Vol. XXIII, No.4
JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Copyright © 1975 by the American Geriatrics Society
Printed in U.S.A.
Mental Decline in the Elderly: Pharmacotherapy (Ergot Alkaloids versus Papaverine) HERBERT J. ROSEN, MD*
Medical Associates, P.A., Dover, New Jersey ABSTRACf: This is the first double-blind study in outpatients to evaluate the effectiveness of dihydrogenated ergot alkaloids (DEA) (Hydergine) versus papaverine in the treatment of selected symptoms associated with mental aging. In addition, this is the first study comparing these two pharmacologic agents in relatively young geriatric patients, with a mean age in the mid-sixties. After twelve weeks of treatment, ratings of overall clinical condition and global change showed that the 26 patients given DEA improved more than twice as much as the 27 patients given papaverine. Of the 14 individual symptoms rated, 13 improved significantly more in the DEA group than in the papaverine group. These symptoms included confusion, dizziness, unsociability, depressive mood, and mental alertness. Other data confirmed the generally superior results with DEA. In view of its demonstrated beneficial clinical actions and of its notable scarcity of contraindications or side effects, DEA appears to represent a significant pharmacologic contribution to the care of elderly persons showing selected symptoms of mental and functional decline. Until fairly recently, physicians had few if any useful drugs to employ in treating or alleviating the symptoms of mental and functional decline in elderly persons. Confusion, depressed mood, dizziness, unsociability, neglect of self-care and other distressing symptoms only further impaired the patient's ability to carry on normal activities from day to day. During the past two decades, a number of physicians in Europe and America have used dihydrogenated ergot alkaloids (DEA) (Hydergine, Sandoz) in the treatment of essential hypertension or peripheral vascular disease. They found that many elderly patients became less confused, had fewer memory problems and displayed greater cheerfulness and ability in dealing with the tasks of daily living. These observations led to further study of the clinical
and physiologic effects of DEA and eventually to its investigational use by various physicians as a specific aid for alleviation of many cognitive and behavioral symptoms in the elderly. The clinical investigation reported here is the first double-blind study of DEA dealing with a typical office sampling of geriatric patients. The findings should be of practical significance to many physicians, since 97 of every 100 persons older than 65 in this country still live within the community rather than in institutions, and therefore the majority can be expected to seek outpatient or office-based medical care. MATERIALS AND METHODS
Patients Sixty private office patients, each at least 60 years old and showing clinical evidence of mental aging, took part in this 12-week doubleblind investigation. Its purpose was to compare the effects of dihydrogenated ergot alkaloids
* ACP,
FACCP, ACC, FAGS; Chief Attending, Medicine, Dover General Hospital. Address: Herbert J. Rosen, MD, Medical Associates, P.A., Doctors Building, 77 Union Street, Dover NJ 07801.
169
H. J. ROSEN
(DEA) and papaverine on the symptomatology of mental and functional decline in the elderly. Each patient manifested at least a moderate degree of 6 or more of the following 15 symptoms: Impaired mental alertness Confusion Impaired memory for recent events Impaired orientation Abnormal emotional lability Impaired self-care Depression Abnormal anxiety or fears Impaired motivation or initiative Impaired cooperation Impaired sociability Impaired locomotion Anorexia Dizziness Abnormal fatigue. All patients showed at least two characteristics of senescent mental decline, i.e., 2 or more of the first 7 symptoms listed. Comprehensive histories, physical examinations and appropriate laboratory studies were performed before and after the 12-week trial. It was ascertained also that none of the patients suffered from psychosis, marked mental deterioration, brain disease secondary to trauma or infection, cerebral neoplasm, or any other diagnosable clinical disorder which might significantly affect the study assessments. If any patient had been receiving major or minor tranquilizers, antidepressants, or vasodilators, such therapy was withdrawn at least three weeks before the study began. Patients who required occasional nighttime sedation during the study were permitted only chloral hydrate; no barbiturates were used. Thirty patients were assigned to each treatment group through the use of a random numbers table (1). Four DEA and 3 papaverine patients were subsequently dropped from the investigation for various administrative reasons. The demographic information for the 53 patients who completed the trial follows:
DEA group Papaverine group
170
Men
Women
Mean Age
Age Range
12 12
14 15
67 yrs. 66 yrs.
60-80 60-81
Vol. XXIII
The two groups were statistically comparable. More than 40 per cent of the study population was in the 60-64 age group; consequently, the mean age of the entire population was at least 10 years lower than that of patients reported in previous published trials of DEl\..
Drug therapy Because of the different methods of administration for DEA and papaverine (sublingual vs swallowing), a double-placebo blind technique was used. Each patient received either two 0.5-mg sublingual DEA tablets plus two papaverine placebo capsules three times daily (active DEA group, 3 mg of DEA per day), or two 50-mg papaverine hydrochloride capsules plus two sublingual DEA placebo tablets three times daily (active papaverine group, 300 mg of papaverine per day).
Mental evaluations The patients' emotional, behavioral and intellectual responses to each drug regimen were evaluated according to 5 different techniques: 1. An Overall Clinical Impression - the physician's total assessment of the patient's condition; scored pretrial and at Weeks 3, 6, 9 and 12 on a seven-point scale ranging from 1 (normal) through 7 (markedly abnormal). 2. A Global Change Rating - the physician's judgment of the patient's global therapeutic response during the trial; scored at Weeks 3, 6, 9 and 12 on a scale ranging from -3 (very much worse) through 0 (no change) to +3 (very much improved). 3. An Assessment of Clinical Status - the physician's rating of the severity of each of 15 specific symptoms (listed previously); scored on a seven-point scale, again ranging from 1 (normal) through 7 (markedly abnormal), and recorded pretrial, and at Weeks 3, 6, 9 and 12. 4. A Mental Status Checklist - the patient's response to 17 questions or tasks reflecting 6 areas of intellectual function (orientation, successive subtractions, general information, object identification, abstraction, and writing performance); each item scored individually at Weeks 6 and 12. 5. A rating of Additional Symptoms was at-
April 1975
MENTAL DECLrNE IN THE ELDERLY: PHARMACOTHERAPY
tempted, but too few patients manifested problems that were not covered by the original 15-item symptom list. In addition, the safety of the 2 test drugs was assessed pretrial, at intervals during the study, and at the end of the study, by appropriate physical and laboratory examinations. RESULTS The analyses of data from the various ratings yielded strikingly consistent results. Overall Clinical Impression and Global Change Rating: At the outset of the study the mean Clinical Impression rating for both treatment groups ranged from moderately to markedly abnormal (score of 5 to 6). Time-response curves, which represent the comparative changes for each group, are shown in Figure 1. These reveal that by the end of the study, the mean Clinical Impression rating decreased and the mean Global Change rating improved-in each case more than twice as much (p < 0.01) for the DEA group as for the papaverine group. Thus, in terms of their observable condition and their therapeutic response, the DEA patients achieved significantly better results after twelve weeks than the papaverine patients. Assessment of Clinical Status: By the end of twelve weeks, 13 of the 15 specific symptoms (as follows) were improved two to five times more (p < 0.01 for all 13) for the DEA patients than for the papaverine patients: im-
paired mental alertness, confusion, impaired recent memory, impaired orientation, abnormal emotional lability, depression, abnormal anxiety, impaired motivation, impaired cooperation, impaired sociability, impaired locomotion, dizziness, and abnormal fatigue. Although one symptom, anorexia, was improved somewhat more in the papaverine than in the DEA patients, this difference was not statistically significant. The last symptom, impaired self-care, was present before the trial in too few patients for valid statistical analysis, and thus was not included in the results. This was not unexpected since the patients tested in this study were outpatients as opposed to the institutionalized types of patients used in previous studies. Figure 2 shows characteristic time-response curves for confusion, impaired orientation, depressive mood, unsociability, dizziness, and anorexia. These curves are representative of the general symptomatic responses shown by patients in both groups. The first 5 curves illustrate the quantitative changes characteristic of those responding better to DEA, and the sixth illustrates the single superior symptomatic response to papaverine. Figure 3 presents numerical data on the Overall Clinical Impression and Global Change rating and on each of the 14 symptoms evaluated. Here (in what is known as a contingencytable analysis), the percentages of patients in each treatment group are depicted according to GLOBAL CHANGE-
CLINICAL IMPRESSION-
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Improved
• Significantly (P(O.Ol) Greater
Change Favoring Hydergine Patients
Fig. 1. Rating changes through time. (Hydergine vs. papaverine.)
171
Vol. XXIiI·
H. J. ROSEN
4
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-
•-
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3
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Fig. 2. Rating changes through time-Representative symptom results. (Hydergine vs.
papaverine. )
whether they improved by 3 to 6 rating levels, by 1 to 2 rating levels, did not change at all, or became worse. Again, in each symptom area the percentages favored DEA over papaverine. Mental Status Checklist: Two of the 6 categories on this Checklist (successive subtractions and abstraction) as well as the total score showed greater mean improvement for the DEA group than for the papaverine group. Changes in vital signs and laboratory determinations: These infrequent changes were minor and not of clinical or statistical significance.
172
Side effects: No side effects were detected in any of the patients in either group. DISCUSSION Until recently it had been customary to regard mental aging as largely a consequence of the progressive reduction in cerebral circulation generally associated with cerebral arteriosclerosis. Indeed, so commonly did the medical profession simply take this relationship for granted that such terms as "mental senility," "chronic cerebrovascular insufficiency," or
MENTAL DECLINE IN THE ELDERLY: PHARMACOTHERAPY
April 1975
t====1!••• •••
DID
o
~
31
ERAll CLI ICAl I PRESSIO
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"cerebral arteriosclerosis" were often used interchangeably (2). Recently, however, this hemodynamic view of geriatric brain failure has been subjected to serious question. In a number of studies during the past two decades undertaken to determine the precise relationship between the degree of impairment of cerebral blood flow and the degree of mental impairment exhibited by the patient, results were mixed. No consistent correlation between these two measures was uniformly found (3, 4), not only from study to study, but in some instances even from patient to patient within
the same study. Although many older patients proved to have both reduced cerebral circulation and reduced mental function, some showed no mental impairment despite measurably reduced blood flow in the brain, whereas others exhibited prominent degenerative mental changes despite normal cerebrovascular circulation. Over ten years ago, Heyck (5) and Geraud et al. (6), in independent investigations on brain circulation in humans, concluded that the administration of DEA caused a reduction in cerebrovascular resistance. Several years later,
173
H. J. ROSEN
Gerin (7) noted that elderly patients given DEA showed clinical improvement in a number of symptoms of brain senescence. In accord with the prevailing opinion that mental senility was due to impaired blood flow in the brain, he also concluded that DEA's beneficial effect was directly attributable to a hemodynamic action. However, a number of subsequent studies (8-13)-one by Bazo and one by this writerhave failed to support Gerin's assumption concerning the basis of this beneficial effect. Using the present study as a case in point, we observed that two essentially equivalent groups of mentally aging patients responded in markedly different degrees to DEA and to papaverine treatment. The group given DEA consistently exhibited far greater symptomatic improvement than did the group receiving papaverine. Consequently, although it may be too early for precise conclusions, it seems that sufficient clinical evidence now exists to warrant at least a working assumption that the mental changes of aging are not directly due to diminished cerebrovascular circulation alone. Although the specific mechanism of action of DEA on selected symptoms of mental and functional decline in the elderly is not known at present, recent animal investigations may offer a clue. In highly sophisticated studies with cat brains, Cerletti et al. (14) found that DEA might act to improve the intracellular metabolic status of functionally impaired neuronal cells. Such speculations from animal experimentation are both exciting and promising, but the data thus far available are still too fragmentary to warrant more than conjecture. Although a definitive understanding of exactly how DEA works its benefits may lie in the future, the efficacy of DEA in alleviating selected symptoms in elderly patients showing mental and functional decline has been demonstrated amply. Indeed, the results of this and previous trials with DEA should be a strong encouragement to many physicians who have long felt thwarted in their previous attempts to
174
Vol. XXIII
provide effective care to their patients of advanced age.
Acknowledgment The author wishes to express his appreciation for the invaluable assistance of Mrs. Valerie Mieles in the conduct of this study.
REFERENCES 1. Moses L and Oakford R: Tables of Random Permutations. Palo Alto, Calif., Stanford University Press, 1973. 2. Rosen H: Chronic cerebrovascular insufficiency in the elderly, J Med Soc New Jersey 69: 445, 1972. 3. Bower HM et al: Dementia and cerebral blood flow, Med J Australia 1: 207, 1970. 4. Wang HS et al: Neurophysiological correlates of intel1ectual function of elderly persons living in the community, Am J Psychiat 126: 1205, 1970. 5. Heyck H: The influence of initial values upon. sympatholytic effects on brain circulation in cerebral vascular disorders, Arztl Forsch 15: 243, 1961. 6. Geraud J et al: Measurement of cerebral blood flow using Krypton 85. Some physiopathological and clinical applications, Rev. Neurol. 108: 542, 1963. 7. Gerin J: Symptomatic treatment of cerebrovascular insufficiency with Hydergine, Curr Therap Res 11; 539, 1969. 8. Triboletti F and Ferri H: Hydergine for treatment of symptoms of cerebrovascular insufficiency, Curr Therap Res 11: 609, 1969. 9. Roubicek J et al: An ergot alkaloid preparation (Hydergine) in geriatric therapy, J Am Geriatrics Soc 20: 222, 1972. 10. Ditch Met al: An ergot preparation (Hydergine) in the treatment of cerebrovascular disorders in the geriatric patient: double-blind study, J Am Geriatrics Soc 19: 208, 1971. 11. Banen DM: An ergot preparation (Hydergine) for relief of symptoms of cerebrovascular insufficiency. J Am Geriatrics Soc 20: 22,1972. 12. Rao DB and Norris JR: A double-blind investigation of Hydergine in the treatment of cerebrovascular insufficiency in the elderly, Johns Hopkins Med J 130: 317,1972. 13. Bazo AJ: An ergot alkaloid preparation (Hydergine) versus papaverine in treating common complaints of the aged: double-blind study, J Am Geriatrics Soc 21: 63, 1973. 14. Cerletti A et al: Experimental cerebral insufficiency. Models for the quantification of dihydrogenated ergot effects on brain metabolism and function. Scientific Exhibit, Federation of American Societies for Experimental Biology, April 15-20,1973, Atlantic City, New Jersey.
JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Copyright © 1975 by the American Geriatrics Society
Printed in U.S.A.
Mental Decline in the Elderly: Pharmacotherapy (Ergot Alkaloids versus Papaverine) HERBERT J. ROSEN, MD*
Medical Associates, P.A., Dover, New Jersey ABSTRACf: This is the first double-blind study in outpatients to evaluate the effectiveness of dihydrogenated ergot alkaloids (DEA) (Hydergine) versus papaverine in the treatment of selected symptoms associated with mental aging. In addition, this is the first study comparing these two pharmacologic agents in relatively young geriatric patients, with a mean age in the mid-sixties. After twelve weeks of treatment, ratings of overall clinical condition and global change showed that the 26 patients given DEA improved more than twice as much as the 27 patients given papaverine. Of the 14 individual symptoms rated, 13 improved significantly more in the DEA group than in the papaverine group. These symptoms included confusion, dizziness, unsociability, depressive mood, and mental alertness. Other data confirmed the generally superior results with DEA. In view of its demonstrated beneficial clinical actions and of its notable scarcity of contraindications or side effects, DEA appears to represent a significant pharmacologic contribution to the care of elderly persons showing selected symptoms of mental and functional decline. Until fairly recently, physicians had few if any useful drugs to employ in treating or alleviating the symptoms of mental and functional decline in elderly persons. Confusion, depressed mood, dizziness, unsociability, neglect of self-care and other distressing symptoms only further impaired the patient's ability to carry on normal activities from day to day. During the past two decades, a number of physicians in Europe and America have used dihydrogenated ergot alkaloids (DEA) (Hydergine, Sandoz) in the treatment of essential hypertension or peripheral vascular disease. They found that many elderly patients became less confused, had fewer memory problems and displayed greater cheerfulness and ability in dealing with the tasks of daily living. These observations led to further study of the clinical
and physiologic effects of DEA and eventually to its investigational use by various physicians as a specific aid for alleviation of many cognitive and behavioral symptoms in the elderly. The clinical investigation reported here is the first double-blind study of DEA dealing with a typical office sampling of geriatric patients. The findings should be of practical significance to many physicians, since 97 of every 100 persons older than 65 in this country still live within the community rather than in institutions, and therefore the majority can be expected to seek outpatient or office-based medical care. MATERIALS AND METHODS
Patients Sixty private office patients, each at least 60 years old and showing clinical evidence of mental aging, took part in this 12-week doubleblind investigation. Its purpose was to compare the effects of dihydrogenated ergot alkaloids
* ACP,
FACCP, ACC, FAGS; Chief Attending, Medicine, Dover General Hospital. Address: Herbert J. Rosen, MD, Medical Associates, P.A., Doctors Building, 77 Union Street, Dover NJ 07801.
169
H. J. ROSEN
(DEA) and papaverine on the symptomatology of mental and functional decline in the elderly. Each patient manifested at least a moderate degree of 6 or more of the following 15 symptoms: Impaired mental alertness Confusion Impaired memory for recent events Impaired orientation Abnormal emotional lability Impaired self-care Depression Abnormal anxiety or fears Impaired motivation or initiative Impaired cooperation Impaired sociability Impaired locomotion Anorexia Dizziness Abnormal fatigue. All patients showed at least two characteristics of senescent mental decline, i.e., 2 or more of the first 7 symptoms listed. Comprehensive histories, physical examinations and appropriate laboratory studies were performed before and after the 12-week trial. It was ascertained also that none of the patients suffered from psychosis, marked mental deterioration, brain disease secondary to trauma or infection, cerebral neoplasm, or any other diagnosable clinical disorder which might significantly affect the study assessments. If any patient had been receiving major or minor tranquilizers, antidepressants, or vasodilators, such therapy was withdrawn at least three weeks before the study began. Patients who required occasional nighttime sedation during the study were permitted only chloral hydrate; no barbiturates were used. Thirty patients were assigned to each treatment group through the use of a random numbers table (1). Four DEA and 3 papaverine patients were subsequently dropped from the investigation for various administrative reasons. The demographic information for the 53 patients who completed the trial follows:
DEA group Papaverine group
170
Men
Women
Mean Age
Age Range
12 12
14 15
67 yrs. 66 yrs.
60-80 60-81
Vol. XXIII
The two groups were statistically comparable. More than 40 per cent of the study population was in the 60-64 age group; consequently, the mean age of the entire population was at least 10 years lower than that of patients reported in previous published trials of DEl\..
Drug therapy Because of the different methods of administration for DEA and papaverine (sublingual vs swallowing), a double-placebo blind technique was used. Each patient received either two 0.5-mg sublingual DEA tablets plus two papaverine placebo capsules three times daily (active DEA group, 3 mg of DEA per day), or two 50-mg papaverine hydrochloride capsules plus two sublingual DEA placebo tablets three times daily (active papaverine group, 300 mg of papaverine per day).
Mental evaluations The patients' emotional, behavioral and intellectual responses to each drug regimen were evaluated according to 5 different techniques: 1. An Overall Clinical Impression - the physician's total assessment of the patient's condition; scored pretrial and at Weeks 3, 6, 9 and 12 on a seven-point scale ranging from 1 (normal) through 7 (markedly abnormal). 2. A Global Change Rating - the physician's judgment of the patient's global therapeutic response during the trial; scored at Weeks 3, 6, 9 and 12 on a scale ranging from -3 (very much worse) through 0 (no change) to +3 (very much improved). 3. An Assessment of Clinical Status - the physician's rating of the severity of each of 15 specific symptoms (listed previously); scored on a seven-point scale, again ranging from 1 (normal) through 7 (markedly abnormal), and recorded pretrial, and at Weeks 3, 6, 9 and 12. 4. A Mental Status Checklist - the patient's response to 17 questions or tasks reflecting 6 areas of intellectual function (orientation, successive subtractions, general information, object identification, abstraction, and writing performance); each item scored individually at Weeks 6 and 12. 5. A rating of Additional Symptoms was at-
April 1975
MENTAL DECLrNE IN THE ELDERLY: PHARMACOTHERAPY
tempted, but too few patients manifested problems that were not covered by the original 15-item symptom list. In addition, the safety of the 2 test drugs was assessed pretrial, at intervals during the study, and at the end of the study, by appropriate physical and laboratory examinations. RESULTS The analyses of data from the various ratings yielded strikingly consistent results. Overall Clinical Impression and Global Change Rating: At the outset of the study the mean Clinical Impression rating for both treatment groups ranged from moderately to markedly abnormal (score of 5 to 6). Time-response curves, which represent the comparative changes for each group, are shown in Figure 1. These reveal that by the end of the study, the mean Clinical Impression rating decreased and the mean Global Change rating improved-in each case more than twice as much (p < 0.01) for the DEA group as for the papaverine group. Thus, in terms of their observable condition and their therapeutic response, the DEA patients achieved significantly better results after twelve weeks than the papaverine patients. Assessment of Clinical Status: By the end of twelve weeks, 13 of the 15 specific symptoms (as follows) were improved two to five times more (p < 0.01 for all 13) for the DEA patients than for the papaverine patients: im-
paired mental alertness, confusion, impaired recent memory, impaired orientation, abnormal emotional lability, depression, abnormal anxiety, impaired motivation, impaired cooperation, impaired sociability, impaired locomotion, dizziness, and abnormal fatigue. Although one symptom, anorexia, was improved somewhat more in the papaverine than in the DEA patients, this difference was not statistically significant. The last symptom, impaired self-care, was present before the trial in too few patients for valid statistical analysis, and thus was not included in the results. This was not unexpected since the patients tested in this study were outpatients as opposed to the institutionalized types of patients used in previous studies. Figure 2 shows characteristic time-response curves for confusion, impaired orientation, depressive mood, unsociability, dizziness, and anorexia. These curves are representative of the general symptomatic responses shown by patients in both groups. The first 5 curves illustrate the quantitative changes characteristic of those responding better to DEA, and the sixth illustrates the single superior symptomatic response to papaverine. Figure 3 presents numerical data on the Overall Clinical Impression and Global Change rating and on each of the 14 symptoms evaluated. Here (in what is known as a contingencytable analysis), the percentages of patients in each treatment group are depicted according to GLOBAL CHANGE-
CLINICAL IMPRESSION-
3
Cl
4
/.-----
/..........
z
i~ ~
5
~
•
-. .. _--.
~
a: +2
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_ •-
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9
6
12
WEEK
WEEK
5 = Moderately Abnormal
0= No Change
2 = Much Improved
7 = Markedly Abnormal
1 = Slightly Improved
3= Very Much
Hydergine Patients Papeverlne Patients
Improved
• Significantly (P(O.Ol) Greater
Change Favoring Hydergine Patients
Fig. 1. Rating changes through time. (Hydergine vs. papaverine.)
171
Vol. XXIiI·
H. J. ROSEN
4
z
i= 0( a: 5
6
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Hydergine Patients
-
•-
• - Papaverine Patients
3
6 WEEK
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12
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Fig. 2. Rating changes through time-Representative symptom results. (Hydergine vs.
papaverine. )
whether they improved by 3 to 6 rating levels, by 1 to 2 rating levels, did not change at all, or became worse. Again, in each symptom area the percentages favored DEA over papaverine. Mental Status Checklist: Two of the 6 categories on this Checklist (successive subtractions and abstraction) as well as the total score showed greater mean improvement for the DEA group than for the papaverine group. Changes in vital signs and laboratory determinations: These infrequent changes were minor and not of clinical or statistical significance.
172
Side effects: No side effects were detected in any of the patients in either group. DISCUSSION Until recently it had been customary to regard mental aging as largely a consequence of the progressive reduction in cerebral circulation generally associated with cerebral arteriosclerosis. Indeed, so commonly did the medical profession simply take this relationship for granted that such terms as "mental senility," "chronic cerebrovascular insufficiency," or
MENTAL DECLINE IN THE ELDERLY: PHARMACOTHERAPY
April 1975
t====1!••• •••
DID
o
~
31
ERAll CLI ICAl I PRESSIO
••••••
rapll~
DEGREE OF CHA GE IGlOBAl) ASSE
;!j
HYDERGI E' PAPAVERI E H"
P
E T O F CLINICAL STA TUS H"
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"cerebral arteriosclerosis" were often used interchangeably (2). Recently, however, this hemodynamic view of geriatric brain failure has been subjected to serious question. In a number of studies during the past two decades undertaken to determine the precise relationship between the degree of impairment of cerebral blood flow and the degree of mental impairment exhibited by the patient, results were mixed. No consistent correlation between these two measures was uniformly found (3, 4), not only from study to study, but in some instances even from patient to patient within
the same study. Although many older patients proved to have both reduced cerebral circulation and reduced mental function, some showed no mental impairment despite measurably reduced blood flow in the brain, whereas others exhibited prominent degenerative mental changes despite normal cerebrovascular circulation. Over ten years ago, Heyck (5) and Geraud et al. (6), in independent investigations on brain circulation in humans, concluded that the administration of DEA caused a reduction in cerebrovascular resistance. Several years later,
173
H. J. ROSEN
Gerin (7) noted that elderly patients given DEA showed clinical improvement in a number of symptoms of brain senescence. In accord with the prevailing opinion that mental senility was due to impaired blood flow in the brain, he also concluded that DEA's beneficial effect was directly attributable to a hemodynamic action. However, a number of subsequent studies (8-13)-one by Bazo and one by this writerhave failed to support Gerin's assumption concerning the basis of this beneficial effect. Using the present study as a case in point, we observed that two essentially equivalent groups of mentally aging patients responded in markedly different degrees to DEA and to papaverine treatment. The group given DEA consistently exhibited far greater symptomatic improvement than did the group receiving papaverine. Consequently, although it may be too early for precise conclusions, it seems that sufficient clinical evidence now exists to warrant at least a working assumption that the mental changes of aging are not directly due to diminished cerebrovascular circulation alone. Although the specific mechanism of action of DEA on selected symptoms of mental and functional decline in the elderly is not known at present, recent animal investigations may offer a clue. In highly sophisticated studies with cat brains, Cerletti et al. (14) found that DEA might act to improve the intracellular metabolic status of functionally impaired neuronal cells. Such speculations from animal experimentation are both exciting and promising, but the data thus far available are still too fragmentary to warrant more than conjecture. Although a definitive understanding of exactly how DEA works its benefits may lie in the future, the efficacy of DEA in alleviating selected symptoms in elderly patients showing mental and functional decline has been demonstrated amply. Indeed, the results of this and previous trials with DEA should be a strong encouragement to many physicians who have long felt thwarted in their previous attempts to
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Vol. XXIII
provide effective care to their patients of advanced age.
Acknowledgment The author wishes to express his appreciation for the invaluable assistance of Mrs. Valerie Mieles in the conduct of this study.
REFERENCES 1. Moses L and Oakford R: Tables of Random Permutations. Palo Alto, Calif., Stanford University Press, 1973. 2. Rosen H: Chronic cerebrovascular insufficiency in the elderly, J Med Soc New Jersey 69: 445, 1972. 3. Bower HM et al: Dementia and cerebral blood flow, Med J Australia 1: 207, 1970. 4. Wang HS et al: Neurophysiological correlates of intel1ectual function of elderly persons living in the community, Am J Psychiat 126: 1205, 1970. 5. Heyck H: The influence of initial values upon. sympatholytic effects on brain circulation in cerebral vascular disorders, Arztl Forsch 15: 243, 1961. 6. Geraud J et al: Measurement of cerebral blood flow using Krypton 85. Some physiopathological and clinical applications, Rev. Neurol. 108: 542, 1963. 7. Gerin J: Symptomatic treatment of cerebrovascular insufficiency with Hydergine, Curr Therap Res 11; 539, 1969. 8. Triboletti F and Ferri H: Hydergine for treatment of symptoms of cerebrovascular insufficiency, Curr Therap Res 11: 609, 1969. 9. Roubicek J et al: An ergot alkaloid preparation (Hydergine) in geriatric therapy, J Am Geriatrics Soc 20: 222, 1972. 10. Ditch Met al: An ergot preparation (Hydergine) in the treatment of cerebrovascular disorders in the geriatric patient: double-blind study, J Am Geriatrics Soc 19: 208, 1971. 11. Banen DM: An ergot preparation (Hydergine) for relief of symptoms of cerebrovascular insufficiency. J Am Geriatrics Soc 20: 22,1972. 12. Rao DB and Norris JR: A double-blind investigation of Hydergine in the treatment of cerebrovascular insufficiency in the elderly, Johns Hopkins Med J 130: 317,1972. 13. Bazo AJ: An ergot alkaloid preparation (Hydergine) versus papaverine in treating common complaints of the aged: double-blind study, J Am Geriatrics Soc 21: 63, 1973. 14. Cerletti A et al: Experimental cerebral insufficiency. Models for the quantification of dihydrogenated ergot effects on brain metabolism and function. Scientific Exhibit, Federation of American Societies for Experimental Biology, April 15-20,1973, Atlantic City, New Jersey.
