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Psychopharmacology: Part III: Stimulants and Antidepressants
Psychopharmacology Part III Stimulants and Antidepressants JOHN
H.
NODINE,
M.D.
hibition of some inhibitory system.~ The end result in psychological effect might, therefore, be due to any of several mechanisms which act entirely differently, depending upon the chemical structure and pharmacologic effect of the particular drug. Active work is currently being carried out in this field in order to further elucidate the immediate enzymatic mechanisms of action of the various psychopharmacologic agents. Clinically, a neurotic or a psychotic depressive reaction is actually a psychiatric diagnostic classification, based upon symptoms and behavior.: Although attempts have been made to describe its psychodynamics, many patients require more definitive measures than psychotherapy. Johnson suggests that a depressive patient is best managed with "eclectic opportunism," by which he implies "a broad flexible attitude making use of all available methods and of all conditions and variables as may be present in a specific case."·, In patients with depressive reactions, actually more than a single or particular psychodynamic or biochemical disturbance may be present. Much more precise information must be available in understanding the etiology of depression, so that our therapeutic approach now must remain somewhat empiric. In considering the problem of study and use of psychopharmacologic agents in this broad field of psychiatry, one must not consider the use of drugs to be an "either-or" type of approach. One may combine drugs with other modes of therapy in order to facilitate the recovery of the patient; other modes of therapy may be selected preferentially for the treatment of individual patients. In making a decision regarding the use of drugs under these circumstances, one must always From the Department of Medicine, Hahnemann be aware of the potential risk of suicide in Medical College and Hospital, Philadelphia, Pa. Doctor Nodine is Assistant Professor of Medicine, many depressed patients. In addition, the Head, Section of Clinical Phannacology, Hahnemann exact mode of management should be inMedical College.
• Many diHerent types of drugs, belonging to various chemical classes, exert some type of stimulant effect on the central nervous system. Although xanthine derivatives (caffeine) and cocaine, were known for centuries in crude plant forms, thus illustrating the long use of psychostimulants, fortunately much better agents are currently available and much more is understood about their mechanism of action. Many compounds stimulate the central nervous system in a way which does not cause major psychic effects and hence they are eliminated from the discussion of psychopharmacology. These compounds include convulsants such as pentylenetetrazol (Metrazol@), strychnine, nikethamide, and more recently vanillic acid diethylamide (Emivan$). The term stimulant, used in the psychopharmacologic sense signifies an agent which will initiate central nervous system stimulation in the clinical sense of counteracting fatigue or exhaustion, or increasing drive. In contrast to this, a pure antidepressant is expected to exert little effect on a normal individual and relieve depression only in a depressed person. 1 From the purist's point of view, one must remember that in dealing with central nervous system function, one is dealing basically with discharges of neurons and chemical transmission across the synapse between neurons. A drug can either facilitate or hamper discharge, or facilitate or hamper transmission across the synapse. Since the central nervous system is divided into excitatory and inhibitory systems, the net clinical effect (Le., stimulation), may actually result from facilitation of some activating system or through in-
March-April, 1963
j
73
PSYCHOSOMATICS
dividualized depending upon the age of the patient, the duration of the depressive reaction, the rigidity of the personality structure, the intellectual resources, and the insight (or lack of it) in a particular patient. As in the previous paper we shall consider animal methods and clinical methods, followed by the current status and future outlook in the field of stimulants and antidepressants.' ANIMAL PHARMACOLOGIC TECHNIQUES
In this field, particularly, it has become apparent that animal pharmacologic techniques have followed clinical discoveries in the development of new agents. Because of the psychostimulant effects of cocaine and epinephrine which were studied early, behavioral techniques were developed to evaluate the stimulating effects of sympathomimetic drugs upon the central nervous system, separate from their ability to stimulate the cardiovascular system and other autonomic functions. After recognition of the antidepressant effect of iproniazid (Marsilid®), the technique of measuring in vitro monoamine oxidase inhibition was expanded and applied more extensively. Finally, after observing the clinical effects of imipramine, (Tofranil®), additional techniques were developed for identifying drugs with more subtle modes of action in the antidepressant field. A summary of the current stimulant and antidepressant drugs in wide use is given in Table II. t Because of the wide variety of sympathomimetic drugs which are available, only two of the most commonly used are mentioned. The pharmacologic differences between these groups will become apparent as the individual pharmacologic techniques are discussed: 1. Behavioral Observations.-A wide variety of behavioral observations in multiple species are used in assessing the psychostimulant action of various drugs. The simplest techniques include the measurement of motor activity in rats in jiggle cages or in other types of mechanical recording apparatus.! Suppression of sleep, or neutralization of sleep induced by barbiturates, may be used as well as the more complicated behavioral methods, including effects on maze learning, et cetera. In short, a standard psychostimulant may be tEDlTOR'S NOTE: Table I appeared in Part II, page 459, November-December, 1962.
74
measured by a particular technique; the activity of a new agent may be compared with this by giving various doses to determine the dose equivalent to the standard agent. Tests such as these are effective in identifying the psychostimulant effects in drugs belonging to the sympathomimetic group and the marginal sympathomimetic group. The major difference in these two groups lies in the fact that the stimulant properties are more marked in the marginal sympathomimetic group, as compared to the other autonomic effects which may be found for a given dose of drug. More psychic stimulation occurs and less cardiovascular stimulation, for example. The difference between these groups is more quantitative than qualitative. TABLE II. SUMMARY OF STIMULANTS AND ANTIDEPRESSANTS
I.
II.
Ill.
IV. V.
Sympathomimetic Drugs 1. amphetamine 2. d-amphetamine Marginal Sympathomimetic and Related Drugs 3. deanol, Deaner® 4. methylphenidate, Ritalin® 5. phenmatrazine, Preludin® 6. pipadrol. Meratran® Monoamine Oxidase Inhibitors A. Hydrazines 7. iscarboxazid, Marplan® 8. nialamide, Niamid® 9. phenelzine, Nardil® B. Others 10. tranylcypromine, Pamate® Iminodibenzyl Derivatives 11. amitriptyline, Elavi\® 12. imipramine, Tofrani\® Psychotogens 13. LSD.. 14. psilocybin
2. Inhibition of Monoamine Oxidase.-A wide variety of test procedures has been used in evaluating the effect of the monoamine oxidase inhibitors on monoamine oxidase itself and upon the biogenic amines which occur endogenously and which are not oxidized in the absence of monoamine oxidase. 6 ,"7 Alterations in 5-hydroxytryptamine content in the brain are readily discernible after administration of monoamine oxidase inhibitors. The three most commonly used tests which may be applied in vivo include: (1) the tryptamine potentiation test, in which subconvulsive doses of tryptamine are injected and convulsions are found to occur after pre-treatment with MAO inhibitors; (2) 5-hydroxytryptaphane potentiation test, Volume IV
PSYCHOPHARMACOLOGY-STIMULANTS AND ANTIDEPRESSANTS-NODINE
which is similar, except that 5-hydroxytryptaphane is used instead of tryptamine; (3) in addition, the disappearance of 5-hydroxytryptamine may be observed and the destruction per gram of brain tissue per hour may be compared in normal and drug treated animals so that the per cent of MAO inhibition may be determined. Common to all of these methods is the measurement of tissue alterations in concentration," or in disposal, of endogenous or exogenously administered biogenic amines.
3. Reserpine Reversal.-Since the administration of reserpine causes sleepiness, ptosis, or decreased activity, and is accompanied by release of amines from binding sites in the central nervous system, a presumptive test for monoamine oxidase inhibition consists in administering the MAO inhibitor and following this with a dose of reserpine known to cause behavioral effects in the species being tested. 8 When reserpine releases the biogenic amines from their binding sites, these amines may not be destroyed if MAO inhibition is occurring, so that they accumulate in large amounts within the brain causing a stimulating effect rather than the usual depressant effect seen after reserpine. 4. Amphetamine Potentiation.-Sensitive behavioral techniques have been developed, using animals who have been trained to respond in a conditioned avoidance situation (see part II), or who have implanted electrodes, and who have been taught to obtain gratification by self stimulation of pleasure centers in the brain. 1 Under these specialized circumstances, most of the drugs which do not cause direct stimulation in behavioral observations (as discussed above), but which have antidepressant activity, may be found to act in potentiating the effect of administered sympathomimetic drugs such as amphetamine or methamphetamine. Thus, although the monoamine oxidase inhibitors may cause little behavioral change in the normal animal, they will potentiate the stimulant effects of amphetamine under the specialized experimental conditions. Similarly, the iminodiobenzyl derivatives ( group 4), amitriptyline and imipramine, are capable of augmenting the March-April, 1963
behavioral response induced by sympathomimetic drugs, even though when administered alone they may suppress behavior or have no effect upon it. Although these techniques are capable of showing action with iminodiobenzyl derivatives which cannot be identified by other means, similar effects are shown by other agents of Widely different classes, including antihistamines, anticholinergic drugs and others, so that this test is by no means specific nor does it signify with any degree of certainty that a particular agent will have antidepressant properties in man. In addition to these four main classes of drugs used clinically, an additional class is of interest from the psychopharmacologic point of view, although the drugs therein are not commercially available. Among the most powerful psychostimulants available are the psychotogens, i.e., drugs which may induce profound mental changes including confusion, hallucinations, et cetera. Such agents are difficult to identify in preliminary animal screening with current techniques" although certain behavioral observations in different species may suggest that an agent might mave psychotomimetic properties when applied to man. No adequate animal techniques are presently available for determining the psychotomimetic potential. CLINICAL TECHNIQUES
The general problem of selecting appropriate response parameters for the study of stimulants and antidepressants have been outlined (part I). It is important to emphasize that the application of appropriate behavioral scales should take place only during the third phase of clinical screening. In phases 1 and 2, in the study of stimulant and antidepressant drugs, one must explore the dose range which is effective and the clinical and laboratory side effects which may occur. The most important instrument in the early evaluation of drugs of this type is the alert clinician who is capable of making the diagnosis of depression and can note observations which show that the symptoms and subjective response have changed. Subsequently, when the dose of a drug is well determined, appropriate scales may be administered in assessing the change in individual patients. The Dean 75
PSYCHOSOMATICS
Clyde Mood Scale has been used very widely, but was found to be inappropriate in illiterate and semi-literate clinic populations. A more streamlined method which has proven useful and which has been adequately standardized and replicated, consists of the Beck Scale which can be administered in 10 to 15 minutes hy a trained secretary. til Performance tests, as discussed in part II, may also be appropriate since improved performance may occur with alleviation of depression, as well as relief of anxiety. The problem of evaluating antidepressant drugs is complicated by the fact that these patients very commonly do not complain of their depression and are not motivated for return visits to the physician, thus differing from those suffering from anxiety which drives them to return again and again for relief. When a patient feels better, he may also forget that medications may be related to his improvement and may neglect treatment or follow-up visits. Clinically it is much more difficult to carry out studies with ambulatory depressed patients and, therefore, additional response parameters including the drop-out rate may be of particular importance in considering therapeutic response to a new agent. Of particular interest has been the development of methods which permit the evaluation of monoamine oxidase inhibition directly in man.' Three simple tests have been applied. One is the serotonin conversion test which consists of the administration of 20 mg. of serotonin and measurement of the output of 5-hydroxyindoleacetic acid (5 HIAA) in the urine in the subsequent 24-hour period. This method has largely been abandoned because it is not specific for generalized systemic inhibition of MAO and may be altered with drugs which affect MAO in the blood only. A second method consists of demonstrating an increase in the urinary excretion of amines. Tyramine and tryptamine may be measured after loading, assuming that an adequate and reasonably constant intake of protein, including tyrosine and tryptophane, is present. An additional method, which is highly sensitive, consists of the direct assaying of jejunal mucosa for MAO when such specimens are obtained by oral tube biopsy techniques. The problem of evaluating stimulant and antidepressant drugs in man is magnified by 76
the fact that some drugs may have more than one mode of action. For example, tranylcypromine not only inhibits MAO, but also has secondary sympathomimetic properties which may alter the clinical response and which must he considered in the drug evaluation. A final variable is the secondary pharmacologic effect. Many of these antidepressant drugs possess antihistaminic and anticholinergic activities which may again influence the clinical result and the spectrum of symptomatic improvement and side effects which occur, depending upon which particular physiologic alterations may be associated with the depression. CURRE:>;T STATUS OF STIl\IULANTS AND ANTIDEPRESSANTS
The clinical use of various stimulants amI antidepressants must be a matter of individual choice. The first decision must be that the patient requires some type of psychopharmacologic therapy. The risk of suicide must be appropriately evaluated and concomitant therapy may be indicated using other modalities. The following general principles are worthwhile in considering the primary and secondary pharmacologic properties of the stimulants and antidepressants, and in skillfully applying their use in individual patients. 't In general, the sympathomimetic and marginal sympathomimetic drugs are ineffective in severe depressive reactions. These drugs may be highly effective in a mild depressive reaction, particularly if this condition is associated with an acute environmental problem; they may also be the treatment of choice because of their known safety and essential lack of serious toxicity, even with chronic administration. It is important to emphasize individual dose adjustment, because the problem of insomnia is usually the limiting factor in permitting higher doses. When this does not occur or when it can be controlled by administering the drug early in the day, dosage may be safely increased. For example, although methylphenidate (Ritalin'ID) may be effective in doses of 10 mg., two or three times daily, in some patients, others may require as much as 40 to 60 mg., three or four times daily. Instead of trying to use all six of the drugs Volume IV
PSYCHOPHARMACOLOGY-STIMULANTS AND ANTIDEPRESSANTS-NODINE
listed in the sympathomimetic and marginal sympathomimetic group on Table II, it is better for each physician to learn more about one or two drugs and to use these skillfully, with correct dose adjustments, depending upon the severity of each patient's symptoms and the particular side effects which may be troublesome to that patient. The clinically available monoamine oxidase inhibitors include three hydrazine derivatives and tranylcypromine. Definite pharmacologic differences may be observed between the hydrazines and tranylcypromine, in that tranylcypromine possesses certain properties which make it resemble the sympathomimetic and marginal sympathomimetic drugs. These properties include the relatively prompt onset of action, a stimulant effect with occasional hypertensive type of reaction, and hypertensive headaches. Controlled studies of its antidepressant action have not permitted an exact comparison 0 f its effectiveness to that of the hydrazines. Isocarboxazid, nialamide and phenelzine have been used much more widely in clinical practice than has tranylcypromine, and their effectiveness in many cases of more severe depression have been well substantiated. On the other hand, with all three of the hydrazine type of MAO inhibitors, hepatic damage has been found in animals receiving high doses and has been reported in rare humans who may be unusually sensitive to standard therapeutic dosage. Fatal reactions have been reported in some instances. A delay in the onset of effect after the institution of treatment is common; often one to three weeks pass before a significant effect occurs. Some patients fail to respond after receiving MAO inhibitors. From the practical point of view, if one knows how to use one of the hydrazine MAO inhibitors and tranylcypromine, one can effectively judge the dosage for a particular patient and use appropriate adjustment in order to see what benefit may be derived from these potent agents. Here again, dose adjustment may be important since some patients may respond well, for example to 75 mg. of nialamide daily, whereas other patients require 300 to 400 mg. daily. Iminodibenzyl derivatives exert a more subtle action than that seen with the hydrazines or the marginal sympathomimetic March-April. 1963
agents. Onset of action is commonly delayed for two to four weeks after drug administration, and improvement occurs so gradually that the patient may fail to associate this improvement with the drug. Major differences are found between the clinical use of amitriptyline and imipramine, because amitriptyline may have more sedative or phenothiazine-like properties than does imipramine. These secondary pharmacologic effects may be important in considering a patient with depression who also suffers from intermittent or relatively continuous anxiety, since such a patient may obtain more relief with amitriptyline than with imipramine. With both drugs, excessive doses cause anticholinergic effects which may be particularly troublesome to certain patients, or which may be beneficial if the disturbance is associated with psychophysiologic alterations in which an anticholinergic drug is helpful. Thus, both the basic pharmacologic properties and secondary characteristics of these drugs may be used effectively in outlining treatment for a particular patient. Summary.-The follOWing general approach seems to be rational for the outpatient management of a psychoneurotic depressive real~ tion. If the depressive reaction is milrl, a therapeutic trial of one to two weeks, using one of the marginal sympathomimetic drugs may be undertaken; if no response occurs after two weeks, the patient may be shifted to tranylcypromine or one of the other MAO inhibitors. With a more severe depression, response to the marginal sympathomimetic drugs is not anticipated, so that initiation of therapy employing one of the hydrazine MAO inhibitors, which have been most widely studied and shown to be effective, seems warranted. The risk of toxicity is easily counterbalanced with the potential risk of suicide if such a patient is not treated, and the monoamine oxidase inhibitors are selected because the onset of action of these agents is ordinarily more rapid than with the available iminodibenzol derivatives. There is some disagreement among workers in the field regarding this sequence, since some feel the iminodibenzol derivatives may be safer and that less problems are encountered if therapy must he changed after using these deriva77
PSYCHOSOMATICS
tives. Extremely alarming reactions may occur in combining an MAO inhibitor with one of the iminodibenzol derivatives. Such combinations have resulted in sudden collapse, convulsions, hyperpyrexia, and even death. One cannot, therefore, judiciously shift from therapy with a monoamine oxidase inhibitor to an iminodibenzol derivative. If the MAO inhibitor has failed to induce an adequate clinical response within three to four weeks, it may then be warranted to stop treatment for at least two weeks and to begin using either amitriptyline or imipramine as the third line of defense. As mentioned, some authorities prefer to use one of these drugs before the MAO inhibitor, since these drugs are eliminated in a few days and MAO inhibitors may safely be started three to seven days following discontinuation of the drug. As will be discussed below, currently available agents suggest that in the future such a sequential regimen as this just outlined will need major revision when new drugs become clinical1y available. FtrrURE OUTLOOK
The future outlook in the field of stimulants and antidepressants is bright, owing to the large number of compounds which have become available in recent months for clinical screening and evaluation. Active research is going on in the basic laboratory in an effort to identify more compounds and to determine the effects of these in animals and the clinical correlations which occur. Of particular interest is the development of other derivatives in the iminodibenzol series which may have different properties from the currently available amitryptyline and imipramine. Current studies would suggest that desipramine has human pharmacologic effects and antidepressant activity similar to that found with imipramine, but that the onset of action is much more rapid. If this is borne out by further studies, a safe and more useful clinical agent will become available. Active biochemical research into the causes of fatigue and investigation of the biochemical changes in depression are being carried out so that our pharmacologic approach in the future may have a more rational basis. In short, it is reasonable to hope that drugs 78
which ameliorate depression more promptly and which may be used with little or no risk will become available; their prompt action may minimize the ever present risk of suicide in a higher percentage of patients. Another promising approach which may permit the combination of psychopharmacologic agents and psychotherapy to attack problems which currently cannot be treated, includes the use of the various psychotogens in uncovering unconscious material. Rapid and sometimes sustained personality changes have been observed after the investigative use of various psychotogenic agents, including LSD 2 " psilocybin and others. Conditions which may be closely related to depression and which may be called "masked depression" (Le., psychophysiologic equivalents, and even chronic personality disorders such as alcoholism) may wen succumb to a biochemical attack using these more powerful agents under more precise and controlled conditions as more and more investigators become familiar with their unusual properties. In short, through the use of psychopharmacological agents, which are available in an investigative phase now, or which may become available in the next few years, physicians may be provided with therapeutic methods for attacking not only the resistant depressed patient, but many of the psychoneurotic conditions and personality disorders which have resisted attack with currently available drugs. A bright and interesting future is anticipated. A change has already been seen in the number of depressed patients admitted to state mental institutions; this is due at least in part to the effective drugs which are used promply in ambulatory depressed patients. 12 REFEREl':CES 1. Stein, L.: ~Iethods for evaluating stimulant and antidepressant drugs. In Psychosomatic Medicine, p. 297, eds. Nodine and Moyer. Philadelphia: Lee and Febiger, 1962. 2. Marrazzi, A. S.: Pharmacodynamics of sympathomimetic and marginal sympathomimetic drugs. In Psychosomatic Medicine, p. 565, eds. Nodine and Moyer. Philadelphia: Lea and Febiger, 1962. 3. Slap, J. W.: Classification of psychoneuroses. In Psychosomatic Medicine, p. 7, eds. Nodine and Moyer. Philadelphia: Lea and Febiger, 1962. 4. Johnson. D. E.: Management of depressive reactions. In Psychosomatic Medicine, p. 820, eds. Nodine and Moyer. Philadelphia: Lea and Febiger,I962.
Volume IV
PSYCHOPHARMACOLOGY-STIMULANTS AND ANTIDEPRESSANTS-NODINE 5. Mapp, Y. and Nodine, J. H.: Psychopharmacology II: tranquilizers and antipsychotic drugs. Psyc1lOsom. 3:458,1962. 6. Tedeschi, D. H., Tedeschi, R. E., Fowler, P. J., Green, H., and Fellows, E. J.: Monoamine oxidase inhibition: methods of evaluation in animals. In Psychosomatic Medicine, p. 318, eds. Nodine and rvlOyer. Philadelphia: Lea and Febiger, 1962. 7. Sjoerdsma, A.: Monoamine oxidase inhibition: methods or evaluation in man. In Psychosolllatic Medicine, p. 325, eds. Nodine and ~Ioyer. Philadelphia: Lea and Febiger, 1962. 8. Pletscher, A. and Gey, K. F.: Pharmacodynamics of monoamine oxidase inhibitors of the hydrazine type. In Psychosomatic Medicine, p. 595, eds. Nodine and Moyer. Philadelphia: Lea and Fehiger, 1962.
9. Winter, C. A.: Psychotomimetic compounds: pharmacologic and behavioral effects in animals. In Psychosomatic .\tedicine, p. 329, eds. Nodine and Moyer. Philadelphia: Lea and Febiger, 1962. 10. Beck, A. T., Ward, C. H., Mendelson, M., Mock, J. and Erbough, J.: An inventory for measuring depression. Arch. Gen. Psychiat., 4:561. 1961. 11. Siegler, P. E., Bodi, T., Levy, H. A., Slap, J. W., Ducanes, A., Brecher, H. and Nodine, J. H.: Depression in medical practice. Postgrad. Med., 33:159,1963. 12. Goldman, D.: Panel discussion on Pharmacodynamics and clinical use of stimulants and antidepressants. 1. In Psychosomatic Medicine, p. 620, eds. Nodine and Moyer. Philadelphia: Lea and Febiger, 1962.
It is high time . . . that in psychologic questions . . . serious and conscientious investigation of specific problems replace the clever contentions and profound inventions. With that which is undemonstrable, or irrefutable, we can go no further. Wl> need facts, not theories. . . . No science can do without integrative points of view and tentative assumptions; but we must never forget that they have no independent inherent value. They are merely a means to an end; their justification can be found only in the fact that they lead to definite questions and thereby to new investigations. . . . \Ve now ought to proceed to answer them not at the green table (or arm chair) but in the laboratory; not with hrilliant suggestions but with observation and measurement. KRAEPELlN: Introduction to Psychologische Arbeiten (1896). Quoted by JOSEPH ZUUIN, Ph.D., in Dewession by Hoeh and Zubin, p. 141, Grum' and Stratton, New York, 1954.
March-April, 1963
79
H.
NODINE,
M.D.
hibition of some inhibitory system.~ The end result in psychological effect might, therefore, be due to any of several mechanisms which act entirely differently, depending upon the chemical structure and pharmacologic effect of the particular drug. Active work is currently being carried out in this field in order to further elucidate the immediate enzymatic mechanisms of action of the various psychopharmacologic agents. Clinically, a neurotic or a psychotic depressive reaction is actually a psychiatric diagnostic classification, based upon symptoms and behavior.: Although attempts have been made to describe its psychodynamics, many patients require more definitive measures than psychotherapy. Johnson suggests that a depressive patient is best managed with "eclectic opportunism," by which he implies "a broad flexible attitude making use of all available methods and of all conditions and variables as may be present in a specific case."·, In patients with depressive reactions, actually more than a single or particular psychodynamic or biochemical disturbance may be present. Much more precise information must be available in understanding the etiology of depression, so that our therapeutic approach now must remain somewhat empiric. In considering the problem of study and use of psychopharmacologic agents in this broad field of psychiatry, one must not consider the use of drugs to be an "either-or" type of approach. One may combine drugs with other modes of therapy in order to facilitate the recovery of the patient; other modes of therapy may be selected preferentially for the treatment of individual patients. In making a decision regarding the use of drugs under these circumstances, one must always From the Department of Medicine, Hahnemann be aware of the potential risk of suicide in Medical College and Hospital, Philadelphia, Pa. Doctor Nodine is Assistant Professor of Medicine, many depressed patients. In addition, the Head, Section of Clinical Phannacology, Hahnemann exact mode of management should be inMedical College.
• Many diHerent types of drugs, belonging to various chemical classes, exert some type of stimulant effect on the central nervous system. Although xanthine derivatives (caffeine) and cocaine, were known for centuries in crude plant forms, thus illustrating the long use of psychostimulants, fortunately much better agents are currently available and much more is understood about their mechanism of action. Many compounds stimulate the central nervous system in a way which does not cause major psychic effects and hence they are eliminated from the discussion of psychopharmacology. These compounds include convulsants such as pentylenetetrazol (Metrazol@), strychnine, nikethamide, and more recently vanillic acid diethylamide (Emivan$). The term stimulant, used in the psychopharmacologic sense signifies an agent which will initiate central nervous system stimulation in the clinical sense of counteracting fatigue or exhaustion, or increasing drive. In contrast to this, a pure antidepressant is expected to exert little effect on a normal individual and relieve depression only in a depressed person. 1 From the purist's point of view, one must remember that in dealing with central nervous system function, one is dealing basically with discharges of neurons and chemical transmission across the synapse between neurons. A drug can either facilitate or hamper discharge, or facilitate or hamper transmission across the synapse. Since the central nervous system is divided into excitatory and inhibitory systems, the net clinical effect (Le., stimulation), may actually result from facilitation of some activating system or through in-
March-April, 1963
j
73
PSYCHOSOMATICS
dividualized depending upon the age of the patient, the duration of the depressive reaction, the rigidity of the personality structure, the intellectual resources, and the insight (or lack of it) in a particular patient. As in the previous paper we shall consider animal methods and clinical methods, followed by the current status and future outlook in the field of stimulants and antidepressants.' ANIMAL PHARMACOLOGIC TECHNIQUES
In this field, particularly, it has become apparent that animal pharmacologic techniques have followed clinical discoveries in the development of new agents. Because of the psychostimulant effects of cocaine and epinephrine which were studied early, behavioral techniques were developed to evaluate the stimulating effects of sympathomimetic drugs upon the central nervous system, separate from their ability to stimulate the cardiovascular system and other autonomic functions. After recognition of the antidepressant effect of iproniazid (Marsilid®), the technique of measuring in vitro monoamine oxidase inhibition was expanded and applied more extensively. Finally, after observing the clinical effects of imipramine, (Tofranil®), additional techniques were developed for identifying drugs with more subtle modes of action in the antidepressant field. A summary of the current stimulant and antidepressant drugs in wide use is given in Table II. t Because of the wide variety of sympathomimetic drugs which are available, only two of the most commonly used are mentioned. The pharmacologic differences between these groups will become apparent as the individual pharmacologic techniques are discussed: 1. Behavioral Observations.-A wide variety of behavioral observations in multiple species are used in assessing the psychostimulant action of various drugs. The simplest techniques include the measurement of motor activity in rats in jiggle cages or in other types of mechanical recording apparatus.! Suppression of sleep, or neutralization of sleep induced by barbiturates, may be used as well as the more complicated behavioral methods, including effects on maze learning, et cetera. In short, a standard psychostimulant may be tEDlTOR'S NOTE: Table I appeared in Part II, page 459, November-December, 1962.
74
measured by a particular technique; the activity of a new agent may be compared with this by giving various doses to determine the dose equivalent to the standard agent. Tests such as these are effective in identifying the psychostimulant effects in drugs belonging to the sympathomimetic group and the marginal sympathomimetic group. The major difference in these two groups lies in the fact that the stimulant properties are more marked in the marginal sympathomimetic group, as compared to the other autonomic effects which may be found for a given dose of drug. More psychic stimulation occurs and less cardiovascular stimulation, for example. The difference between these groups is more quantitative than qualitative. TABLE II. SUMMARY OF STIMULANTS AND ANTIDEPRESSANTS
I.
II.
Ill.
IV. V.
Sympathomimetic Drugs 1. amphetamine 2. d-amphetamine Marginal Sympathomimetic and Related Drugs 3. deanol, Deaner® 4. methylphenidate, Ritalin® 5. phenmatrazine, Preludin® 6. pipadrol. Meratran® Monoamine Oxidase Inhibitors A. Hydrazines 7. iscarboxazid, Marplan® 8. nialamide, Niamid® 9. phenelzine, Nardil® B. Others 10. tranylcypromine, Pamate® Iminodibenzyl Derivatives 11. amitriptyline, Elavi\® 12. imipramine, Tofrani\® Psychotogens 13. LSD.. 14. psilocybin
2. Inhibition of Monoamine Oxidase.-A wide variety of test procedures has been used in evaluating the effect of the monoamine oxidase inhibitors on monoamine oxidase itself and upon the biogenic amines which occur endogenously and which are not oxidized in the absence of monoamine oxidase. 6 ,"7 Alterations in 5-hydroxytryptamine content in the brain are readily discernible after administration of monoamine oxidase inhibitors. The three most commonly used tests which may be applied in vivo include: (1) the tryptamine potentiation test, in which subconvulsive doses of tryptamine are injected and convulsions are found to occur after pre-treatment with MAO inhibitors; (2) 5-hydroxytryptaphane potentiation test, Volume IV
PSYCHOPHARMACOLOGY-STIMULANTS AND ANTIDEPRESSANTS-NODINE
which is similar, except that 5-hydroxytryptaphane is used instead of tryptamine; (3) in addition, the disappearance of 5-hydroxytryptamine may be observed and the destruction per gram of brain tissue per hour may be compared in normal and drug treated animals so that the per cent of MAO inhibition may be determined. Common to all of these methods is the measurement of tissue alterations in concentration," or in disposal, of endogenous or exogenously administered biogenic amines.
3. Reserpine Reversal.-Since the administration of reserpine causes sleepiness, ptosis, or decreased activity, and is accompanied by release of amines from binding sites in the central nervous system, a presumptive test for monoamine oxidase inhibition consists in administering the MAO inhibitor and following this with a dose of reserpine known to cause behavioral effects in the species being tested. 8 When reserpine releases the biogenic amines from their binding sites, these amines may not be destroyed if MAO inhibition is occurring, so that they accumulate in large amounts within the brain causing a stimulating effect rather than the usual depressant effect seen after reserpine. 4. Amphetamine Potentiation.-Sensitive behavioral techniques have been developed, using animals who have been trained to respond in a conditioned avoidance situation (see part II), or who have implanted electrodes, and who have been taught to obtain gratification by self stimulation of pleasure centers in the brain. 1 Under these specialized circumstances, most of the drugs which do not cause direct stimulation in behavioral observations (as discussed above), but which have antidepressant activity, may be found to act in potentiating the effect of administered sympathomimetic drugs such as amphetamine or methamphetamine. Thus, although the monoamine oxidase inhibitors may cause little behavioral change in the normal animal, they will potentiate the stimulant effects of amphetamine under the specialized experimental conditions. Similarly, the iminodiobenzyl derivatives ( group 4), amitriptyline and imipramine, are capable of augmenting the March-April, 1963
behavioral response induced by sympathomimetic drugs, even though when administered alone they may suppress behavior or have no effect upon it. Although these techniques are capable of showing action with iminodiobenzyl derivatives which cannot be identified by other means, similar effects are shown by other agents of Widely different classes, including antihistamines, anticholinergic drugs and others, so that this test is by no means specific nor does it signify with any degree of certainty that a particular agent will have antidepressant properties in man. In addition to these four main classes of drugs used clinically, an additional class is of interest from the psychopharmacologic point of view, although the drugs therein are not commercially available. Among the most powerful psychostimulants available are the psychotogens, i.e., drugs which may induce profound mental changes including confusion, hallucinations, et cetera. Such agents are difficult to identify in preliminary animal screening with current techniques" although certain behavioral observations in different species may suggest that an agent might mave psychotomimetic properties when applied to man. No adequate animal techniques are presently available for determining the psychotomimetic potential. CLINICAL TECHNIQUES
The general problem of selecting appropriate response parameters for the study of stimulants and antidepressants have been outlined (part I). It is important to emphasize that the application of appropriate behavioral scales should take place only during the third phase of clinical screening. In phases 1 and 2, in the study of stimulant and antidepressant drugs, one must explore the dose range which is effective and the clinical and laboratory side effects which may occur. The most important instrument in the early evaluation of drugs of this type is the alert clinician who is capable of making the diagnosis of depression and can note observations which show that the symptoms and subjective response have changed. Subsequently, when the dose of a drug is well determined, appropriate scales may be administered in assessing the change in individual patients. The Dean 75
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Clyde Mood Scale has been used very widely, but was found to be inappropriate in illiterate and semi-literate clinic populations. A more streamlined method which has proven useful and which has been adequately standardized and replicated, consists of the Beck Scale which can be administered in 10 to 15 minutes hy a trained secretary. til Performance tests, as discussed in part II, may also be appropriate since improved performance may occur with alleviation of depression, as well as relief of anxiety. The problem of evaluating antidepressant drugs is complicated by the fact that these patients very commonly do not complain of their depression and are not motivated for return visits to the physician, thus differing from those suffering from anxiety which drives them to return again and again for relief. When a patient feels better, he may also forget that medications may be related to his improvement and may neglect treatment or follow-up visits. Clinically it is much more difficult to carry out studies with ambulatory depressed patients and, therefore, additional response parameters including the drop-out rate may be of particular importance in considering therapeutic response to a new agent. Of particular interest has been the development of methods which permit the evaluation of monoamine oxidase inhibition directly in man.' Three simple tests have been applied. One is the serotonin conversion test which consists of the administration of 20 mg. of serotonin and measurement of the output of 5-hydroxyindoleacetic acid (5 HIAA) in the urine in the subsequent 24-hour period. This method has largely been abandoned because it is not specific for generalized systemic inhibition of MAO and may be altered with drugs which affect MAO in the blood only. A second method consists of demonstrating an increase in the urinary excretion of amines. Tyramine and tryptamine may be measured after loading, assuming that an adequate and reasonably constant intake of protein, including tyrosine and tryptophane, is present. An additional method, which is highly sensitive, consists of the direct assaying of jejunal mucosa for MAO when such specimens are obtained by oral tube biopsy techniques. The problem of evaluating stimulant and antidepressant drugs in man is magnified by 76
the fact that some drugs may have more than one mode of action. For example, tranylcypromine not only inhibits MAO, but also has secondary sympathomimetic properties which may alter the clinical response and which must he considered in the drug evaluation. A final variable is the secondary pharmacologic effect. Many of these antidepressant drugs possess antihistaminic and anticholinergic activities which may again influence the clinical result and the spectrum of symptomatic improvement and side effects which occur, depending upon which particular physiologic alterations may be associated with the depression. CURRE:>;T STATUS OF STIl\IULANTS AND ANTIDEPRESSANTS
The clinical use of various stimulants amI antidepressants must be a matter of individual choice. The first decision must be that the patient requires some type of psychopharmacologic therapy. The risk of suicide must be appropriately evaluated and concomitant therapy may be indicated using other modalities. The following general principles are worthwhile in considering the primary and secondary pharmacologic properties of the stimulants and antidepressants, and in skillfully applying their use in individual patients. 't In general, the sympathomimetic and marginal sympathomimetic drugs are ineffective in severe depressive reactions. These drugs may be highly effective in a mild depressive reaction, particularly if this condition is associated with an acute environmental problem; they may also be the treatment of choice because of their known safety and essential lack of serious toxicity, even with chronic administration. It is important to emphasize individual dose adjustment, because the problem of insomnia is usually the limiting factor in permitting higher doses. When this does not occur or when it can be controlled by administering the drug early in the day, dosage may be safely increased. For example, although methylphenidate (Ritalin'ID) may be effective in doses of 10 mg., two or three times daily, in some patients, others may require as much as 40 to 60 mg., three or four times daily. Instead of trying to use all six of the drugs Volume IV
PSYCHOPHARMACOLOGY-STIMULANTS AND ANTIDEPRESSANTS-NODINE
listed in the sympathomimetic and marginal sympathomimetic group on Table II, it is better for each physician to learn more about one or two drugs and to use these skillfully, with correct dose adjustments, depending upon the severity of each patient's symptoms and the particular side effects which may be troublesome to that patient. The clinically available monoamine oxidase inhibitors include three hydrazine derivatives and tranylcypromine. Definite pharmacologic differences may be observed between the hydrazines and tranylcypromine, in that tranylcypromine possesses certain properties which make it resemble the sympathomimetic and marginal sympathomimetic drugs. These properties include the relatively prompt onset of action, a stimulant effect with occasional hypertensive type of reaction, and hypertensive headaches. Controlled studies of its antidepressant action have not permitted an exact comparison 0 f its effectiveness to that of the hydrazines. Isocarboxazid, nialamide and phenelzine have been used much more widely in clinical practice than has tranylcypromine, and their effectiveness in many cases of more severe depression have been well substantiated. On the other hand, with all three of the hydrazine type of MAO inhibitors, hepatic damage has been found in animals receiving high doses and has been reported in rare humans who may be unusually sensitive to standard therapeutic dosage. Fatal reactions have been reported in some instances. A delay in the onset of effect after the institution of treatment is common; often one to three weeks pass before a significant effect occurs. Some patients fail to respond after receiving MAO inhibitors. From the practical point of view, if one knows how to use one of the hydrazine MAO inhibitors and tranylcypromine, one can effectively judge the dosage for a particular patient and use appropriate adjustment in order to see what benefit may be derived from these potent agents. Here again, dose adjustment may be important since some patients may respond well, for example to 75 mg. of nialamide daily, whereas other patients require 300 to 400 mg. daily. Iminodibenzyl derivatives exert a more subtle action than that seen with the hydrazines or the marginal sympathomimetic March-April. 1963
agents. Onset of action is commonly delayed for two to four weeks after drug administration, and improvement occurs so gradually that the patient may fail to associate this improvement with the drug. Major differences are found between the clinical use of amitriptyline and imipramine, because amitriptyline may have more sedative or phenothiazine-like properties than does imipramine. These secondary pharmacologic effects may be important in considering a patient with depression who also suffers from intermittent or relatively continuous anxiety, since such a patient may obtain more relief with amitriptyline than with imipramine. With both drugs, excessive doses cause anticholinergic effects which may be particularly troublesome to certain patients, or which may be beneficial if the disturbance is associated with psychophysiologic alterations in which an anticholinergic drug is helpful. Thus, both the basic pharmacologic properties and secondary characteristics of these drugs may be used effectively in outlining treatment for a particular patient. Summary.-The follOWing general approach seems to be rational for the outpatient management of a psychoneurotic depressive real~ tion. If the depressive reaction is milrl, a therapeutic trial of one to two weeks, using one of the marginal sympathomimetic drugs may be undertaken; if no response occurs after two weeks, the patient may be shifted to tranylcypromine or one of the other MAO inhibitors. With a more severe depression, response to the marginal sympathomimetic drugs is not anticipated, so that initiation of therapy employing one of the hydrazine MAO inhibitors, which have been most widely studied and shown to be effective, seems warranted. The risk of toxicity is easily counterbalanced with the potential risk of suicide if such a patient is not treated, and the monoamine oxidase inhibitors are selected because the onset of action of these agents is ordinarily more rapid than with the available iminodibenzol derivatives. There is some disagreement among workers in the field regarding this sequence, since some feel the iminodibenzol derivatives may be safer and that less problems are encountered if therapy must he changed after using these deriva77
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tives. Extremely alarming reactions may occur in combining an MAO inhibitor with one of the iminodibenzol derivatives. Such combinations have resulted in sudden collapse, convulsions, hyperpyrexia, and even death. One cannot, therefore, judiciously shift from therapy with a monoamine oxidase inhibitor to an iminodibenzol derivative. If the MAO inhibitor has failed to induce an adequate clinical response within three to four weeks, it may then be warranted to stop treatment for at least two weeks and to begin using either amitriptyline or imipramine as the third line of defense. As mentioned, some authorities prefer to use one of these drugs before the MAO inhibitor, since these drugs are eliminated in a few days and MAO inhibitors may safely be started three to seven days following discontinuation of the drug. As will be discussed below, currently available agents suggest that in the future such a sequential regimen as this just outlined will need major revision when new drugs become clinical1y available. FtrrURE OUTLOOK
The future outlook in the field of stimulants and antidepressants is bright, owing to the large number of compounds which have become available in recent months for clinical screening and evaluation. Active research is going on in the basic laboratory in an effort to identify more compounds and to determine the effects of these in animals and the clinical correlations which occur. Of particular interest is the development of other derivatives in the iminodibenzol series which may have different properties from the currently available amitryptyline and imipramine. Current studies would suggest that desipramine has human pharmacologic effects and antidepressant activity similar to that found with imipramine, but that the onset of action is much more rapid. If this is borne out by further studies, a safe and more useful clinical agent will become available. Active biochemical research into the causes of fatigue and investigation of the biochemical changes in depression are being carried out so that our pharmacologic approach in the future may have a more rational basis. In short, it is reasonable to hope that drugs 78
which ameliorate depression more promptly and which may be used with little or no risk will become available; their prompt action may minimize the ever present risk of suicide in a higher percentage of patients. Another promising approach which may permit the combination of psychopharmacologic agents and psychotherapy to attack problems which currently cannot be treated, includes the use of the various psychotogens in uncovering unconscious material. Rapid and sometimes sustained personality changes have been observed after the investigative use of various psychotogenic agents, including LSD 2 " psilocybin and others. Conditions which may be closely related to depression and which may be called "masked depression" (Le., psychophysiologic equivalents, and even chronic personality disorders such as alcoholism) may wen succumb to a biochemical attack using these more powerful agents under more precise and controlled conditions as more and more investigators become familiar with their unusual properties. In short, through the use of psychopharmacological agents, which are available in an investigative phase now, or which may become available in the next few years, physicians may be provided with therapeutic methods for attacking not only the resistant depressed patient, but many of the psychoneurotic conditions and personality disorders which have resisted attack with currently available drugs. A bright and interesting future is anticipated. A change has already been seen in the number of depressed patients admitted to state mental institutions; this is due at least in part to the effective drugs which are used promply in ambulatory depressed patients. 12 REFEREl':CES 1. Stein, L.: ~Iethods for evaluating stimulant and antidepressant drugs. In Psychosomatic Medicine, p. 297, eds. Nodine and Moyer. Philadelphia: Lee and Febiger, 1962. 2. Marrazzi, A. S.: Pharmacodynamics of sympathomimetic and marginal sympathomimetic drugs. In Psychosomatic Medicine, p. 565, eds. Nodine and Moyer. Philadelphia: Lea and Febiger, 1962. 3. Slap, J. W.: Classification of psychoneuroses. In Psychosomatic Medicine, p. 7, eds. Nodine and Moyer. Philadelphia: Lea and Febiger, 1962. 4. Johnson. D. E.: Management of depressive reactions. In Psychosomatic Medicine, p. 820, eds. Nodine and Moyer. Philadelphia: Lea and Febiger,I962.
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PSYCHOPHARMACOLOGY-STIMULANTS AND ANTIDEPRESSANTS-NODINE 5. Mapp, Y. and Nodine, J. H.: Psychopharmacology II: tranquilizers and antipsychotic drugs. Psyc1lOsom. 3:458,1962. 6. Tedeschi, D. H., Tedeschi, R. E., Fowler, P. J., Green, H., and Fellows, E. J.: Monoamine oxidase inhibition: methods of evaluation in animals. In Psychosomatic Medicine, p. 318, eds. Nodine and rvlOyer. Philadelphia: Lea and Febiger, 1962. 7. Sjoerdsma, A.: Monoamine oxidase inhibition: methods or evaluation in man. In Psychosolllatic Medicine, p. 325, eds. Nodine and ~Ioyer. Philadelphia: Lea and Febiger, 1962. 8. Pletscher, A. and Gey, K. F.: Pharmacodynamics of monoamine oxidase inhibitors of the hydrazine type. In Psychosomatic Medicine, p. 595, eds. Nodine and Moyer. Philadelphia: Lea and Fehiger, 1962.
9. Winter, C. A.: Psychotomimetic compounds: pharmacologic and behavioral effects in animals. In Psychosomatic .\tedicine, p. 329, eds. Nodine and Moyer. Philadelphia: Lea and Febiger, 1962. 10. Beck, A. T., Ward, C. H., Mendelson, M., Mock, J. and Erbough, J.: An inventory for measuring depression. Arch. Gen. Psychiat., 4:561. 1961. 11. Siegler, P. E., Bodi, T., Levy, H. A., Slap, J. W., Ducanes, A., Brecher, H. and Nodine, J. H.: Depression in medical practice. Postgrad. Med., 33:159,1963. 12. Goldman, D.: Panel discussion on Pharmacodynamics and clinical use of stimulants and antidepressants. 1. In Psychosomatic Medicine, p. 620, eds. Nodine and Moyer. Philadelphia: Lea and Febiger, 1962.
It is high time . . . that in psychologic questions . . . serious and conscientious investigation of specific problems replace the clever contentions and profound inventions. With that which is undemonstrable, or irrefutable, we can go no further. Wl> need facts, not theories. . . . No science can do without integrative points of view and tentative assumptions; but we must never forget that they have no independent inherent value. They are merely a means to an end; their justification can be found only in the fact that they lead to definite questions and thereby to new investigations. . . . \Ve now ought to proceed to answer them not at the green table (or arm chair) but in the laboratory; not with hrilliant suggestions but with observation and measurement. KRAEPELlN: Introduction to Psychologische Arbeiten (1896). Quoted by JOSEPH ZUUIN, Ph.D., in Dewession by Hoeh and Zubin, p. 141, Grum' and Stratton, New York, 1954.
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