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Research subject recruitment for gerontological studies of pharmacological agents
Neurobiologyof Aging, Vol. 3, pp. 77-79, 1982. Printed in the U.S.A.
BRIEF COMMUNICATION
Research Subject Recruitment for Gerontological Studies of Pharmacological Agents MICHAEL
I. L E V Y , R I C H A R D C. M O H S , W l L M A AND KENNETH L. DAVIS
G. ROSEN
Department o f Psychiatry, Veterans Administration Medical Center, Bronx, N Y 10468 and Department o f Psychiatry, Mount Sinai School o f Medicine, N e w York, N Y 10029 R e c e i v e d 21 D e c e m b e r 1981 LEVY, M. I., R. C. MOHS, W. G. ROSEN AND K. L. DAVIS. Research subject recruitmentfor gerontological studies of pharmacological agents. NEUROBIOL. AGING 3(1) 77-79, 1982.wEIderly subjects were recruited for a study of the effect of intravenous physostigmine on the memory disturbance of Alzheimer's Disease. Approximately one out of every twelve people screened was suitable for the study. Subjects were ruled out either because they did not meet research diagnostic criteria for AD, because they could not cooperate with the studies or because of medical contraindications. The data indicate that large numbers of potential subjects are required to select relatively small groups for pharmacological studies. The implications of some of these developments for future research are discussed. Aging
Research
Alzheimer's disease
Physostigmine
AS the demography of our country shifts toward a larger percentage of elderly, the clinical research on diseases affecting the elderly is becoming increasingly urgent [4,10]. A distinguishing feature of geriatric practice is the treatment of patients who have a number of illnesses and are receiving several medications. In fact, the average geriatric patient has been reported to have five diseases and take 13 different drugs [2]. Thus, research with elderly subjects is made particularly difficult because the number o f potential subjects for any proposed pharmacological or biological investigation is greatly reduced by diseases or treatments contraindicating participation in studies. In this paper we review our experience in recruiting patients for a study o f cholinomimetic agents in Alzheimer's Disease (AD). The method by which subjects are selected for these studies, the outcome of that selection process and implications for pharmacological research studies involving elderly subjects are presented.
Physical illness
were initially screened on the telephone by a research assistant who obtained information regarding past history, current medical problems and medications. Questions asked concerned specific details of the subject's memory complaint and major psychiatric, neurologic and medical illnesses, particularly hypertension. Those patients who passed the initial telephone screening were interviewed to ascertain that the memory disorder was of insidious onset and that they met inclusion criteria on either the Memory Information Test (MIT) or Dementia Rating Scale (DRS). Scores on both scales have been demonstrated to correlate with neuropathological changes in the brains of people with AD [l]. The acceptance criteria used for this study (MIT score less than 10, DRS score greater than 4) have been shown to separate all normal elderly and over 90 percent of affectively ill elderly from a cohort of patients with senile dementia [7]. A medical history, physical examination, and psychiatric evaluation were then performed. Electrocardiogram, CT scan, complete blood count, SMA-18, thyroid function tests, Bl2 and folate levels, VDRL, and arterial blood gas determinations were part o f the medical evaluation. Each subject selected had to be cleared for studies by an internist who gave particular attention to contraindications for the use of cholinomimetic agents.
METHOD Advertisements appeared in newspapers throughout the N e w York metropolitan area. Public service announcements were broadcast regularly on a major radio station. In addition the staff gave a series of lectures in a large number of senior centers throughout the metropolitan area. The objective was to recruit memory impaired people who are at least 55 years old for participation in a drug study. Respondents
RESULTS One hundred and six potential subjects were not ruled out
1Send reprint requests to Kenneth L. Davis, Department of Psychiatry, V.A. Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468.
77
78
LEVY, MOHS, ROSEN AND I)AV~S
by the initial telephone interview, and were seen on the research ward for complete evaluation. This represented approximately 50% o f all patients who initially responded. The most common contraindications to participation in the study encountered on the telephone were cardiac disease or hypertension. Less frequently reported were lack o f spare time, concerns about side effects, or another major psychiatric illness, usually depression. Nineteen of the 106 potential subjects met all diagnostic and medical entry criteria and eventually completed studies. Eighty seven potential subjects were excluded for the reasons listed in Table 1. The most common exclusion criterion was that the subject did not have memory problems severe enough to meet the MIT or DRS cut-off scores. The second most frequently encountered exclusion criterion was quite the opposite of the first, namely that the patient was so agitated, uncooperative and demented that participation in a study was impossible. Thereafter medical problems resulted in the exclusion of other potential subjects.
TABLE 1 REASONS FOR EXCLUDING SUBJECTS FROM DRUG STUDIES
Problem
Number of Subjects
No apparent memory disorder Uncooperative/untestable Cardiac/EKG abnormality Lost to follow-up Hypertension Respiratory disorder Other psychiatry disorder Neurological disorder Miscellaneous medical disorders Died before study began
25 1!:.~ ~~ • ..; ~ ~ ~'
Total
87
:
J
Pe~-cent meeting MIT:DRS cr)leria ', 89 ~9 2g 50 ~C 67 50 40 100
DISCUSSION
Elderly men and women with the complaint of a memory disorder were recruited from the community for a research drug trial. Approximately one out of every 12 who made an initial inquiry and one out of every 6 who passed the initial telephone screening ultimately took part in the trial. These yields are lower than the roughly one out of two rate of participation for other psychiatric drug studies at this center. Some of the reasons for this seem to be a function of the drugs under investigation, and the disease being studied. This study involved the administration of a cholinomimetic drug, physostigmine [3]. Because of the widespread distribution of cholinergic innervation to vital organs, cholinergic compounds can have profound and serious side-effects. Thus subjects with concurrent minor medical problems were often ruled out because of the theoretical potential o f altered cholinergic activity to exacerbate these problems. However, it should be noted that some o f these subjects might have been included in studies o f drugs with less potent potential adverse effects, such as lecithin or piracetam. The largest number was o f subjects with E K G abnormalities, usually a conduction defect or evidence of ischemic disease. The principal cardiac effect of cholinergic drugs is bradycardia [9]. Some patients with ischemic disease may not tolerate the decreased perfusion that can accompany a bradycardia, while a conduction defect may be exacerbated by a cholinergic drug. However, given the critical role cholinergic activity plays in AD, it is likely that future investigations Will also involve the administration of drugs that affect cholinergic activity. Whether the risk and benefit analysis of cholinomimetic drug administration to patients with a severe and largely untreatable condition such as AD and some cardiac disease is still favorable will be a question that may need to be addressed by gerontologists, as it has been by cancer chemotherapists who also must deal with potentially toxic drugs. AD is a disease that is conclusively diagnosed only at autopsy. The only instruments that have been found to correlate with this histopathological diagnosis are the M1T and DRS and similarly constructed rating scales [1]. Any pharmacological study of AD requires that drug be administered to a relatively homogenous population of patients with AD. Thus it is necessary to rely on screening devices like the MIT and DRS, combined with a careful examination to rule out
other causes of dementia. In practice this approach defines a group with moderate to severe dementia, ruling out the mild dementias that so often prove not to be AD [5], Unfortunately those patients with severe dementias are often unable to cooperate with the procedures designed to test efficacy. Hence the sample size is further reduced. These factors are apparent in the number of subjects excluded as uncooperative, and the group judged to have no memory problem• Actually, among the latter group of 25 people it was our impression that several may have had early AD, but not so severe as to meet either the MIT or DRS cut off. Thus peculiarities of drug research in, AD further reduces the study population. Nearly all of the patients in the uncooperative/untestable group met the MIT or DRS criteria for Atzheimer's Disease. They were excluded because they could not comply with the medical work-up or attend to the task of formal selective recall tests for about 30 minutes. Some of them may have been suitable for studies of drugs with relatively few potential side-effects requiring medical surveillance. Perhaps half of this group might have been able to participate in studies in which evaluation was done by observation and global rating rather than formal cognitive testing. However, the potential for rater bias would seem to be greater when relatively objectified testing procedures are not used. The implications of this experience are disquieting. Essentially, to conduct a study with a drug that appreciably enhances cholinergic activity or other drugs with more than minimal potential side effects an investigator needs to project that for every patient who will enter a study 10--12 must be initially available, and 5-6 must undergo a detailed screening. This reality both increases the time required to conduct pharmacological studies among the elderly, and decreases the sample size likely to be obtained. Small subject group studies with marginal statistical power become inevitable, so that a few incorrectly diagnosed subjects may obscure a potential finding [6,8]. Although not without pitfalls a partial solution is to use patients as their own controls in clinical studies. Assigning each patient to both experimental and control conditions (in randomized sequence) rather than
RESEARCH SUBJECT R E C R U I T M E N T
79
using separate groups requires fewer patients and avoids the problem of intergroup differences. However broader concerns need to be raised. At what point should patients with AD and mild contraindications to
drug treatment be included in a study? When should a population likely containing a few false positive diagnoses of AD be studied? Clinical investigators will inevitably face these issues.
REFERENCES 1. Blessed, G., B. E. Tomlinson and M. Roth. The association between quantitative measures of dementia and senile change in the cerebral gray matter of elderly subjects. Br. J. Psychiat. 114: 797--811, 1968. 2. Butler, R. N. Clinical needs assessment studies can benefit research on aging. Hospitals 55: 94-98, 1981. 3. Davis, K. L., R. C. Mohs, B. M. Davis, T. B. Horvath, J. R. Tinklenberg, G. S. Rosenberg and M. I. Levy. Human memory and the effects of physostigmine and choline chloride. Psychopharmac. Bull. 16: 27-28, 1980. 4. Kane, R., D. Solomon, J. Beck, E. Keeler and R. Kane. The future need for geriatric manpower in the United States. New Engl. J. Med. 302: 1327-1332, 1980. 5. Kay, D. W. K. The epidemiology and identification of brain deficit in the elderly. In: Cognitive and Emotional Disturbance in the Elderly. edited by C. Eisdorfer and R. O. Friedel. Chicago: Year Book Medical Publishers. 1977, pp. 11-26.
6. Levenson, R. L. Statistical power analysis: Implications for researchers, planners, and practitioners in gerontology. Gerontologist 209: 494-498, 1980. 7. Roth, M. and B. Hopkins. Psychological test performance in patients over sixty. I. Senile psychosis and the affective disorders of old age. J. ment. Sci. 99: 439-450, 1953. 8. Rothpearl, A. B., R. C. Mohs and K. L. Davis. Statistical power in biological psychiatry. Psychiat. Res. 5: 257--266, 1981. 9. Taylor, P. Antilcholinesterase drugs. In: The Pharmacological Basis of Therapeutics, edited by A. G. Gilman, L. S. Goodman and A. Gilman. New York: Macmillan, 1980. 10. Tower, D. B. Alzheimer's disease--senile dementia and related disorders: Neurobiological status. In: AIzheimer's Disease: Senile Dementia and Related Disorders, edited by R. Katzman, R. D. Terry and K. L. Bick. New York: Raven Press, 1978, pp. I--4.
BRIEF COMMUNICATION
Research Subject Recruitment for Gerontological Studies of Pharmacological Agents MICHAEL
I. L E V Y , R I C H A R D C. M O H S , W l L M A AND KENNETH L. DAVIS
G. ROSEN
Department o f Psychiatry, Veterans Administration Medical Center, Bronx, N Y 10468 and Department o f Psychiatry, Mount Sinai School o f Medicine, N e w York, N Y 10029 R e c e i v e d 21 D e c e m b e r 1981 LEVY, M. I., R. C. MOHS, W. G. ROSEN AND K. L. DAVIS. Research subject recruitmentfor gerontological studies of pharmacological agents. NEUROBIOL. AGING 3(1) 77-79, 1982.wEIderly subjects were recruited for a study of the effect of intravenous physostigmine on the memory disturbance of Alzheimer's Disease. Approximately one out of every twelve people screened was suitable for the study. Subjects were ruled out either because they did not meet research diagnostic criteria for AD, because they could not cooperate with the studies or because of medical contraindications. The data indicate that large numbers of potential subjects are required to select relatively small groups for pharmacological studies. The implications of some of these developments for future research are discussed. Aging
Research
Alzheimer's disease
Physostigmine
AS the demography of our country shifts toward a larger percentage of elderly, the clinical research on diseases affecting the elderly is becoming increasingly urgent [4,10]. A distinguishing feature of geriatric practice is the treatment of patients who have a number of illnesses and are receiving several medications. In fact, the average geriatric patient has been reported to have five diseases and take 13 different drugs [2]. Thus, research with elderly subjects is made particularly difficult because the number o f potential subjects for any proposed pharmacological or biological investigation is greatly reduced by diseases or treatments contraindicating participation in studies. In this paper we review our experience in recruiting patients for a study o f cholinomimetic agents in Alzheimer's Disease (AD). The method by which subjects are selected for these studies, the outcome of that selection process and implications for pharmacological research studies involving elderly subjects are presented.
Physical illness
were initially screened on the telephone by a research assistant who obtained information regarding past history, current medical problems and medications. Questions asked concerned specific details of the subject's memory complaint and major psychiatric, neurologic and medical illnesses, particularly hypertension. Those patients who passed the initial telephone screening were interviewed to ascertain that the memory disorder was of insidious onset and that they met inclusion criteria on either the Memory Information Test (MIT) or Dementia Rating Scale (DRS). Scores on both scales have been demonstrated to correlate with neuropathological changes in the brains of people with AD [l]. The acceptance criteria used for this study (MIT score less than 10, DRS score greater than 4) have been shown to separate all normal elderly and over 90 percent of affectively ill elderly from a cohort of patients with senile dementia [7]. A medical history, physical examination, and psychiatric evaluation were then performed. Electrocardiogram, CT scan, complete blood count, SMA-18, thyroid function tests, Bl2 and folate levels, VDRL, and arterial blood gas determinations were part o f the medical evaluation. Each subject selected had to be cleared for studies by an internist who gave particular attention to contraindications for the use of cholinomimetic agents.
METHOD Advertisements appeared in newspapers throughout the N e w York metropolitan area. Public service announcements were broadcast regularly on a major radio station. In addition the staff gave a series of lectures in a large number of senior centers throughout the metropolitan area. The objective was to recruit memory impaired people who are at least 55 years old for participation in a drug study. Respondents
RESULTS One hundred and six potential subjects were not ruled out
1Send reprint requests to Kenneth L. Davis, Department of Psychiatry, V.A. Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468.
77
78
LEVY, MOHS, ROSEN AND I)AV~S
by the initial telephone interview, and were seen on the research ward for complete evaluation. This represented approximately 50% o f all patients who initially responded. The most common contraindications to participation in the study encountered on the telephone were cardiac disease or hypertension. Less frequently reported were lack o f spare time, concerns about side effects, or another major psychiatric illness, usually depression. Nineteen of the 106 potential subjects met all diagnostic and medical entry criteria and eventually completed studies. Eighty seven potential subjects were excluded for the reasons listed in Table 1. The most common exclusion criterion was that the subject did not have memory problems severe enough to meet the MIT or DRS cut-off scores. The second most frequently encountered exclusion criterion was quite the opposite of the first, namely that the patient was so agitated, uncooperative and demented that participation in a study was impossible. Thereafter medical problems resulted in the exclusion of other potential subjects.
TABLE 1 REASONS FOR EXCLUDING SUBJECTS FROM DRUG STUDIES
Problem
Number of Subjects
No apparent memory disorder Uncooperative/untestable Cardiac/EKG abnormality Lost to follow-up Hypertension Respiratory disorder Other psychiatry disorder Neurological disorder Miscellaneous medical disorders Died before study began
25 1!:.~ ~~ • ..; ~ ~ ~'
Total
87
:
J
Pe~-cent meeting MIT:DRS cr)leria ', 89 ~9 2g 50 ~C 67 50 40 100
DISCUSSION
Elderly men and women with the complaint of a memory disorder were recruited from the community for a research drug trial. Approximately one out of every 12 who made an initial inquiry and one out of every 6 who passed the initial telephone screening ultimately took part in the trial. These yields are lower than the roughly one out of two rate of participation for other psychiatric drug studies at this center. Some of the reasons for this seem to be a function of the drugs under investigation, and the disease being studied. This study involved the administration of a cholinomimetic drug, physostigmine [3]. Because of the widespread distribution of cholinergic innervation to vital organs, cholinergic compounds can have profound and serious side-effects. Thus subjects with concurrent minor medical problems were often ruled out because of the theoretical potential o f altered cholinergic activity to exacerbate these problems. However, it should be noted that some o f these subjects might have been included in studies o f drugs with less potent potential adverse effects, such as lecithin or piracetam. The largest number was o f subjects with E K G abnormalities, usually a conduction defect or evidence of ischemic disease. The principal cardiac effect of cholinergic drugs is bradycardia [9]. Some patients with ischemic disease may not tolerate the decreased perfusion that can accompany a bradycardia, while a conduction defect may be exacerbated by a cholinergic drug. However, given the critical role cholinergic activity plays in AD, it is likely that future investigations Will also involve the administration of drugs that affect cholinergic activity. Whether the risk and benefit analysis of cholinomimetic drug administration to patients with a severe and largely untreatable condition such as AD and some cardiac disease is still favorable will be a question that may need to be addressed by gerontologists, as it has been by cancer chemotherapists who also must deal with potentially toxic drugs. AD is a disease that is conclusively diagnosed only at autopsy. The only instruments that have been found to correlate with this histopathological diagnosis are the M1T and DRS and similarly constructed rating scales [1]. Any pharmacological study of AD requires that drug be administered to a relatively homogenous population of patients with AD. Thus it is necessary to rely on screening devices like the MIT and DRS, combined with a careful examination to rule out
other causes of dementia. In practice this approach defines a group with moderate to severe dementia, ruling out the mild dementias that so often prove not to be AD [5], Unfortunately those patients with severe dementias are often unable to cooperate with the procedures designed to test efficacy. Hence the sample size is further reduced. These factors are apparent in the number of subjects excluded as uncooperative, and the group judged to have no memory problem• Actually, among the latter group of 25 people it was our impression that several may have had early AD, but not so severe as to meet either the MIT or DRS cut off. Thus peculiarities of drug research in, AD further reduces the study population. Nearly all of the patients in the uncooperative/untestable group met the MIT or DRS criteria for Atzheimer's Disease. They were excluded because they could not comply with the medical work-up or attend to the task of formal selective recall tests for about 30 minutes. Some of them may have been suitable for studies of drugs with relatively few potential side-effects requiring medical surveillance. Perhaps half of this group might have been able to participate in studies in which evaluation was done by observation and global rating rather than formal cognitive testing. However, the potential for rater bias would seem to be greater when relatively objectified testing procedures are not used. The implications of this experience are disquieting. Essentially, to conduct a study with a drug that appreciably enhances cholinergic activity or other drugs with more than minimal potential side effects an investigator needs to project that for every patient who will enter a study 10--12 must be initially available, and 5-6 must undergo a detailed screening. This reality both increases the time required to conduct pharmacological studies among the elderly, and decreases the sample size likely to be obtained. Small subject group studies with marginal statistical power become inevitable, so that a few incorrectly diagnosed subjects may obscure a potential finding [6,8]. Although not without pitfalls a partial solution is to use patients as their own controls in clinical studies. Assigning each patient to both experimental and control conditions (in randomized sequence) rather than
RESEARCH SUBJECT R E C R U I T M E N T
79
using separate groups requires fewer patients and avoids the problem of intergroup differences. However broader concerns need to be raised. At what point should patients with AD and mild contraindications to
drug treatment be included in a study? When should a population likely containing a few false positive diagnoses of AD be studied? Clinical investigators will inevitably face these issues.
REFERENCES 1. Blessed, G., B. E. Tomlinson and M. Roth. The association between quantitative measures of dementia and senile change in the cerebral gray matter of elderly subjects. Br. J. Psychiat. 114: 797--811, 1968. 2. Butler, R. N. Clinical needs assessment studies can benefit research on aging. Hospitals 55: 94-98, 1981. 3. Davis, K. L., R. C. Mohs, B. M. Davis, T. B. Horvath, J. R. Tinklenberg, G. S. Rosenberg and M. I. Levy. Human memory and the effects of physostigmine and choline chloride. Psychopharmac. Bull. 16: 27-28, 1980. 4. Kane, R., D. Solomon, J. Beck, E. Keeler and R. Kane. The future need for geriatric manpower in the United States. New Engl. J. Med. 302: 1327-1332, 1980. 5. Kay, D. W. K. The epidemiology and identification of brain deficit in the elderly. In: Cognitive and Emotional Disturbance in the Elderly. edited by C. Eisdorfer and R. O. Friedel. Chicago: Year Book Medical Publishers. 1977, pp. 11-26.
6. Levenson, R. L. Statistical power analysis: Implications for researchers, planners, and practitioners in gerontology. Gerontologist 209: 494-498, 1980. 7. Roth, M. and B. Hopkins. Psychological test performance in patients over sixty. I. Senile psychosis and the affective disorders of old age. J. ment. Sci. 99: 439-450, 1953. 8. Rothpearl, A. B., R. C. Mohs and K. L. Davis. Statistical power in biological psychiatry. Psychiat. Res. 5: 257--266, 1981. 9. Taylor, P. Antilcholinesterase drugs. In: The Pharmacological Basis of Therapeutics, edited by A. G. Gilman, L. S. Goodman and A. Gilman. New York: Macmillan, 1980. 10. Tower, D. B. Alzheimer's disease--senile dementia and related disorders: Neurobiological status. In: AIzheimer's Disease: Senile Dementia and Related Disorders, edited by R. Katzman, R. D. Terry and K. L. Bick. New York: Raven Press, 1978, pp. I--4.