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650 Noncholinergic agents in Alzheimer's dementia
S162
FIFFH INTERNATIONAL CONFERENCE ON ALZHEIMER'S DISEASE
Interview-Based Impression of change (CIBI, p=0.02), and the Mini-Mental State Examination (MMSE, p =0.07). Design/Methods.-30-week, randomized double-blind, placebo-controlled, multicenter trial in which some women with mild to moderate AD, 250 years of age, were receiving ERT prior to randomization to placebo or tacrine (see Knapp et al 1994). Patients were genotyped for ApoE (ApoE 4 v. non-ApoE 4) as reported previously (Poirier et al, 1995; Farlow et al, in prep). Results.--Baseline ADASc did not differ by ApoE genotype. Intent-to-treat analyses of the relationship between ApoE genotype and the effect of tacrine on ADASc showed that ApoE genotype did not significantly modify the effect of tacrine in these women. When the analysis was stratified by genotype, there was evidence that the non-ApoE 4 subjects receiving tacrine (but not the ApoE 4) improved versus those receiving placebo (p = 0.01). Including ERT as a potential modifier of the ApoE/tacrine effect revealed that among subjects not taking ERT, those with a non-ApoE 4 genotype improved while those with an ApoE 4 allele worsened relative to placebo. Among ERT using subjects, those on tacrine tended to improve overall, but with greater improvement among non-ApoE 4 subjects relative to placebo, although the relationship was less clear. Similar results were noted with the MMSE and CIBI. Conclusion.--ERT may enhance response to cholinesterase inhibitors in women with AD, in particular among these who do not have an ApoE 4 allele. Potential mechanisms will be discussed. Limitations to this analysis include post hoc analysis, small sample, and low statistical power. Clinical trials are necessary to confirm these observations.
650 Noneholinergic Agents in Alzheimer's Dementia M. Dysken* and K. Hoover GRECC Program, Minneapolis VA Med Ca-, One Veterans Drive, Minneapolis, MN, 55417, USA A variety of noncholinergic agents have been tested in clinical trials to determine if they offer any benefit in either improving cognition or slowing cognitive decline in patients with Alzheimer's dementia. These agents all have compelling rationales, either theoretical or empirical or both, that have provided the impetus for testing in human subjects. In this paper, we review 20 clinical trials involving 14 noncholinergic agents that were published between 1984-1995. The theoretical justification, preclinical empirical data, and methodology will be presented for these pharmacological agents that include aeetyl-Lcarnitine, alapreclate, buflomedil, ceranapril, cycloserine, desferrioxamine, monosialoganglioside (GM-1), indomethaein, milaeemide, nerve growth factor (NGF), nimodipine, phosphatidylserine, thiamine, and zimeldine. Four of these medications showed unequivocal improvement (aeetyl-I.,-camitine, buflomedil, indomethacin, and nimodipine). The other agents were either insignificant in demonstrating cognitive improvement (alaproclate, eeranapril, cycloserine, GM-I, milacemide, and zimeldine) or showed mixed results (desferrioxamine, NGF, phosphatidylserine, and thiamine). Implications for further drug development will be discussed with respect to each agent's mechanism of action.
Results: Those who took neuroleptics declined almost twice as fast as those who did not (eMMS decline over 20 months: 17.1±2.6 versus 9.6±1.4, p=0.02). Although cognitive decline was also greater amongst those with more severe persecutory ideas, aggression and sleep disturbance, linear regression analysis revealed that only the use of neurolepties and the severity of persecutory ideas were independently associated with more rapid cognitive decline. Furthermore, in 20 subjects who started neuroleptic medication after the start of the study, the rate of decline was significantly greater in the year after the start of the medication than in the year before. Cortical Lewy body pathology did not account for the effect of neuroleptics. Cotwhtsions: The neuroleptic medication used to treat behavioural complications of dementia worsens the already poor cognitive function.
652 The Treatment of Behavioral Symptoms in Dementia: Haloperidol, Thioridazine, and Fluoxetine: A Double-Blind, Placebo-Controlled, Eight Month Study S.R.Auer*, I. Monteiro, C. Torossian, E. Sinaiko , I. Boksay and B. Reisberg Aging and Dementia Research Center, NYU Medical Center, 550 First Avenue,New York, NY 10016, USA Behavioral symptoms are a major source of stress for the dementia patient and their caregiver. Nearoleptics have been viewed as the treatment of choice for behavioral symptoms such as psychotic symptoms and agitation. While there is a rational for using neuroleptics, little data support the use of neuroleptics in dementia. There is only anecdotal evidence which indicates that SSRI's might be useful in the treatment of agitation. Design : A double blind, placebo controlled, parallel group design with a duration of 32 weeks and an open label phase. Patients were randomly assigned to either haloperidol, thioridazine, fluoxetine or placebo. Eligible outpatients were enrolled in the study (N=l13). Of these, 69 patients completed the double blind protocol and 44 patients dropped .fi'om the study. All four groups (including placebo) showed a significant reduction (p<0.05) in BEHAVE-AD total scores. The haloperidol and thioridazine groups showed a significant decline in MMSE. A significant functional decline was noted in the haloperidol, thioridazine and fluoxetine groups. A significant increase in extrapyramidal signs (e.g. rigidity) was found in the two neuroleptie groups. Conclusion: Considering the significant increase of extrapyramidal symptoms, the usefulness of the neuroleptics studied has tO be questioned. Fluoxetine and placebo both seemed to be efficacious." The clear superiority of any pharmacological agent over a non-specific treatment intervention remains to be demonstrated. The strong placebo effect may point to the likely utility of an interactive approach with social and pharmacological interventions in the treatment of behavioral symptoms in dementia. Supported by USDHHS Grant # AG09127
651 The impact of neuroleptic medication on cognitive decline in dementia R. McShaoe*, T. Hope, R. Jacoby Section of Old Age Psychiatry, Wameford Hospital, Oxford, OX3 7JX, UK. emaU: [email protected] Background: Patients with dementia who have symptoms of psychosis, aggression or sleep disturbance have a faster rate of subsequent cognitive decline than those without. The reason for this is unknown. We examined the possibility that neuroleptie medication, which is often used to treat these symptoms, accounts for the link between non-cognitive symptoms and more rapid decline. Method: The impact on the rate &cognitive decline of neuroleptic use, physical aggression, sleep disturbance, persecutory ideas, hallucinations, sex, age, duration of illness and initial level of cognitive function was examined in a cohort of 71 patients with dementia who were each assessed every four months on at least six occasions. The instruments used were the Present Behavioural Examination and an expanded version of the MiniMental State Examination (eMMS). Neuropathology was available in 37 cases, of whom 7 had cortical Lewy body pathology.
POSTER SESSION V
Clinical Course & Diagnosis IV 653 Event-related potentials (ERP) during lexieal decision task in patients with dementia of the Alzheimer type. J. Ito.*, S. KoyamaI and Y. Nageishi2 Department of Laboratory Medicine and Clinical Science, Kyoto University School of Medicine, Kyoto, 1Department of Integrative Physiology, National Institute of Physiology, Okazald and 2Teaching Profession Center, Asahi University, Crifu, Japan To evaluate a disorder of language in the early stage of patients with dementia of the Alz.heirner type (DAT), ERPs using lexieal decision paradigm
FIFFH INTERNATIONAL CONFERENCE ON ALZHEIMER'S DISEASE
Interview-Based Impression of change (CIBI, p=0.02), and the Mini-Mental State Examination (MMSE, p =0.07). Design/Methods.-30-week, randomized double-blind, placebo-controlled, multicenter trial in which some women with mild to moderate AD, 250 years of age, were receiving ERT prior to randomization to placebo or tacrine (see Knapp et al 1994). Patients were genotyped for ApoE (ApoE 4 v. non-ApoE 4) as reported previously (Poirier et al, 1995; Farlow et al, in prep). Results.--Baseline ADASc did not differ by ApoE genotype. Intent-to-treat analyses of the relationship between ApoE genotype and the effect of tacrine on ADASc showed that ApoE genotype did not significantly modify the effect of tacrine in these women. When the analysis was stratified by genotype, there was evidence that the non-ApoE 4 subjects receiving tacrine (but not the ApoE 4) improved versus those receiving placebo (p = 0.01). Including ERT as a potential modifier of the ApoE/tacrine effect revealed that among subjects not taking ERT, those with a non-ApoE 4 genotype improved while those with an ApoE 4 allele worsened relative to placebo. Among ERT using subjects, those on tacrine tended to improve overall, but with greater improvement among non-ApoE 4 subjects relative to placebo, although the relationship was less clear. Similar results were noted with the MMSE and CIBI. Conclusion.--ERT may enhance response to cholinesterase inhibitors in women with AD, in particular among these who do not have an ApoE 4 allele. Potential mechanisms will be discussed. Limitations to this analysis include post hoc analysis, small sample, and low statistical power. Clinical trials are necessary to confirm these observations.
650 Noneholinergic Agents in Alzheimer's Dementia M. Dysken* and K. Hoover GRECC Program, Minneapolis VA Med Ca-, One Veterans Drive, Minneapolis, MN, 55417, USA A variety of noncholinergic agents have been tested in clinical trials to determine if they offer any benefit in either improving cognition or slowing cognitive decline in patients with Alzheimer's dementia. These agents all have compelling rationales, either theoretical or empirical or both, that have provided the impetus for testing in human subjects. In this paper, we review 20 clinical trials involving 14 noncholinergic agents that were published between 1984-1995. The theoretical justification, preclinical empirical data, and methodology will be presented for these pharmacological agents that include aeetyl-Lcarnitine, alapreclate, buflomedil, ceranapril, cycloserine, desferrioxamine, monosialoganglioside (GM-1), indomethaein, milaeemide, nerve growth factor (NGF), nimodipine, phosphatidylserine, thiamine, and zimeldine. Four of these medications showed unequivocal improvement (aeetyl-I.,-camitine, buflomedil, indomethacin, and nimodipine). The other agents were either insignificant in demonstrating cognitive improvement (alaproclate, eeranapril, cycloserine, GM-I, milacemide, and zimeldine) or showed mixed results (desferrioxamine, NGF, phosphatidylserine, and thiamine). Implications for further drug development will be discussed with respect to each agent's mechanism of action.
Results: Those who took neuroleptics declined almost twice as fast as those who did not (eMMS decline over 20 months: 17.1±2.6 versus 9.6±1.4, p=0.02). Although cognitive decline was also greater amongst those with more severe persecutory ideas, aggression and sleep disturbance, linear regression analysis revealed that only the use of neurolepties and the severity of persecutory ideas were independently associated with more rapid cognitive decline. Furthermore, in 20 subjects who started neuroleptic medication after the start of the study, the rate of decline was significantly greater in the year after the start of the medication than in the year before. Cortical Lewy body pathology did not account for the effect of neuroleptics. Cotwhtsions: The neuroleptic medication used to treat behavioural complications of dementia worsens the already poor cognitive function.
652 The Treatment of Behavioral Symptoms in Dementia: Haloperidol, Thioridazine, and Fluoxetine: A Double-Blind, Placebo-Controlled, Eight Month Study S.R.Auer*, I. Monteiro, C. Torossian, E. Sinaiko , I. Boksay and B. Reisberg Aging and Dementia Research Center, NYU Medical Center, 550 First Avenue,New York, NY 10016, USA Behavioral symptoms are a major source of stress for the dementia patient and their caregiver. Nearoleptics have been viewed as the treatment of choice for behavioral symptoms such as psychotic symptoms and agitation. While there is a rational for using neuroleptics, little data support the use of neuroleptics in dementia. There is only anecdotal evidence which indicates that SSRI's might be useful in the treatment of agitation. Design : A double blind, placebo controlled, parallel group design with a duration of 32 weeks and an open label phase. Patients were randomly assigned to either haloperidol, thioridazine, fluoxetine or placebo. Eligible outpatients were enrolled in the study (N=l13). Of these, 69 patients completed the double blind protocol and 44 patients dropped .fi'om the study. All four groups (including placebo) showed a significant reduction (p<0.05) in BEHAVE-AD total scores. The haloperidol and thioridazine groups showed a significant decline in MMSE. A significant functional decline was noted in the haloperidol, thioridazine and fluoxetine groups. A significant increase in extrapyramidal signs (e.g. rigidity) was found in the two neuroleptie groups. Conclusion: Considering the significant increase of extrapyramidal symptoms, the usefulness of the neuroleptics studied has tO be questioned. Fluoxetine and placebo both seemed to be efficacious." The clear superiority of any pharmacological agent over a non-specific treatment intervention remains to be demonstrated. The strong placebo effect may point to the likely utility of an interactive approach with social and pharmacological interventions in the treatment of behavioral symptoms in dementia. Supported by USDHHS Grant # AG09127
651 The impact of neuroleptic medication on cognitive decline in dementia R. McShaoe*, T. Hope, R. Jacoby Section of Old Age Psychiatry, Wameford Hospital, Oxford, OX3 7JX, UK. emaU: [email protected] Background: Patients with dementia who have symptoms of psychosis, aggression or sleep disturbance have a faster rate of subsequent cognitive decline than those without. The reason for this is unknown. We examined the possibility that neuroleptie medication, which is often used to treat these symptoms, accounts for the link between non-cognitive symptoms and more rapid decline. Method: The impact on the rate &cognitive decline of neuroleptic use, physical aggression, sleep disturbance, persecutory ideas, hallucinations, sex, age, duration of illness and initial level of cognitive function was examined in a cohort of 71 patients with dementia who were each assessed every four months on at least six occasions. The instruments used were the Present Behavioural Examination and an expanded version of the MiniMental State Examination (eMMS). Neuropathology was available in 37 cases, of whom 7 had cortical Lewy body pathology.
POSTER SESSION V
Clinical Course & Diagnosis IV 653 Event-related potentials (ERP) during lexieal decision task in patients with dementia of the Alzheimer type. J. Ito.*, S. KoyamaI and Y. Nageishi2 Department of Laboratory Medicine and Clinical Science, Kyoto University School of Medicine, Kyoto, 1Department of Integrative Physiology, National Institute of Physiology, Okazald and 2Teaching Profession Center, Asahi University, Crifu, Japan To evaluate a disorder of language in the early stage of patients with dementia of the Alz.heirner type (DAT), ERPs using lexieal decision paradigm