated, but that I had been moving through my afternoon's work \vith my usual amount of alertness and attention to my tasks. 'rhere was nothing dramatic about it. I had merely been able to receive enough stimulation to carry on normally despite my fatigue. It was only then that I remembered that I had ingested the drug. Ilepeated use of Meratran for such purpose is not advocated. Drug-induced lethargy and drowsiness may be overcome with Meratran. Epileptics who are controlled by anticonvulsant drugs may have such lassitude that they report the cure to be worse than the disease, and sonle of thenl abandon medication on this account. Meratran in divided doses of 2 to 6 mg. daily will often get around this difficulty. Antihistamines, analgesics, antispasmodics, insulin and sedatives can also be the cause of lethargy and apathy. The newer tranquilizing or ataractic drugs, chlorpromazime and reserpine, also have this as perhaps their most common side-reaction. 'l'he use of Meratran in small doses has been advocated in these instances as "reIl. Meratran appears to have some usefulness in controlling lnild cases of uncomplicated enuresis in children. By giving them 1 mg. or perhaps 2 mg. of the drug in the early evening hours, sleep is not so deep, and they are awakened by a full bladder and are able to get to the toilet and empty it. H yperlcinetic syndromes 19 in retarded and brain-injured children SOlnetimes are relieved by doses of the drug ranging from 2 to 10 rng. daily, in the same fashion that drugs of the amphetamine group seem to be efficacious in these syndromes. Recent personal experience, however, indicates that chlorpromazine and reserpine, which undoubtedly operate in a different fashion pharmacologically, are better therapeutic agents in such pediatric problems. Side Reactions
Meratran has no effect on appetite, and there appears to be no need for advising its use at any specific time in relation to meals; convenience may dictate in this matter. No blood dyscrasias have been reported
The Newer Analeptic Drugs with its use, nor have kidney or liver damage been seen. Reports on skin rash have been rare and questionable, and those which have occurred have been fleeting. On rare occasions a sense of itching has been reported in the face or on the forearms with its use. No appreciable cardiovascular pressor effects have been noted. The major side reaction of Meratran is the development of the sOlllatic (and psychic) accompaniments of anxiety, and this is an all-important consideration in the use of the drug. SOlne patients do not tolerate it at all without developing these unpleasant responses, whereas others, may take as much as 100 mg. daily vvithout any subjective experience of this kind. '-fhis profound variation in tolerance is one of the riddles of all analeptic drugs. There is no explanation why one human being can take massive doses of these compounds whereas others can tolerate them only in small doses, if at all. l'hese responses may be listed as motor restlessness, apprehension, a tense feeling in somatic muscles, overt tremor of the hands and lips, palpitation, "butterflies" in the abdomen and urinary frequency. With this comes a sense of foreboding and panicky anxiety. Withdra,val of the drug will bring these symptollls to an end vvithin a 111atter of hours, and if they are severe, a single dose of barbiturate medication ,vill reduce their severity. '"foxic Effects
We have seen one case of psychosis of paranoid type develop in a middle-aged ,voman with torticollis when her dose was pushed up to 35 mg. daily. She developed the idea that a man in her apartment house was attempting to rape her and she called the police. This psychosis disappeared in two days with the help of barbiturate sedation. A few other investigators20 have reported the development of similar psychotic episodes. This appears to be a rare danger inherent in the use of the drug, and calls for careful observation while the dosage is being advanced. Two cases of massive overdose of the drug have been reported, OTIe in an adult and one in a child. Marked hyperkinesis, perseverative stereotyped movements, profound agitation and some degree of insomnia resulted. Paren~eral use of Sodiul11 Amytal controlled the symptoms in each instance within 36 hours. Evaluation of Results
Meratran appears to have therapeutic indication as a central stimulating or analeptic drug. Its tendency to produce anxiety symptoms is the limiting factor in its usefulness. Dosage is variable from one person to another, and this can be worked out only by the trial and error method. Failures probably result as often ,vith underdosage as they do with overdosage. Its usefulness is greatest in states of mild to moderate depression, whether they be psychogenic or organic or drug-induced, and it may be attempted in selected neurological syndromes.
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H oward D. F abing RITALIN
In a comparative study of a great number of different piperidine compounds of the phenyl-piperidyl-acetic acid group, Meier et a1. 21 found in 1954 that the central stimulating action of Ritalin (phenylpiperidyl-[2]-acetic acid methylester) was particularly strong. Pharmacologic and clinical studies have determined that this compound, quite similar to Meratran in its action, is another analeptic of the piperidine family which has usefulness in therapeutics. Pharmacology
Meier et al. noted an increase in coordinated motility in experimental animals when the drug was given orally or parenterally. They exhibited an urge to move about and run, and an urge to eat and gnaw without becoming snappish or aggressive. These effects lasted for several hours on doses of 0.5 to 1.5 mg./kg. in various species. Larger doses produced ataxia and convulsions. Spring cage and revolving drum movement studies demonstrated that motor activity increased fourfold in rats and mice. On large doses dogs ran excitedly and developed circling movements. The drug showed an antagonism to barbiturates, chloral hydrate and urethane, and failed to produce sympathomimetic effects. Toxicity studies in the rat showed that there was a great margin of safety between the effective and lethal dose. The LD 50 was 367 mg/kg., whereas the dose producing pharamcologic response lay within the 1 to 5 mg.jkg. range. Clinical Indications
In the human Ritalin is a mild stimulant indicated in chronic fatigue and depressed states including those associated with reserpine and chlorpromazine therapy. It is also helpful in narcolepsy and in psychoses and psychoneuroses of depressive type. The indications, therefore, parallel those of Meratran. Published reports on this drug are few in number at this time, but quite a number are in press22 and should be available for study within the next year. Most investigators have studied its effectiveness in combating the drowsiness and depression which may accompany reserpine and chlorpromazine therapy. They are in agreement that the compound is of definite value in this regard. Ferguson23 has reported on Ritalin's effect in overcoming the depression and drowsiness induced in chronic psychiatric patients in a state hospital. In his pilot group ten chronic catatonic patients receiving only 10 mg. daily seemed brighter and more cooperative. A second group of 68 chronic apathetic patients underwent a more careful trial with the drug in larger doses. They ranged in age from 24 to 71 years and had a hospital stay varying from three to 52 years. Dosages were individualized in response to therapeutic demand) and ranged from 10 to 40 mg. t.i.d.,
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given at 8:00 A.M., 12:00 noon, and 4:00 P.M. A Behavior Profile Chart was kept on each patient before Ritalin therapy was instituted and was continued throughout the study. A decrease in need for helpful supervision, improvement in personal habits and hygiene, and a drift of speech, attention and alertness toward the normal were noted. With an improvement in animation came an increased interest in food, and the group averaged an 8-pound weight gain during the study period. An increase in cooperativeness in ward routine and rehabilitation programs was noted as well. The majority of these severely regressed psychotic patients required 30 to 40 mg. Ritalin t.i.d., and Ferguson noted improvement in 87% of the group. A third group of 25 patients who had reserpine drowsiness and depression were then given Ritalin. The dose was individualized, varying from 10 to 40 mg. Ritalin t.i.d. regardless of the amount of reserpine being given, with the lower dose proving the most efficacious in the majority of patients. Ferguson states that the action of Ritalin does not counteract or oppose the effect of reserpine, but the combination causes a slow awakening to reality and an increase in motor activity toward normal, with improved cooperativeness, appearance and socialization. Twenty-two of the 25 patients were benefited by the combination therapy and some were discharged. A relieving of reserpine-induced nasal stuffiness was noted as well. Ferguson24 has continued this combination therapy since his first report, and finds that his results remain good. Best results have been seen in hebephrenic and catatonic types of schizophrenia, with the paranoid variety showing the least change. The senile group has shown clearing of confusion with consequent improvement. The ward atmosphere has improved and the rehabilitation program has undergone great expansion. Carter,25 Madi and Kovitz 26 and others have also found Ritalin to be helpful in combating reserpine-induced depres~}on and lethargy, and Ayd21 found it of value in both reserpine and chlorpromazine oversedation. Plummer et a1. 28 found Ritalin capable of overcoming the depressive effects of reserpine without influencing the hypotensive mechanism of the drug. In these reports the dose generally prescribed has been 10 mg. t.i.d. Fazekas29 finds Ritalin of value in overcoming chlorpromazine oversedation effects when given intravenously. Ferguson30 has used Ritalin parenterally in 204 patients in doses from 5 to 20 mg. to counteract reserpine, chlorpromazine or barbiturate overdosage. No untoward effects have been noted. Response to intravenous injection occurs in one to five minutes, to intramuscular injection in five to 30 minutes. N atensohn31 has used Ritalin in general practice in the chronically ill and incurables including terminal carcinoma patients, in the convales... cent group after surgical operation or illness, in psychogenic mild depressive states, and in drug depression. In general he has found that these
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H oward ]J. F abing
groups get a favorable response with 10 to 20 lng. tvvicc or three tirncs daily, that an elevation in vigor and mood results without euphoria, that appetite is not affected, that no cardiovascular pressor reactions occur, and that no deleterious effects on hemopoietic organs, liver or kidneys have been noted. Side Reactions
These have been minimal, and appear to be similar to those of MeratraIl. They have been confined to overstimulation, vvith the production of jitteriness and the somatopsychic accompaniments of anxiety, vvhich dissipate quickly \vhcn the drug is withdrawn. One case of habituation is reported in a patient formerly habituated to barbiturates, but the drug ,vas withdrawn vvithout consequence. Evaluation of Results
Ritalin appears to be of special usefulness in counteracting the depressant and sedative effects of reserpine, chlorpromazine and promazine. The large number of investigations on this aspect of the drug's indication give promise that the effectiveness of these hypotensive and ataractic agents can be enlarged if Ritalin is given in combination with them. It is also a general-purpose analeptic, according to report, which can be used to counteract states of fatigue and depression psychogenically induced as well as those which follow organic disease. In endogenous depression of psychotic proportions it is of possible value, but one must be prepared to abandon it for electrotherapy if results are not forthcoming. In agitated melancholia it is contraindicated and in psychoneurotic depressions anxiety reactions may arise to vitiate the moodelevating effect of the drug. COMPARISON OF MERATRAN AND RITALIN, AND COMPARISON OF THESE AGENTS WITH OTHER ANALEPTICS
SO far as I am aware, no pharmacologic studies have been carried out in experimental animals to determine the relative central nervous system stimulating action of Meratran and Ilitalin. If I may be permitted a guess from clinical observation, I should say that the effectiveness of the t,vo drugs as eNS stimulants in man, milligram for milligram, is as one of Meratran to five of Ritalin. No study has been carried out in a controlled series of patients to determine the relative therapeutic effectiveness of one or the other of these drugs. This would be hard to accomplish because of a number of variable factors, including the changing nature of depressive states, the difficulty of maintaining completely objective attitudes in clinical observers, try as they might, and the consideration of obtaining a reasonable objectivity in patients under such experimental conditions even if a blind technique were employed. For the present we shall have to be content with the information that
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t\VO nc\v piperidine-containing analeptics are now available, that their dosage range is variable, and that the indieations for their use are sinlilar. l-'herapeutic trial of one or the other or both nlay be made to determine their therapeutic value in a specific patient. Both of these drugs have advantages over the amphetamine group of analeptics in that they do not decrease appetite nor cause cardiovascular pressor reactions because of sympathomilnetic effects. On the other hand, they are relatively mild mood-elevators, and drugs of the amphetalnine series may turn out to have greater usefulness in this therapeutic sphere in a given patient, with or without the addition of small doses of barbiturates, than either one of the newer analeptics discussed in this presentation may be able to offer. This is a difficult area of therapeutics, in which one must be guided mostly by the subjective reports of the patient without the help of laboratory methods. It calls for an attitude of prudent adventurousness on the part of the clinician, with a \villingness to abandon any and all of these agents if they fail to produce tangible results or if they cause troublesome side reactions. SUMMARY
Within the past few years two new analeptic cOlnpounds of piperidine structure have crossed the horizon as therapeutic agents. They are not sympathomimetic agents and thus do not cause cardiovascular pressor reactions nor appetite loss, nor do they interfere with nocturnal sleep as much as do the drugs of amphetamine type. They are indicated in mild fatigue and depressive states arising in psychoneuroses and in the course of organic illness or drug-induced states of oversedation and neural depression. '-rheir dosage is variable from patient to patient, and clinical artistry is necessary to determine the quantity and the timing of these medications. They do not fill the bill as agents in the treatment of severe psychotic depression. They are relatively free of toxic effects and do not compromise the function of any of the major organ systems of the body. Their usefulness is lin1ited by the subjective symptoms of anxiety and tension \vhich they are capable of inducing in the patient under treatluent. They constitute a tangible increase in the therapeutic armamentarium of the clinician in search of drugs to produce improved emotional tone and a lessened sense of fatigue in many varieties of patients. REFERENCES 1. Goodman, L. and Gilman, A.: The Pharmacological Basis of Therapeutics. New York, Macmillan Co., 1941, p. 256, et seq., inter alia. 2. Hauschild, F.: Zur Pharmakologie del' Phenylalkylalnine. Arch. Expel'. Path. u. Phannakol. 191: 465, 1939. Zur Pharmakologie des 1-Phenyl-2-methylaminopropans (Pervitin). Arch. ~~xper. Path. u. Pharmakol. 195: 647, 1940. 3. Brown, B. B., Feldman, R. and Braun, D. L.: Pharmacologic Studies of an LSD Antagonist, 4-Piperidyl Diphenyl Carbinol. Fed. Proc. 14: 322, 1955.
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4. Fabing, H. D.: New Blocking Agent Against the Development of LSD-25 Psychosis. Science 121: 208, 1955. Rinaldi, F. and Himwich, H. E.: Frenquel Corrects Certain Cerebral Electographic Changes. Science 122: 198, 1955. Allin, T. G. and Pogge, R. C.: The Use of Azocyc1onol and Pipradrol in General Practice. Internat. Rec. Med. 169: 222, 1956. 5. Fabing, H. D.: Designation of "Tranquilizing Agents" in Neuropharmacology. J.A.M.A. 158: 1461 and Am. J. Psychiat. 112: 392, 1955. 6. Brown, B. B. and Werner, H. W.: Pharmacologic Studies on Alpha-(2-piperidyl) Benzhydrol Hydrochloride, a New Type of Central Stimulant. Fed. Proc. 12: 304, 1953. Brown, B. B. and Werner, H. W.: Pharmacologic Studies on a New Cerebral Stimulant, Alpha-(2-piperidyl) Benzhydrol Hydrochloride (MRD-I08). J. Pharmacol. & Exper. Therap. 110: 180, 1954. 7. Fabing, H. D.: Alpha-(2-piperidyl) Benzhydrol Hydrochloride, a New Central Stimulant, in the Treatment of Blepharospasm, Spasmodic Torticollis and Narcolepsy, Preliminary Report. Trs. Am. Neurol. A. 79: 159, 1954. 8. Klingman, W. 0.: Use of Meratran in Certain Neurological Disorders. Presented before the Am. Col. Surg., Regional Meeting, Feb. 24, 1955. 9. Talley, J. E.: Meratran, a New Central Stimulant: Report on the Results of Clinical Investigation. Psychiat. Research Reports, No. 1, Am. Psychiat. A. Galveston, Texas Meeting, 1955, p. 133. 10. Fabing, H. D.: Clinical Experience with Meratran. Dis. Nerv. Syst. 16: 10,1955. Fabing, H. D., Hawkins, J. R. and Moulton, J.: Clinical Studies on Alpha.. (2-piperidyl) Benzhydrol Hydrochloride, aNew Antidepressant Drug. Am. J. Psychiat. 111: 832, 1955. Autos, R. J.: Preliminary Report of Clinical Studies on aNew Stimulant. Arizona Med. 11: 397, 1954. Begg, W. G. A. and Reid, A. A.: "Meratran," a New Stimulant Drug. Brit. M. J. 1: 946 (April), 1956. Levy, S.: Mild depressive states, Northwest Med. 53:1233, 1954. 11. Andren, H. E.: Treatment of Depression with Meratran and Electroshock. Dis. Nerv. Syst. 15: 275, 1955. 12. Schut, J. W. and Himwich, H. E.: The Effect of Meratran on 25 Institutionalized Mental Patients. Am. J. Psychiat. 111: 837, 1955. 13. Forster, W., Henderson, L. and Schultz, S.: The Clinical Effects of Alpha(2-piperidyl) Benzhydrol Hydrochloride (Meratran) in States of Inactivity in Elderly Psychiatric Patients. Canada M.A.J. 72: 678, 1955. Levy, S.: Drug Therapy in the Emotionally Disturbed Ages. Northwest Med. 55: 298, 1956. 14. Pomeranze, J.: A New Antidepressant. J. Gerontol. 9: 486, 1954. 15. Kleemeier, R. W., Rich, T. A. and Justiss, W. A.: The Effects of Alpha-(2piperidyl) Benzhydrol Hydrochloride (Meratran) on Psychomotor Performance in a Group of Aged Males. J. Gerontol. 11: 165, 1956. 16. Antos, R. J.: Use of an Antidepressant in General Practice. Medical Times 83: 612, 1955. Meratran: Use of a New Antidepressait in Internal Medicine. Southwestern Med. 36: 166, 1955. 17. Kistner, R. W. and Duncan, C. J.: Use of Pipradrol in Obstetrics and Gynecology. New England J. Med. 254: 507, 1956. 18. Proctor, R. C.: ANew Therapeutic Approach to Certain Cases of Alcoholism. Southern M. J. 49: 73, 1956. 19. Oettinger, L.: Meratran: Preliminary Report of aNew Drug for the Treatment of Behavior disorders in Children. Dis. Nerv. Syst. 16: 299, 1955. 20. Sargant, W., London, England and Heath, R., New Orleans, La., personal communications. 21. Meier, R., Gross, R. and Tripod, J.: Ritalin, eine neuartige synthetische Verbindung mit specifischer zentralerregender Wirkungskomponente. Klin. Wchnschr. 32: 445, 1954. 22. "Ritalin" brochure, Ciba Pharmaceutical Products, Summit, N. J., 1956.
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23. Ferguson, J. T.: Treatment of Reserpine-Induced Depression with a New Analeptic: Phenylidate. Ann. New York Acad. Se. 61: 101,1955. 24. Ferguson, J. T.: Improved Behavior Patterns in the Hospitalized Mentally III with Reserpine and Methyl Phenidyl Acetate. Psychiat. Research Reports No. 4, Am. Psychiat. A., Galesburg, Ill. Meeting, April, 1956, 35 pp. 25. Carter, C. H.: Effects of Reserpine and Methyl Phenidyl Acetate (Ritalin) in Mental Defectives, Spastics and Epileptics. Psychiat. Research Reports No. 4, Am. Psychiat. A., Galesburg, Ill. Meeting, April, 1956, p. 44. 26. Madi, M. L. and Kovitz, M. D.: Experience with Ritalin in Psychotic Patients. Unpublished manuscript. 27. Ayd, F. J.: A Clinical Evaluation of Ritalin. J. Clin. & Exper. PsychopathoI. To be published. 28. Plummer, A. J., Maxwell, R. A., Earl, A. E. and Rutledge, R.: Influence of Methyl-alpha-phenyl-2-piperidine-acetate Hydrochloride on the Pharmacological Actions of Reserpine. Fed. Proc. 15: 468, 1956. 29. Fazekas, J. F.: Unpublished data. 30. Fergusofi, J. T.: Unpublished data. 31. N atensohn, A. L.: Clinical Evaluation of Ritalin, aNew Psychomotor Stimulant. Submitted for publication. 2314 Auburn Avenue Cincinnati 19, Ohio
DRUGS which stimulate the central nervous system have interested the pharmacologist and clinician alike throughout the period of modern therapeutics in medicine. Agents which have this property are known as analeptics, a term of difficult derivation from the Greek, which may be translated loosely as "compounds which lift up those who have been cast down." Perhaps the oldest of these compounds in general use are those of the strychnine family.! Nux vomica was widely used in former times for the relief of chronic lassitude, excessive sense of fatigue and that stubborn syndrome which has been so vividly labeled as neurasthenia. Another compound in wide use for the same indications was caffeine, but its effects were less reliable. A group of compounds which exhibited a central stimulating action plus sympathomimetic effects came under study in 1940. 2 These phenylisopropylamines include especially amphetamine and d-desoxyephedrine. The addition of this amphetamine group of compounds enlarged the spectrum of the oral analeptics greatly, and these drugs continue to enjoy wide use at the present time. They not only stimulate the central nervous system, increasing the sense of alertness and elevating mood, but they also act on peripheral adrenergic (sympathetic) receptors. Both the central and peripheral effects vary widely from patient to patient, so that dosage is variable as are their side effects. Anorexia, insomnia, a sense of inward "jitteriness," muscular tension or increase in peripheral blood pressure and heart rate may be of such magnitude that both patient and physician may become discouraged from continuing their use in some cases. This can be circumvented in part on occasion when central stimulant action is needed by adding small doses of barbiturates to the amphetamine compound. In addition to this sympathomimetic group of stimulants, other rapidly and dramatically acting compounds, designed especially for parenteral use, have been added to the analeptics in recent times. These are picrotoxin, cardiazol (Metrazol) and nikethamide (Coramine). They are indicated where massive central stimulation is needed quickly to counteract states of profound neural depression, such as deep barbiturate narcosis. * Chairman of Neurology, Christ Hospital, Cincinnati, Ohio.
339
H o1Dard D. F abing
340
The Piperidyl Group Sinee 195;-~ t\VO separate groups of investigators have found that eonlpounds containing a piperidine nueleus Inay also have analeptie qualities without concomitant peripheral sYlnpathomimetic side effects. l-'he piperidine nucleus is a six-sided ring having one nitrogen atom and five carbon atoms vvithin its confines: /N~ C c I I
c
c
~C/
Piperidine nucTcu's
The tvvo cOlnpounds containing thisnueleus which have undergone clinical study recently are alpha (2-piperidyl) benzhydrol hydrochloride (Meratran)* and phenyl-piperidyl-2-aeetic acid rnethylester (ltitalin).t
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In both these compounds the piperidyl ring is seen on the left, \vith its 2-position nitrogen atolll. l-'his position of the nitrogen atolll is
* Meratran is the trade name of the WIn. S. Merrell Company for pipradrol, or
al pha-(2-piperidyl) benzhydrol hydrochloride.
t Ritalin is the trade name of Ciba Pharmaceutical Products, Inc., for phenidylate. or phenyl-piperidyl-2-acetic acid methylester.
The N eu'er Analeptic Drugs
341
apparently important in producing analeptic action. In the case of Mcratran, for instance, if the nitrogen atom is placed else\vhere in the ring, such as the 4-positioll, azocyclonol, or Frenquel,3 results. 1'he latter compound has quite different pharmacologic propcrties,4 and belongs in the ataractic 5 or tranquilizing group of drugs rather than among the analeptics clinically. MERATRAN
Pharlllacology
The pharmacology of this conlpound was studied by Brown and Werner. 6 Milligram for milligram it is less toxic than dl-amphetamine sulfate orally and subcutaneously in the rat, and of similar toxicity intravenously. Convulsions do not occur until the LD[)o dose is reached and then only \vhen given parenterally. Doses which are quite small in relation to the I--ID. o dose induce prolonged periods of purposeful hyperaetivity in the rat and in the dog. As the dose is increased hyperactivity increases until forced circling nlovements may occur. Dogs remain friendly and eat avidly during these periods of drug-induced overactivity. One-half to one J.JD 50 dose of the drug intravenously rouses rabbits from light barbiturate narcosis, but it is ineffective as an antidote against lethal barbiturate depression. Doses of the conlpound whieh cause motor hyperactivity in the experiluental aninlal have little or no effect on blood pressure, pulse rate or respiratory rate. 1'hese findings indicate that Meratran has central stimulating action without overt convulsant qualities in the experimental animal and that there i,s a \vide margin of safety between the CNS stimulating dose and the lethal dose. In addition, the increased activity of the experimental animals appeared well organized and is not associated with irritability and hostility, since they can be handled and petted and fed throughout the experilnental period. 'rhe absence of sympathomimetic effects indicate that it is a member of a ne\v group of analeptic drugs. Clinical Indications
Meratran has been used therapeutically ill narcolepsy, selected motor tics, mild reactive depressions, the apathy of the senium, the lassitude \vhich may be associated vvith chronic disease, in occasional alcoholics, in enuresis and in hyperkinetic syndron1es in children, and in druginduced sedation. In narcolepsy7 the dose of Meratran lnust be quite high to obtain effects comparable with those of amphetanline. '1'his poorly understood condition appears to defy all dosage schedules for analeptic drugs, since the need for drugs of the arnphetalnine series is also enorlnous on occasion if clinical results are to be obtained. In our experienee the dose must be \vorked out by trial and error. One rniddle-agcd wonlan has reeeived consistent benefit on 5 Illg. Meratran, t.i.d., for more than three years,
H oward D. Fabing but at the other end of the dosage scale another woman requires the unbelievable quantity of 100 mg. daily in divided doses, and even supplements this at times with amphetamine. The narcoleptic sleep attacks and the cataleptic trance states respond best to the drug, whereas the cataplectic attacks of sudden loss of muscular tone with collapse and fall to the floor often continue, but usually with less frequency. Sometimes the cataplectic attacks may be reduced in severity with the drug; instead of the patient falling in a heap, the attack may be limited to the head falling to the chest. This stubborn resistance of the cataplectic feature of the narcolepsy syndrome is common to all therapies for the disorder. It is worth the clinician's effort to attempt to administer Meratran in the treatment of some of the motor tics. 7, 8 Again, the dose required is usually relatively high, and patients fail to get benefit if they cannot tolerate large doses of the drug without side effects. Bilateral eye blinking, or blepharospasm, will often be relieved by 10 to 20 mg. daily in divided doses. Talley 9 has reported favorably on a number of these cases and finds that when he switches the patient to a placebo surreptitiously, the blepharospasm returns fully within the next day. In our experience unilateral facial tics involving the muscles innervated by the seventh nerve do not respond to the drug. Meratran therapy may also be attempted in spasmodic torticollis. To be of any degree of help, the effective dosage range must be from 20 to 40 mg. daily in divided doses. We have not seen any cases of complete relief of torticollis with this drug but have seen partial amelioration on occasion, especially if the patient can tolerate high doses of the drug. If the wryneck is fixed rather than spasmodic, the drug is of no benefit. The greatest area of usefulness of Meratran is in mild to moderately severe mood disorders of the reactive depressive type. 10 Situations of emotional stress which produce tearfulness, psychomotor retardation, anorexia, attention defect, loss of interest in one's ordinary pursuits and withdrawal from social intercourse may often be helped by small doses of the drug, along with support therapy by the physician. Among the most common are prolonged bereavements, ill-starred love affairs, domestic and vocational stresses and business reverses. In such cases it is well to begin with 1 mg. of the drug t.i.d., and to advance the dose to as much as 2.5 mg. t.i.d. if necessary. The final dose should be given at the time of the evening meal, and if any disturbance of sleep results, the final dose should be lessened or omitted. It should be borne in mind that these reactive depressions are often associated with anxiety. If the anxiety element is large, and the depressive element small, the drug will not be of value. In such cases it may relieve the depressive element of the patient's illness, but its tendency to increase the anxiety features may be such that all the beneficial effects may be cancelled out by the unpleasantness of the side reactions. The only guide to the selection of patients in this category is the skill and artfulness of the clinician. When
The Newer Analeptic Drugs
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he is able to assess the depressive and anxiety features accurately, and ,vhen he confines the use of Meratran to those cases in which the depressive element is the major one, the drug is beneficial when the dose is properly regulated. It is more difficult to use Meratran successfully in true melancholia, or depressive reactions of psychotic proportions. I-Iere the doses required are higher, extending from 10 to 15 and perhaps more milligrams daily in divided doses. If the psychotic depression is of the agitated type, the drug is contraindicated because agitation becomes worse with it. In selected cases of simple severe depression with marked psychomotor retardation the drug has been helpful. It is our clinical impression that it not only ameliorates the depressive symptoms but apparently shortens the attack as well. For the majority of psychotic depressions, however, no analeptic drug appears to be able to supplant electroconvulsive therapy at this time. Andrenll has reported that the combination of Meratran plus electroshock therapy (EST) may be worthy of trial in psychotic depressions. One-half hour before EST he injects 1 mg. Meratran intramuscularly, and on alternate days ,vhen electrical treatment is not given, he continues the same regimen of Meratran intramuscularly. He finds the results better than might be expected from EST alone, a lessening of confusion and amnesia attendant upon EST, and a more rapid elevating of mood and dissolution of suicidal urges. Schut and Himwich 12 found Meratran of value in improving the behavior and hygiene of a group of chronic psychotic patients in a state hospital. A useful place for Meratran has been in the treatment of old folks. I3 As senescence steals upon many people they lose their lust for living, and activities which were pleasurable in earlier days often become a bore and a burden. With this comes an attitude of pessimism, concern over security, fretfulness, insomnia, anorexia and morbid preoccupation with the thought of death-the clinical picture of the unhappy and poorly adapted geriatric patient whose life is difficult for both himself and those around him. l'his state often occurs at the time of retirement from active work, as Pomeranze I4 has noted. In these cases Meratran has often proved of value. The dosage is often as little as 1 mg. each morning, or 1 mg. morning and midafternoon, or 1 mg. t.i.d. Kleemeier et. al. 15 made a controlled study of the effect of 2 mg. daily on a group of men varying in age from 66 to 85 years in a brotherhood home, using a double-blind technique of Meratran and placebo, and noted significant results with the drug. In fatigue states which follow organic disease, small doses of Meratran have been advocated for "tonic" purposes. AntosI 6 finds small doses, usually 1 to 3 mg. daily, occasionally going to 6 mg. in divided doses, of value following hepatitis, anemia, cholecystitis, allergic diseases and the like. Hypertensives who experience fatigue may also benefit from small
doses of the drug, as do vvomen with lnild 111enopausal reactions and dysmenorrhea. 17 Convalescents and postoperative patients lnay also be given the drug. Diabetics vvho fatigue easily may have Meratran added to their therapeutic regimen in slnall doses without disturbing sugar chemistry. 'I'he drug has also been advocated in alcoholic problems 18 and in the relief of fatigue brought on by loss of sleep. An example of the last therapeutic indication lnay be taken from personal experience. Some t\VO years ago I found myself in a situation which required me to live on four to five hours sleep for three consecutive days. By noon of the fourth day I was cornpletely \veary, and as I looked at the list of patients I was to see that afternoon I felt that I could not possibly get through the day. I took 2 mg. Meratran and ,vent to work in my office. About 4 P.M. I became aware of the fact that I was not exhilarated, but that I had been moving through my afternoon's work \vith my usual amount of alertness and attention to my tasks. 'rhere was nothing dramatic about it. I had merely been able to receive enough stimulation to carry on normally despite my fatigue. It was only then that I remembered that I had ingested the drug. Ilepeated use of Meratran for such purpose is not advocated. Drug-induced lethargy and drowsiness may be overcome with Meratran. Epileptics who are controlled by anticonvulsant drugs may have such lassitude that they report the cure to be worse than the disease, and sonle of thenl abandon medication on this account. Meratran in divided doses of 2 to 6 mg. daily will often get around this difficulty. Antihistamines, analgesics, antispasmodics, insulin and sedatives can also be the cause of lethargy and apathy. The newer tranquilizing or ataractic drugs, chlorpromazime and reserpine, also have this as perhaps their most common side-reaction. 'l'he use of Meratran in small doses has been advocated in these instances as "reIl. Meratran appears to have some usefulness in controlling lnild cases of uncomplicated enuresis in children. By giving them 1 mg. or perhaps 2 mg. of the drug in the early evening hours, sleep is not so deep, and they are awakened by a full bladder and are able to get to the toilet and empty it. H yperlcinetic syndromes 19 in retarded and brain-injured children SOlnetimes are relieved by doses of the drug ranging from 2 to 10 rng. daily, in the same fashion that drugs of the amphetamine group seem to be efficacious in these syndromes. Recent personal experience, however, indicates that chlorpromazine and reserpine, which undoubtedly operate in a different fashion pharmacologically, are better therapeutic agents in such pediatric problems. Side Reactions
Meratran has no effect on appetite, and there appears to be no need for advising its use at any specific time in relation to meals; convenience may dictate in this matter. No blood dyscrasias have been reported
The Newer Analeptic Drugs with its use, nor have kidney or liver damage been seen. Reports on skin rash have been rare and questionable, and those which have occurred have been fleeting. On rare occasions a sense of itching has been reported in the face or on the forearms with its use. No appreciable cardiovascular pressor effects have been noted. The major side reaction of Meratran is the development of the sOlllatic (and psychic) accompaniments of anxiety, and this is an all-important consideration in the use of the drug. SOlne patients do not tolerate it at all without developing these unpleasant responses, whereas others, may take as much as 100 mg. daily vvithout any subjective experience of this kind. '-fhis profound variation in tolerance is one of the riddles of all analeptic drugs. There is no explanation why one human being can take massive doses of these compounds whereas others can tolerate them only in small doses, if at all. l'hese responses may be listed as motor restlessness, apprehension, a tense feeling in somatic muscles, overt tremor of the hands and lips, palpitation, "butterflies" in the abdomen and urinary frequency. With this comes a sense of foreboding and panicky anxiety. Withdra,val of the drug will bring these symptollls to an end vvithin a 111atter of hours, and if they are severe, a single dose of barbiturate medication ,vill reduce their severity. '"foxic Effects
We have seen one case of psychosis of paranoid type develop in a middle-aged ,voman with torticollis when her dose was pushed up to 35 mg. daily. She developed the idea that a man in her apartment house was attempting to rape her and she called the police. This psychosis disappeared in two days with the help of barbiturate sedation. A few other investigators20 have reported the development of similar psychotic episodes. This appears to be a rare danger inherent in the use of the drug, and calls for careful observation while the dosage is being advanced. Two cases of massive overdose of the drug have been reported, OTIe in an adult and one in a child. Marked hyperkinesis, perseverative stereotyped movements, profound agitation and some degree of insomnia resulted. Paren~eral use of Sodiul11 Amytal controlled the symptoms in each instance within 36 hours. Evaluation of Results
Meratran appears to have therapeutic indication as a central stimulating or analeptic drug. Its tendency to produce anxiety symptoms is the limiting factor in its usefulness. Dosage is variable from one person to another, and this can be worked out only by the trial and error method. Failures probably result as often ,vith underdosage as they do with overdosage. Its usefulness is greatest in states of mild to moderate depression, whether they be psychogenic or organic or drug-induced, and it may be attempted in selected neurological syndromes.
346
H oward D. F abing RITALIN
In a comparative study of a great number of different piperidine compounds of the phenyl-piperidyl-acetic acid group, Meier et a1. 21 found in 1954 that the central stimulating action of Ritalin (phenylpiperidyl-[2]-acetic acid methylester) was particularly strong. Pharmacologic and clinical studies have determined that this compound, quite similar to Meratran in its action, is another analeptic of the piperidine family which has usefulness in therapeutics. Pharmacology
Meier et al. noted an increase in coordinated motility in experimental animals when the drug was given orally or parenterally. They exhibited an urge to move about and run, and an urge to eat and gnaw without becoming snappish or aggressive. These effects lasted for several hours on doses of 0.5 to 1.5 mg./kg. in various species. Larger doses produced ataxia and convulsions. Spring cage and revolving drum movement studies demonstrated that motor activity increased fourfold in rats and mice. On large doses dogs ran excitedly and developed circling movements. The drug showed an antagonism to barbiturates, chloral hydrate and urethane, and failed to produce sympathomimetic effects. Toxicity studies in the rat showed that there was a great margin of safety between the effective and lethal dose. The LD 50 was 367 mg/kg., whereas the dose producing pharamcologic response lay within the 1 to 5 mg.jkg. range. Clinical Indications
In the human Ritalin is a mild stimulant indicated in chronic fatigue and depressed states including those associated with reserpine and chlorpromazine therapy. It is also helpful in narcolepsy and in psychoses and psychoneuroses of depressive type. The indications, therefore, parallel those of Meratran. Published reports on this drug are few in number at this time, but quite a number are in press22 and should be available for study within the next year. Most investigators have studied its effectiveness in combating the drowsiness and depression which may accompany reserpine and chlorpromazine therapy. They are in agreement that the compound is of definite value in this regard. Ferguson23 has reported on Ritalin's effect in overcoming the depression and drowsiness induced in chronic psychiatric patients in a state hospital. In his pilot group ten chronic catatonic patients receiving only 10 mg. daily seemed brighter and more cooperative. A second group of 68 chronic apathetic patients underwent a more careful trial with the drug in larger doses. They ranged in age from 24 to 71 years and had a hospital stay varying from three to 52 years. Dosages were individualized in response to therapeutic demand) and ranged from 10 to 40 mg. t.i.d.,
The:Newer Analeptic Drugs
347
given at 8:00 A.M., 12:00 noon, and 4:00 P.M. A Behavior Profile Chart was kept on each patient before Ritalin therapy was instituted and was continued throughout the study. A decrease in need for helpful supervision, improvement in personal habits and hygiene, and a drift of speech, attention and alertness toward the normal were noted. With an improvement in animation came an increased interest in food, and the group averaged an 8-pound weight gain during the study period. An increase in cooperativeness in ward routine and rehabilitation programs was noted as well. The majority of these severely regressed psychotic patients required 30 to 40 mg. Ritalin t.i.d., and Ferguson noted improvement in 87% of the group. A third group of 25 patients who had reserpine drowsiness and depression were then given Ritalin. The dose was individualized, varying from 10 to 40 mg. Ritalin t.i.d. regardless of the amount of reserpine being given, with the lower dose proving the most efficacious in the majority of patients. Ferguson states that the action of Ritalin does not counteract or oppose the effect of reserpine, but the combination causes a slow awakening to reality and an increase in motor activity toward normal, with improved cooperativeness, appearance and socialization. Twenty-two of the 25 patients were benefited by the combination therapy and some were discharged. A relieving of reserpine-induced nasal stuffiness was noted as well. Ferguson24 has continued this combination therapy since his first report, and finds that his results remain good. Best results have been seen in hebephrenic and catatonic types of schizophrenia, with the paranoid variety showing the least change. The senile group has shown clearing of confusion with consequent improvement. The ward atmosphere has improved and the rehabilitation program has undergone great expansion. Carter,25 Madi and Kovitz 26 and others have also found Ritalin to be helpful in combating reserpine-induced depres~}on and lethargy, and Ayd21 found it of value in both reserpine and chlorpromazine oversedation. Plummer et a1. 28 found Ritalin capable of overcoming the depressive effects of reserpine without influencing the hypotensive mechanism of the drug. In these reports the dose generally prescribed has been 10 mg. t.i.d. Fazekas29 finds Ritalin of value in overcoming chlorpromazine oversedation effects when given intravenously. Ferguson30 has used Ritalin parenterally in 204 patients in doses from 5 to 20 mg. to counteract reserpine, chlorpromazine or barbiturate overdosage. No untoward effects have been noted. Response to intravenous injection occurs in one to five minutes, to intramuscular injection in five to 30 minutes. N atensohn31 has used Ritalin in general practice in the chronically ill and incurables including terminal carcinoma patients, in the convales... cent group after surgical operation or illness, in psychogenic mild depressive states, and in drug depression. In general he has found that these
348
H oward ]J. F abing
groups get a favorable response with 10 to 20 lng. tvvicc or three tirncs daily, that an elevation in vigor and mood results without euphoria, that appetite is not affected, that no cardiovascular pressor reactions occur, and that no deleterious effects on hemopoietic organs, liver or kidneys have been noted. Side Reactions
These have been minimal, and appear to be similar to those of MeratraIl. They have been confined to overstimulation, vvith the production of jitteriness and the somatopsychic accompaniments of anxiety, vvhich dissipate quickly \vhcn the drug is withdrawn. One case of habituation is reported in a patient formerly habituated to barbiturates, but the drug ,vas withdrawn vvithout consequence. Evaluation of Results
Ritalin appears to be of special usefulness in counteracting the depressant and sedative effects of reserpine, chlorpromazine and promazine. The large number of investigations on this aspect of the drug's indication give promise that the effectiveness of these hypotensive and ataractic agents can be enlarged if Ritalin is given in combination with them. It is also a general-purpose analeptic, according to report, which can be used to counteract states of fatigue and depression psychogenically induced as well as those which follow organic disease. In endogenous depression of psychotic proportions it is of possible value, but one must be prepared to abandon it for electrotherapy if results are not forthcoming. In agitated melancholia it is contraindicated and in psychoneurotic depressions anxiety reactions may arise to vitiate the moodelevating effect of the drug. COMPARISON OF MERATRAN AND RITALIN, AND COMPARISON OF THESE AGENTS WITH OTHER ANALEPTICS
SO far as I am aware, no pharmacologic studies have been carried out in experimental animals to determine the relative central nervous system stimulating action of Meratran and Ilitalin. If I may be permitted a guess from clinical observation, I should say that the effectiveness of the t,vo drugs as eNS stimulants in man, milligram for milligram, is as one of Meratran to five of Ritalin. No study has been carried out in a controlled series of patients to determine the relative therapeutic effectiveness of one or the other of these drugs. This would be hard to accomplish because of a number of variable factors, including the changing nature of depressive states, the difficulty of maintaining completely objective attitudes in clinical observers, try as they might, and the consideration of obtaining a reasonable objectivity in patients under such experimental conditions even if a blind technique were employed. For the present we shall have to be content with the information that
The Newer Analeptic Drugs
849
t\VO nc\v piperidine-containing analeptics are now available, that their dosage range is variable, and that the indieations for their use are sinlilar. l-'herapeutic trial of one or the other or both nlay be made to determine their therapeutic value in a specific patient. Both of these drugs have advantages over the amphetamine group of analeptics in that they do not decrease appetite nor cause cardiovascular pressor reactions because of sympathomilnetic effects. On the other hand, they are relatively mild mood-elevators, and drugs of the amphetalnine series may turn out to have greater usefulness in this therapeutic sphere in a given patient, with or without the addition of small doses of barbiturates, than either one of the newer analeptics discussed in this presentation may be able to offer. This is a difficult area of therapeutics, in which one must be guided mostly by the subjective reports of the patient without the help of laboratory methods. It calls for an attitude of prudent adventurousness on the part of the clinician, with a \villingness to abandon any and all of these agents if they fail to produce tangible results or if they cause troublesome side reactions. SUMMARY
Within the past few years two new analeptic cOlnpounds of piperidine structure have crossed the horizon as therapeutic agents. They are not sympathomimetic agents and thus do not cause cardiovascular pressor reactions nor appetite loss, nor do they interfere with nocturnal sleep as much as do the drugs of amphetamine type. They are indicated in mild fatigue and depressive states arising in psychoneuroses and in the course of organic illness or drug-induced states of oversedation and neural depression. '-rheir dosage is variable from patient to patient, and clinical artistry is necessary to determine the quantity and the timing of these medications. They do not fill the bill as agents in the treatment of severe psychotic depression. They are relatively free of toxic effects and do not compromise the function of any of the major organ systems of the body. Their usefulness is lin1ited by the subjective symptoms of anxiety and tension \vhich they are capable of inducing in the patient under treatluent. They constitute a tangible increase in the therapeutic armamentarium of the clinician in search of drugs to produce improved emotional tone and a lessened sense of fatigue in many varieties of patients. REFERENCES 1. Goodman, L. and Gilman, A.: The Pharmacological Basis of Therapeutics. New York, Macmillan Co., 1941, p. 256, et seq., inter alia. 2. Hauschild, F.: Zur Pharmakologie del' Phenylalkylalnine. Arch. Expel'. Path. u. Phannakol. 191: 465, 1939. Zur Pharmakologie des 1-Phenyl-2-methylaminopropans (Pervitin). Arch. ~~xper. Path. u. Pharmakol. 195: 647, 1940. 3. Brown, B. B., Feldman, R. and Braun, D. L.: Pharmacologic Studies of an LSD Antagonist, 4-Piperidyl Diphenyl Carbinol. Fed. Proc. 14: 322, 1955.
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