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Chronic Exposure to Anticholinergic Medications Adversely Affects the Course of Alzheimer Disease
BRIEF REPORTS Chronic Exposure to Anticholinergic Medications Adversely Affects the Course of Alzheimer Disease Ching-ju Lu, B.A. Larry E. Tune, M.D. Objective: Authors examined the effect of chronic exposure to anticholinergics in a cohort of Alzheimer disease (AD) patients. Methods: All patients were examined annually with standard neuropsychologic tests and received the cholinesterase inhibitor donepezil hydrochloride at a dose of 10 mg/day. The study population (N⳱69) was divided into two groups: those receiving one or more concomitant medications with significant anticholinergic properties (N⳱16) and those receiving no concomitant medications with anticholinergic properties (N⳱53). Results: At 2 years, MMSE scores were significantly worse for patients receiving anticholinergic medications than for those not on anticholinergics. Conclusion: Although very preliminary, these data suggest that concomitant therapy with anticholinergics may be associated with significant deleterious effects on acetylcholinesterase therapy, or, more speculatively, that chronic exposure to anticholinergics may have adverse effects on the clinical course of AD. (Am J Geriatr Psychiatry 2003; 11:458–461)
M
edications with significant anticholinergic properties can cause a variety of peripheral and central side effects, including sedation, confusion, hallucinations, delirium, and cognitive impairment.1 The most successful treatment for AD to date is with cholinesterase inhibitors, such as donepezil, rivastigmine, or galantamine, which increase the level
of acetylcholine available by preventing its synaptic metabolism.2 But the addition of medications with anticholinergic properties may diminish any potential benefits from cholinesterase inhibitors and possibly exacerbate the cognitive decline in AD patients. Sunderland et al.3,4 found that patients with AD are more sensitive than age-matched control subjects to the acute effect of anticholinergic medications, specifically scopolamine. AD patients showed more profound impairments at lower doses of scopolamine than did control subjects. Although these studies showed that the cognitive and behavioral effects of acute administration of scopolamine are reversible, the effects of long-term use of anticholinergic medications were not examined. Nishiyama et al.5 examined the effects of anticholinergic medications on short-term memory, longterm memory, and intelligence in Parkinson disease (PD) patients. They found a strong relationship between long-term exposure to anticholinergic medications and cognitive deficits, with older PD patients being especially susceptible to these adverse cognitive effects. In the PD population, the cognitive deficits are reversible, but recur acutely with the reintroduction of anticholinergic medications. To date, no research has specifically examined the long-term effects of anticholinergics in patients with AD. The objective of this preliminary study is look at the possible effects of chronic exposure to anticholinergic medications on AD progression. We hypothesized that decline in cognitive status, as reflected by the Mini-Mental State Exam (MMSE) scores, would differ in individuals exposed to anticholinergic medications as compared with individuals not exposed to these medications.
METHODS This was a retrospective study in which participants were identified through the Emory University Alzheimer’s Disease Center (ADC) database. All participants were diagnosed with AD according to NINCDS-
Received October 29, 2002; revised March 20, 2003; accepted April 4, 2003. From the Department of Psychiatry at Wesley Woods Geriatric Teaching and Research Hospital, Emory University School of Medicine, Atlanta, Georgia. Address correspondence to Dr. Tune, Department of Psychiatry, Wesley Woods Geriatric Teaching and Research Hospital, 1841 Clifton Rd. NE, Emory University School of Medicine, Atlanta, GA 303295102. e-mail: [email protected] Copyright 䉷2003 American Association for Geriatric Psychiatry
458
Am J Geriatr Psychiatry 11:4, July-August 2003
Lu and Tune ADRDA criteria after a diagnostic consensus conference with two research neurologists. Patients are then followed annually with standard neuropsychological tests, including the Dementia Rating Scale (DRS) and MMSE. There were no significant differences between the individuals receiving no anticholinergic medications and those receiving one or more anticholinergic medications with regard to age (76.4 years; standard deviation [SD]: 9.1; and 77.3 years [9.1], respectively); gender (27 men, 26 women, and 6 men, 10 women, respectively); education level (14.1 years [4.0] and 13.4 years [3.6], respectively); duration of illness (3.8 years [2.3] and 4.0 years [1.9], respectively); family history of AD (0.8 family members [0.9] and 1.3 family members [1.7], respectively); baseline DRS scores (118.8 [13.5] and 113.2 [14.2], respectively); and baseline MMSE scores (22.6 [5.5] and 20.6 [4.0], respectively). All participants received the cholinesterase inhibitor donepezil hydrochloride, at a dose of 10 mg/day for the duration of the study period. The study population (N⳱69) was divided into groups: those receiving one or more continuous, concomitant medications with significant anticholinergic effects (N⳱16) and those receiving no concomitant medications with anticholinergic effects (N⳱53). Because of the limited sample size, those individuals receiving anticholinergic medications were not further differentiated by the number of these medications; and, because this was a highly selected group, the overall use of anticholinergic medications was low. Also, because this was a cohort of patients followed as part of a descriptive study, no interventions were made regarding TABLE 1.
lowering anticholinergics. Anticholinergic medications were identified from previously published lists, on the basis of antimuscarinic activity in a radioreceptor assay6 (see Table 1). The primary measure in this study is the MMSE scale.7 The MMSE scale is used to determine the severity of the patient’s cognitive impairment by assessing orientation, registration, attention, calculation, recall, and praxis. Possible scores range from 0 to 30, with lower scores signifying greater cognitive impairment. MMSE scores were collected at the baseline visit into the ADC program and at the subsequent two follow-up visits. Descriptive statistics of mean and standard deviations were calculated for mean MMSE scores; t-tests for equality of means of independent samples were used to examine differences in MMSE scores between the two anticholinergic medication groups.
RESULTS There was no significant difference between the baseline MMSE scores for the two groups (t-test for equality of means: t[67]⳱1.35; p⳱0.182; see Figure 1). At 1 year after baseline, change in MMSE scores failed to reach significance when comparing patients receiving one or more anticholinergic medications and those not receiving anticholinergic medications (t-test for equality of means: t[67]⳱1.821; p⳱0.073). At 2 years after baseline, patients receiving one or more anticholinergic medications demonstrated greater decline in
Medications with anticholinergic effects (adapted from Tune and Egeli6)
Alprazolam Amantadine Amitriptyline Ampicillin Atropine Azathioprine Captopril Cefamandole Cefoxitin Chlorazepate Chlordiazepoxide Chlorthalidone Cimetidine Clindamycin Codeine Corticosterone Cycloserine Cyclosporin Desipramine
Am J Geriatr Psychiatry 11:4, July-August 2003
Dexamethasone Diazepam Digoxin Diltiazem Diphenhydramine Dipyridamole Dyazide Flunitrazepam Flurazepam Furosemide Gentamycin Hydralazine Hydrochlorathiazide Hydrocortisone Hydroxyzine Imipramine Isosorbide Keflin Lanoxin
Methyldopa Nifedipine Oxazepam Oxybutynin chloride Oxycodone Pancuronium bromide Phenelzine Phenobarbitol Piperacillin Prednisolone Ranitidine Theophylline Thioridazine Ticrocillin Tobramycin Triamterene Valproic acid Vancomycin Warfarin
459
Anticholinergic Medications and AD MMSE scores than those receiving no anticholinergic medications (t-test for equality of means: t[34]⳱2.237; p⳱0.032; Figure 1).
FIGURE 1.
Change in MMSE scores over time
5.00
DISCUSSION Although very preliminary, our data suggest that concomitant therapy with anticholinergic medications may be associated with deleterious effects on acetylcholinesterase therapy. Burns et al.8 estimated a mean annual loss of 3.5 points on the MMSE score as the natural progression in patients with AD not receiving cholinesterase-inhibitor therapy. Our data show a significant difference in MMSE scores at 2 years. MMSE scores in the group receiving cholinesterase-inhibitor therapy and no anticholinergic medications declined 3.08 (SD: 4.15) points over 2 years, well below the expected loss of 7 points on the MMSE. By contrast, change in MMSE scores in the group receiving cholinesterase-inhibitor therapy and one or more anticholinergic medications averaged 7.00 (SD: 6.20) points over 2 years. This suggests that long-term concomitant therapy of anticholinergic medications may have a deleterious effect on cholinesterase-inhibitor treatment. This observation is supported by a recent report by Mulsant et al.9 wherein they measured serum anticholinergic activity (SAA) in 201 subjects randomly selected from an epidemiologic community study. There was a highly significant inverse association between SAA and MMSE score. More speculatively, chronic exposure to anticholinergics may have adverse effects on the progression of AD. This study is limited by its retrospective design and non-random, post hoc assignment into anticholinergic groups. Other limitations include other clinical factors that may contribute to the rate of decline, including behavioral and psychological symptoms of dementia and level of caregiver support. Suggestions for future research include larger sample size and
Change in MMSE Score
0.00 N=53 0.00
–2.25 N=53 0.00 N=16
–3.08 N=25
–4.19 N=16
–7.00 N=11
–5.00
–10.00
No anticholinergics One or more anticholinergics
–15.00 Baseline
1-year
2-year
Visit Note: MMSE: Mini-Mental State Exam. At 1 year after baseline testing, t-tests showed a trend toward significance (t[67]⳱1.821; p⳱0.073); at 2 years after baseline testing, group means were significantly different (t[34]⳱2.237; p⳱0.032).
prospective, randomized design. Small sample size was also a limitation in this analysis. We were not able to examine the effect of anticholinergic load (number of anticholinergic medications an individual was receiving) because of the small number of individuals taking more than one anticholinergic medication (N⳱3). It would also be of interest to examine the effect of anticholinergic load, as determined by serum anticholinergic assay,6 in future research. Although this study is limited by several factors, it encourages the further investigation of the potential effects of long-term exposure to anticholinergic medications on the clinical course of AD.
References 1. Feinberg M: The problems of anticholinergic adverse effects in older patients. Drugs Aging 1993; 3:335–348 2. Blusztajan JK, Berse B: The cholinergic neuronal phenotype in Alzheimer’s disease. Metab Brain Dis 2000; 15:45–64 3. Sunderland T, Tariot PN, Cohen RM, et al: Anticholinergic sen-
460
sitivity in patients with dementia of the Alzheimer’s type and agematched controls: a dose–response study. Arch Gen Psychiatry 1987; 44:418–426 4. Sunderland T, Tariot PN, Newhouse PA: Differential responsivity of mood, behavior, and cognition to cholinergic agents in elderly
Am J Geriatr Psychiatry 11:4, July-August 2003
Lu and Tune neuropsychiatric populations. Brain Res Brain Res Rev 1988; 13:371–389 5. Nishiyama K, Sugishita M, Kurisaki H, et al: Reversible memory disturbance and intelligence impairment induced by long-term anticholinergic therapy. Intern Med 1998; 37:514–518 6. Tune LE, Egeli S: Acetylcholine and delirium. Dement Geriatr Cogn Disord 1999; 10:342–344 7. Folstein MF, Folstein SE, McHugh PR: Mini-Mental State: a prac-
Am J Geriatr Psychiatry 11:4, July-August 2003
tical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189–198 8. Burns A, Jacoby R, Levy R: Progression of cognitive impairment in Alzheimer’s disease. J Am Geriatr Soc 1991; 39:39–45 9. Mulsant BH, Pollock BG, Kirshner M, et al: Serum anticholinergic activity in a community-based sample of older adults: relationship with cognitive performance. Arch Gen Psychiatry 2003; 60:198– 203
461
M
edications with significant anticholinergic properties can cause a variety of peripheral and central side effects, including sedation, confusion, hallucinations, delirium, and cognitive impairment.1 The most successful treatment for AD to date is with cholinesterase inhibitors, such as donepezil, rivastigmine, or galantamine, which increase the level
of acetylcholine available by preventing its synaptic metabolism.2 But the addition of medications with anticholinergic properties may diminish any potential benefits from cholinesterase inhibitors and possibly exacerbate the cognitive decline in AD patients. Sunderland et al.3,4 found that patients with AD are more sensitive than age-matched control subjects to the acute effect of anticholinergic medications, specifically scopolamine. AD patients showed more profound impairments at lower doses of scopolamine than did control subjects. Although these studies showed that the cognitive and behavioral effects of acute administration of scopolamine are reversible, the effects of long-term use of anticholinergic medications were not examined. Nishiyama et al.5 examined the effects of anticholinergic medications on short-term memory, longterm memory, and intelligence in Parkinson disease (PD) patients. They found a strong relationship between long-term exposure to anticholinergic medications and cognitive deficits, with older PD patients being especially susceptible to these adverse cognitive effects. In the PD population, the cognitive deficits are reversible, but recur acutely with the reintroduction of anticholinergic medications. To date, no research has specifically examined the long-term effects of anticholinergics in patients with AD. The objective of this preliminary study is look at the possible effects of chronic exposure to anticholinergic medications on AD progression. We hypothesized that decline in cognitive status, as reflected by the Mini-Mental State Exam (MMSE) scores, would differ in individuals exposed to anticholinergic medications as compared with individuals not exposed to these medications.
METHODS This was a retrospective study in which participants were identified through the Emory University Alzheimer’s Disease Center (ADC) database. All participants were diagnosed with AD according to NINCDS-
Received October 29, 2002; revised March 20, 2003; accepted April 4, 2003. From the Department of Psychiatry at Wesley Woods Geriatric Teaching and Research Hospital, Emory University School of Medicine, Atlanta, Georgia. Address correspondence to Dr. Tune, Department of Psychiatry, Wesley Woods Geriatric Teaching and Research Hospital, 1841 Clifton Rd. NE, Emory University School of Medicine, Atlanta, GA 303295102. e-mail: [email protected] Copyright 䉷2003 American Association for Geriatric Psychiatry
458
Am J Geriatr Psychiatry 11:4, July-August 2003
Lu and Tune ADRDA criteria after a diagnostic consensus conference with two research neurologists. Patients are then followed annually with standard neuropsychological tests, including the Dementia Rating Scale (DRS) and MMSE. There were no significant differences between the individuals receiving no anticholinergic medications and those receiving one or more anticholinergic medications with regard to age (76.4 years; standard deviation [SD]: 9.1; and 77.3 years [9.1], respectively); gender (27 men, 26 women, and 6 men, 10 women, respectively); education level (14.1 years [4.0] and 13.4 years [3.6], respectively); duration of illness (3.8 years [2.3] and 4.0 years [1.9], respectively); family history of AD (0.8 family members [0.9] and 1.3 family members [1.7], respectively); baseline DRS scores (118.8 [13.5] and 113.2 [14.2], respectively); and baseline MMSE scores (22.6 [5.5] and 20.6 [4.0], respectively). All participants received the cholinesterase inhibitor donepezil hydrochloride, at a dose of 10 mg/day for the duration of the study period. The study population (N⳱69) was divided into groups: those receiving one or more continuous, concomitant medications with significant anticholinergic effects (N⳱16) and those receiving no concomitant medications with anticholinergic effects (N⳱53). Because of the limited sample size, those individuals receiving anticholinergic medications were not further differentiated by the number of these medications; and, because this was a highly selected group, the overall use of anticholinergic medications was low. Also, because this was a cohort of patients followed as part of a descriptive study, no interventions were made regarding TABLE 1.
lowering anticholinergics. Anticholinergic medications were identified from previously published lists, on the basis of antimuscarinic activity in a radioreceptor assay6 (see Table 1). The primary measure in this study is the MMSE scale.7 The MMSE scale is used to determine the severity of the patient’s cognitive impairment by assessing orientation, registration, attention, calculation, recall, and praxis. Possible scores range from 0 to 30, with lower scores signifying greater cognitive impairment. MMSE scores were collected at the baseline visit into the ADC program and at the subsequent two follow-up visits. Descriptive statistics of mean and standard deviations were calculated for mean MMSE scores; t-tests for equality of means of independent samples were used to examine differences in MMSE scores between the two anticholinergic medication groups.
RESULTS There was no significant difference between the baseline MMSE scores for the two groups (t-test for equality of means: t[67]⳱1.35; p⳱0.182; see Figure 1). At 1 year after baseline, change in MMSE scores failed to reach significance when comparing patients receiving one or more anticholinergic medications and those not receiving anticholinergic medications (t-test for equality of means: t[67]⳱1.821; p⳱0.073). At 2 years after baseline, patients receiving one or more anticholinergic medications demonstrated greater decline in
Medications with anticholinergic effects (adapted from Tune and Egeli6)
Alprazolam Amantadine Amitriptyline Ampicillin Atropine Azathioprine Captopril Cefamandole Cefoxitin Chlorazepate Chlordiazepoxide Chlorthalidone Cimetidine Clindamycin Codeine Corticosterone Cycloserine Cyclosporin Desipramine
Am J Geriatr Psychiatry 11:4, July-August 2003
Dexamethasone Diazepam Digoxin Diltiazem Diphenhydramine Dipyridamole Dyazide Flunitrazepam Flurazepam Furosemide Gentamycin Hydralazine Hydrochlorathiazide Hydrocortisone Hydroxyzine Imipramine Isosorbide Keflin Lanoxin
Methyldopa Nifedipine Oxazepam Oxybutynin chloride Oxycodone Pancuronium bromide Phenelzine Phenobarbitol Piperacillin Prednisolone Ranitidine Theophylline Thioridazine Ticrocillin Tobramycin Triamterene Valproic acid Vancomycin Warfarin
459
Anticholinergic Medications and AD MMSE scores than those receiving no anticholinergic medications (t-test for equality of means: t[34]⳱2.237; p⳱0.032; Figure 1).
FIGURE 1.
Change in MMSE scores over time
5.00
DISCUSSION Although very preliminary, our data suggest that concomitant therapy with anticholinergic medications may be associated with deleterious effects on acetylcholinesterase therapy. Burns et al.8 estimated a mean annual loss of 3.5 points on the MMSE score as the natural progression in patients with AD not receiving cholinesterase-inhibitor therapy. Our data show a significant difference in MMSE scores at 2 years. MMSE scores in the group receiving cholinesterase-inhibitor therapy and no anticholinergic medications declined 3.08 (SD: 4.15) points over 2 years, well below the expected loss of 7 points on the MMSE. By contrast, change in MMSE scores in the group receiving cholinesterase-inhibitor therapy and one or more anticholinergic medications averaged 7.00 (SD: 6.20) points over 2 years. This suggests that long-term concomitant therapy of anticholinergic medications may have a deleterious effect on cholinesterase-inhibitor treatment. This observation is supported by a recent report by Mulsant et al.9 wherein they measured serum anticholinergic activity (SAA) in 201 subjects randomly selected from an epidemiologic community study. There was a highly significant inverse association between SAA and MMSE score. More speculatively, chronic exposure to anticholinergics may have adverse effects on the progression of AD. This study is limited by its retrospective design and non-random, post hoc assignment into anticholinergic groups. Other limitations include other clinical factors that may contribute to the rate of decline, including behavioral and psychological symptoms of dementia and level of caregiver support. Suggestions for future research include larger sample size and
Change in MMSE Score
0.00 N=53 0.00
–2.25 N=53 0.00 N=16
–3.08 N=25
–4.19 N=16
–7.00 N=11
–5.00
–10.00
No anticholinergics One or more anticholinergics
–15.00 Baseline
1-year
2-year
Visit Note: MMSE: Mini-Mental State Exam. At 1 year after baseline testing, t-tests showed a trend toward significance (t[67]⳱1.821; p⳱0.073); at 2 years after baseline testing, group means were significantly different (t[34]⳱2.237; p⳱0.032).
prospective, randomized design. Small sample size was also a limitation in this analysis. We were not able to examine the effect of anticholinergic load (number of anticholinergic medications an individual was receiving) because of the small number of individuals taking more than one anticholinergic medication (N⳱3). It would also be of interest to examine the effect of anticholinergic load, as determined by serum anticholinergic assay,6 in future research. Although this study is limited by several factors, it encourages the further investigation of the potential effects of long-term exposure to anticholinergic medications on the clinical course of AD.
References 1. Feinberg M: The problems of anticholinergic adverse effects in older patients. Drugs Aging 1993; 3:335–348 2. Blusztajan JK, Berse B: The cholinergic neuronal phenotype in Alzheimer’s disease. Metab Brain Dis 2000; 15:45–64 3. Sunderland T, Tariot PN, Cohen RM, et al: Anticholinergic sen-
460
sitivity in patients with dementia of the Alzheimer’s type and agematched controls: a dose–response study. Arch Gen Psychiatry 1987; 44:418–426 4. Sunderland T, Tariot PN, Newhouse PA: Differential responsivity of mood, behavior, and cognition to cholinergic agents in elderly
Am J Geriatr Psychiatry 11:4, July-August 2003
Lu and Tune neuropsychiatric populations. Brain Res Brain Res Rev 1988; 13:371–389 5. Nishiyama K, Sugishita M, Kurisaki H, et al: Reversible memory disturbance and intelligence impairment induced by long-term anticholinergic therapy. Intern Med 1998; 37:514–518 6. Tune LE, Egeli S: Acetylcholine and delirium. Dement Geriatr Cogn Disord 1999; 10:342–344 7. Folstein MF, Folstein SE, McHugh PR: Mini-Mental State: a prac-
Am J Geriatr Psychiatry 11:4, July-August 2003
tical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189–198 8. Burns A, Jacoby R, Levy R: Progression of cognitive impairment in Alzheimer’s disease. J Am Geriatr Soc 1991; 39:39–45 9. Mulsant BH, Pollock BG, Kirshner M, et al: Serum anticholinergic activity in a community-based sample of older adults: relationship with cognitive performance. Arch Gen Psychiatry 2003; 60:198– 203
461