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Effects of rivastigmine on behavioral and psychological symptoms of dementia in Alzheimer's disease
CLINICAL THERAPEUTICS®/VoL.2 6 , N o . 7, 2 0 0 4
Effects of Rivastigmine on Behavioral and Psychological Symptoms of Dementia in Alzheimer's Disease Sanford I. Finkel, MD
Department of Psychiatry, University of Chicago Medical School, Chicago, Illinois
ABSTRACT
Background: The presence of certain behavioral and psychological symptoms (eg, paranoia, hallucinations, aggression, activity disturbances) in Alzheimer's disease (AD) may predict faster cognitive and functional decline; therefore, such symptoms represent an important treatment target. Behavioral and psychological symptoms of dementia (BPSD) may be caused at least in part by cholinergic deficits. Regulatory studies of rivastigmine in AD were not designed to evaluate effects on BPSD, but further investigation of rivastigmine in AD was prompted by later studies demonstrating behavioral benefits in other types of dementia. Objective: The primary aim of this article was to review available data on the behavioral benefits of rivastigmine in patients with AD. Methods: Relevant data were identified through a MEDLINE search for studies published in peer-reviewed journals through January 2004. The search terms were Alzheimer, behavior, psychosis, and rivastigmine. Data presented at international scientific congresses were also reviewed to ensure that the most recent data were considered. Results: A meta-analysis of three 6-month, placebo-controlled trials of rivastigmine in mild to moderate AD indicated that rivastigmine 6 to 12 mg/d may improve or prevent disruptive BPSD (P < 0.05 vs placebo). In patients with more advanced AD, 2 open-label studies of up to 12 months' duration found that improvements in BPSD were accompanied by a decrease in the use of psychotropic medications. Rivastigmine demonstrated behavioral benefits in patients with dementia with Lewy bodies (DLB) in a double-blind, placebo-controlled study (P < 0.05). In open-label extension studies, rivastigmine provided sustained effects (up to 2 years) in patients with mild to moderate AD or DLB. Conclusions: The available data suggest that rivastigmine may be a well-tolerated treatment option for improving or preventing psychotic and nonpsychotic symptoms associated with AD. Prospective, double-blind studies are needed to evaluate these preliminary findings. (Clin 7her. 2004;26:980-990) Copyright @ 2004 Excerpta Medica, Inc. Key words: Alzheimer's disease, behavior, cholinergic deficits, psychosis, rivastigmine. AcceptedJor publication April 29, 2004. Printed in the USA. Reproduction in whole or part is not permitted.
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S.I. Finkel
INTRODUCTION
Behavioral and psychological symptoms of dementia (BPSD) are an important aspect of dementing illnesses, affecting 50% to 80% of patients with dementia. 1-~ In general, these symptoms worsen as Alzheimerg disease (AD) progresses, 5,6 but similar symptoms have been reported in patients with mild cognitive impairment] indicating that some BPSD are present across the continuum of dementia severity. Psychotic and nonpsychotic symptoms such as delusions, agitation, aggression, and aberrant motor behavior (eg, wandering, rummaging) are among the most common symptoms in patients with AD. 7 Studies have shown that patients exhibiting these symptoms experience faster cognitive deterioration and functional decline, as well as reduced survival. 8-12 For example, certain behavioral problems (eg, agitation, aberrant motor behavior, sleep disturbances) have been found to predict faster progression of cognitive impairment, 8,9 whereas others (eg, paranoid behavior, hallucinations, aberrant motor behavior) appeared to predict faster functional decline. 8,1° A negative association has been reported between certain neurologic and psychiatric symptoms and survival, M although this relationship may apply to men only. 12 Taken together, these findings suggest that treatment interventions may improve the long-term prognosis of patients with AD. The treatment of BPSD is a challenge for physicians managing patients with AD. Prescribed cautiously, psychotropic drugs may enhance the physical and psychological well-being of elderly patients (age >65 years). However, this age group is particularly sensitive to undesirable drug effects, which can lead to a decline in medical and functional status or to the use of additional prescriptions and an increased risk for drug interactions. 13 In addition, some newer antipsychotic agents (eg, olanzapine, risperidone) recently have been associated with an increased risk for cerebrovascular events in the elderly. 1~ It is now widely accepted that cholinergic deficits are involved in the cognitive symptoms of AD. 15 There is accruing evidence that behavioral alterations in patients with AD may also have a cholinergic basis. 16,17 Although all layers of the cerebral cortex receive cholinergic innervation, the limbic system, which is involved in BPSD and includes such structures as the amygdala and hippocampus, has the high-
est density of cholinergic axons within the human cortex. 18 Moreover, the afferent input to the nucleus basalis is largely from limbic brain regions. 19 This has led to a "revised" cholinergic hypothesis, which proposes that the BPSD of AD, as well as the cognitive impairment, may result from cholinergic deficits. 16,2° This theory has important implications for AD treatment strategies, particularly for use of cholinesterase inhibitors. A recent meta-analysis indicated that these agents may provide modest benefits in terms of BPSD. 21 Patients randomized to receive cholinesterase inhibitors had a 1.92-point improvement in scores on the Neuropsychiatric Inventory (NPI) compared with placebo recipients (95% CI, 0.87-2.57), indicating a small but statistically significant benefit with the use of cholinesterase inhibitors.21 Two types of cholinesterase are present in the human central nervous system--acetylcholinesterase (ACHE) and butyrylcholinesterase (BuChE)--both of which are involved in the regulation of cholinergic transmission. 22 Three cholinesterase inhibitors have been approved in the United States and Europe for the symptomatic treatment of AD: rivastigmine, donepezil, and galantamine. 23,2. Whereas donepezil and galantamine are AChE selective, rivastigmine inhibits both AChE and BuChE. 25 It has been hypothesized that inhibition of both enzymes may provide additional benefits beyond those of ACHEselective i n h i b i t o r s . 26-29 In particular, the presence of high levels of BuChE in structures such as the hippocampus, amygdala, and thalamus 3°,31 suggests that inhibition of both enzymes may have an important role in the treatment of BPSD. Pivotal trials of cholinesterase inhibitors in AD were not designed to evaluate BPSD because the regulatory focus at the time was on cognitive performance. However, in more recent trials of these agents in other types of dementia, rivastigmine demonstrated promising behavioral benefits in patients with mixed dementia (improvement in NPI scores at 26 weeks, P = 0.044 vs baseline)32; subcortical vascular dementia (improvement in NPI and Behavioral Pathology in Alzheimer's Disease [BEHAVE-AD] scores at 22 months vs baseline and vs control [aspirin]; all comparisons, P < 0.05)33; and Parkinson's disease dementia (improvement in NPI scores at 14 weeks, P < 0.004 vs baseline). 3. One 6-month study of donepezil in patients with moderate to severe AD demon981
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strated benefits on anxiety, depression, and apathy (P < 0.05), 35 although studies of donepezil in patients with mild to moderate AD, 36 patients with Down syndrome and AD,3r or nursing home patients with AD 38 have not shown behavioral benefits. In a 5-month, placebo-controlled study, 39 galantamine delayed the emergence of BPSD in patients with mild to moderate AD. NPI scores were significantly improved compared with placebo at 5 months (P < 0.05), but were not significantly different from baseline. The new focus on BPSD, the revised cholinergic hypothesis, and the potential behavioral effects of cholinesterase inhibitors reported in other types of dementia warranted further trials and analyses in patients with AD. METHODS
This article reviews new and current evidence for the behavioral benefits of rivastigmine in patients with AD. Data were identified through searches of MEDLINE through January 2004 and the reference lists of relevant articles. The search terms were Alzheimer, behavior, psychosis, and rivastigmine. To ensure maximum topicality, recent data presented at international scientific congresses or provided by colleagues in the field also were reviewed. RESULTS Mild to M o d e r a t e Alzheimer's Disease
Meta-analyses evaluating the effects of rivastigmine on behaviors associated with mild to moderate AD have been performed and presented in poster form. *°#~ Data were derived from a pooled population of 1840 patients for whom scores were available on the behavioral component of the Clinician's Interview-Based Impression of Change Plus Caregiver Input scale (CIBIC-plus, adapted from BEHAVE-AD) from three 6-month, double-blind, placebo-controlled regulatory trials of rivastigmine in patients with mild to moderate AD (mean baseline Mini-Mental State Examination [MMSE] score, 19.93). *2-** To investigate the effects of the drug in terms of improvement in existing symptoms and prevention of the emergence of new symptoms, patients were stratified by the presence or absence of disruptive BPSD at baseline. Many patients with BPSD were excluded from the original studies because receipt of antipsychotics was an exclusion criterion. Nevertheless, a large pro982
portion of patients had BPSD at study entry: 63.7% had activity disturbances, 44.8% aggressiveness, 42.8% delusions, and 20.9% hallucinations. .1,.2 These symptoms were generally mild and tended to be more frequent in patients with greater severity of disease at baseline. .2 The results after 6 months of treatment with rivastigmine 6 to 12 mg/d suggested interesting differential effects on individual symptoms. Despite a strong placebo effect, patients with symptoms at baseline had significant improvements in paranoid and delusional ideation and aggressiveness with rivastigmine compared with placebo (P = 0.002 and P = 0.046, respectively) (Figure 1). .1 With regard to the prevention of symptom emergence (defined as development of symptoms in a smaller proportion of patients who were symptom free at study entry), rivastigmine treatment appeared to prevent the emergence of activity disturbances compared with placebo (P = 0.016) (Figure 2). *°#~ Treatment differences in the effect on hallucinations were not statistically significant in the pooled population, probably reflecting the low baseline prevalence of these symptoms (20.9% of patients). However, in a cohort of patients with more advanced AD (MMSE score <12) and hallucinations at baseline (32.4% of patients), significant improvements in hallucinations (P = 0.039) and aggressiveness (P = 0.030) were observed in patients who received rivastigmine compared with those who received placebo (Figure 3). *~ The authors of these poster presentations (which have not yet undergone full peer review) suggested that rivastigmine may improve existing psychotic symptoms in patients with mild to moderate AD and may improve or prevent the emergence of nonpsychotic symptoms. These observations warrant further investigation in prospective, controlled clinical studies in patients with moderate to severe symptoms. The benefits of rivastigmine in patients with mild to moderate AD appear to be sustained over the long term. An open-label extension of a 6-month, doubleblind, placebo-controlled regulatory study of rivastigmine in patients with mild to moderate AD (N = 725; mean baseline MMSE score, 10-26) *3 reported significant sustained effects on BPSD for up to 2 years. .5 At 6 months (the end of the double-blind phase), 34 patients receiving rivastigmine had significant improvements from baseline in scores on the behavioral component of the CIBIC-plus (P = 0.02), where-
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Figure I. Proportions of patients with mild to moderate Alzheimer's disease and the following symptoms at study entry who showed improvements in (A) paranoia and delusions, and (B) aggressiveness after receiving rivastigmine or placebo for 6 months. 41 *P = 0.002 versus placebo; *p = 0.046 versus placebo.
as placebo recipients had no improvement. During the open-label extension, all patients received rivastigmine 3 to 12 mg/d for a further 18 months. At 12 months (6 months into the open-label phase), additional improvements were reported in patients who had received rivastigmine from the start of the study; at 24 months, symptoms in this group continued to be rated as mild to moderate. At all times after baseline, BPSD were significantly better in the patients who had received rivastigmine for the entire study compared with those who had received placebo for the first 6 months (P < 0.05). With regard to particular items on the BEHAVE-AD, symptoms of hallucinations, aggressiveness, activity disturbances, and paranoid and delusional ideation were improved for >2 years in patients receiving rivastigmine (Figure 4). Moreover, significant improvements from baseline in mood symptoms were reported at 12 and 24 months (P = 0.001). Significant worsening of these symptoms would have been expected in untreated patients over this time period. The failure of patients who had initially received placebo to "catch up" to patients who had received rivastigmine from the outset suggests that rivastigmine may have
prevented the emergence of symptoms in patients receiving active treatment over the longer term. This possibility suggests an effect on the underlying disease process. Rivastigmine also has demonstrated behavioral benefits in patients with dementia with Lewy bodies (DLB), including patients with both DLB and AD. In a double-blind, placebo-controlled study in patients with DLB (N = 120; mean baseline MMSE score, 17.9), .6 receipt of rivastigmine 2 to 12 mg/d was associated with improvements in psychiatric symptoms, as assessed using the NPI. More than twice as many patients receiving rivastigmine (38%) than placebo (18%) had >30% improvement on the NPI from baseline. A 30% reduction in NPI score is considered clinically relevant and comparable in magnitude to changes observed with conventional antipsychotic agents used for disruptive behavioral symptoms of dementia. *r The psychiatric features that were most improved in patients who received rivastigmine were apathy, anxiety, delusions, and hallucinations. Hallucinations and psychotic features resolved almost completely in more than half of patients receiving rivastigmine. ~6 A separate analysis 983
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Figure 3. Proportions of patients with advanced AIzheimer's disease and symptoms of hallucinations and aggressiveness at study entry who showed improvement in these symptoms after receiving rivastigmine or placebo for 6 months. 4m Logistic regression analysis: *P = 0.039; tp = 0.030.
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Figure 4. Improvements from baseline in scores on individual items of the Behavioral Pathology in Alzheimer's Disease scale after 12 and 24 months of rivastigmine therapy in an open-label extension study in patients with mild to moderate Alzheimer's disease (n = 29, observed-case analysis).4sA negative change indicates symptom improvement.*P = 0.02 versus baseline.
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calculated the response to rivastigmine treatment as the sum of scores for hallucinations and delusions, with response defined as improvements in those with psychotic symptoms at baseline or the prevention of symptom emergence in those without symptoms at baseline. 4~ Significantly more patients responded to rivastigmine than to placebo (P = 0.027). Moreover, the effects of rivastigmine on BPSD in patients with DLB were maintained over the long term. At the end of the study period, NPI scores remained at baseline levels in patients who had received rivastigmine for 96 weeks. Because DLB is a progressive illness, the authors had expected to see a substantial worsening of NPI scores over 96 weeks; instead, rivastigmine appeared to prevent the emergence of new behavioral and psychological symptoms. Disruptive Behaviors in More Advanced Alzheimer's Disease
The efficacy of rivastigmine in the treatment of BPSD also has been studied in patients with moderate to severe AD living in long-term care facilities. In a 6-month study in 113 patients with severe AD (mean baseline NPI-nursing home version [NPI-NH] score, 15.5; mean baseline MMSE score, 10.9), 49 >53% of patients showed improvements on all NPI-NH items, including those relating to psychotic and
nonpsychotic behaviors (Figure 5), and had a mean improvement of 0.7 point on the MMSE. More than 40°,6 of patients had >_30% improvement from baseline in NPI-NH scores. Among patients without BPSD at baseline, up to 93% developed no symptoms during active treatment. Thus, rivastigmine treatment seemed to reduce the emergence or development of BPSD in patients with advanced AD. These benefits were maintained during a 6-month extension of this study, 49 in which sustained improvements in BPSD were accompanied by a decrease in the use of psychotropic medications. In a 6-month study in 173 patients (mean baseline NPI-NH score, 16.5; mean baseline MMSE score, 9.3), ~° 59% of patients had improvements in NPI-NH scores, and improvements in disruptive BPSD were accompanied by a substantial decrease in the use of psychotropic medications. In particular, there were improvements in mean scores on the NPI-NH categories of aberrant motor behavior, agitation, delusions, hallucinations, irritability, apathy, appetite changes, and nighttime behavior. An extension of this study found that the efficacy of rivastigmine was maintained in these patients for >_12 months. 51 After 12 months of treatment, 57% of patients who had exhibited BPSD at baseline demonstrated improvements on the NPI-NH, with -50% of these patients
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Figure 5. Proportions of nursing home patients with Alzheimer's disease showing improvement on individual items of the Neuropsychiatric Inventory-nursing home version (NPI-NH) (N = 151; baseline NPI-NH score, 15.5; baseline Mini-Mental State Examination score, 10.9).49
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having >30% improvement. These behavioral benefits were associated with a reduction in the use of drugs for the treatment of behavioral symptoms (Figure 6). 52 Further analyses indicated that these benefits occurred both in patients with moderate AD (baseline MMSE score >10) and in those with severe AD (baseline MMSE score <10). 53 At 52 weeks, patients with moderate AD maintained a mean 3.1point improvement in NPI-NH score from baseline, whereas patients with severe AD maintained a mean improvement of 0.2 point. Neuroleptic use decreased by 68% and 62% in the subgroups with moderate and severe AD, respectively. As a result, significantly more patients with moderate AD were able to discontinue all psychotropic use compared with those with severe AD (P = 0.04). Because these were open-label studies, it is not possible to quantify any placebo (psychosocial) effects.
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It is important that drugs do not cause behavioral problems while improving or preventing the emergence of BPSD. Some reports have indicated that use of some cholinesterase inhibitors may be associated with treatment-emergent neuropsychiatric events. 35S,5~-5r NPI scores were reported to be better in placebo recipients compared with donepezil recipients in studies involving patients with Down syndrome (2.5point difference; P < 0.05) 3r and patients with AD residing in a nursing home (3.0-point difference; P = NS)J 8 possibly reflecting a potential for donepezil to cause treatment-emergent events. Dunn et a155 recommended that donepezil not be given to patients with such problems as insomnia or agitation. It is not known whether the more frequent reports of treatment-emergent neuropsychiatric events with donepezil compared with other cholinesterase inhibitors 29 reflect a problem particular to this agent or simply the fact that donepezil is the most commonly prescribed agent in this class. As stated in the product informationj 8 rivastigmine has been studied in >3300 patients. Adverse events associated with rivastigmine generally have been mild to moderate, transient, and dose dependent, the most common being nausea, vomiting, dizziness, anorexia, asthenia, and somnolence. 23 Because of the cholinomimetic nature of this drug, special care may be necessary when prescribing rivastigmine for patients with
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Figure 6. Reductions in the concomitant use of antipsychotic medications in nursing home patients receiving rivastigmine for 12 months, s2
sick-sinus syndrome or conduction defects, active gastric or duodenal ulcers or a predisposition to either, a history of asthma or obstructive pulmonary disease, a predisposition to urinary obstruction, or a predisposition to seizures. 58 Rivastigmine is unlikely to be involved in significant interactions with other medications. It is almost completely independent of metabolism and elimination by liver microsomal enzymes and does not bind significantly to plasma proteins. However, in view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic drugs and may interfere with the activity of anticholinergic medications. DISCUSSION
In addition to its effects on cognitive performance and ability to perform activities of daily living in patients with AD, 23'2"+ rivastigmine treatment may provide clinically relevant behavioral benefits across the spectrum of AD severity. Some of rivastigmine's benefit appears to be the result of improvements in existing symptoms, but its main behavioral effect seems to be in preventing the emergence of symp-
S.I. Finkel
toms. These benefits have been reflected in a reduction in the use of concomitant psychotropic drugs. 52 The positive effects of rivastigmine in patients with AD appear to be clinically relevant. In particular, in patients with DLB, ~6 which is noted for its high prevalence of BPSD, the effects of rivastigmine have been reported to be significant, meaningful, and comparable in magnitude to changes observed with conventional psychotropic a g e n t s S The reported benefits of rivastigmine therapy in patients with AD support the revised hypothesis concerning cholinergic control of behavioral symptoms. 16,2° The effects of rivastigmine on BPSD also may help clarify the specific roles of AChE and BuChE in different regions of the human brain. For example, levels of BuChE are particularly high in structures such as the hippocampus, amygdala, and thalamus3°,31--brain regions involved in aspects of behavior and emotion. Delusional thoughts have recently been linked to frontal/temporal cortex hypometabolism, 59 and rivastigmine has been shown to improve glucose metabolism in these regions of the human brain. 6°,61 Because these brain structures are believed to be involved in aspects of behavior and emotion, the ability of rivastigmine to inhibit both BuChE and AChE in these regions may predict important clinical effects. This review is limited by the fact that most of the analyses of rivastigmine in patients with mild to moderate AD were retrospective. Pivotal studies of rivastigmine in this population were not designed to prospectively evaluate effects on BPSD. Moreover, patients were excluded from studies if they had severe behavioral problems, so the present results are relevant only to the subpopulation of AD patients with minimal behavioral problems. As such, these data should be interpreted with caution. CONCLUSIONS
The findings of this review suggest a basis for further revisions to the cholinergic hypothesis, specifically the inclusion of BuChE as a rational target for the treatment of AD, particularly in patients with BPSD. Rivastigmine may provide a well-tolerated treatment option for the improvement or prevention of psychotic and nonpsychotic symptoms associated with AD. These preliminary findings require further investigation in prospective, randomized, double-blind studies.
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38. Tariot PN, Cummings JL, Katz IR, et al. A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting, d Am Geriatr 5oc. 2001;49:1590-1599. 39. Tariot PN, Solomon PR, Morris JC, et al, for the Galantamine USA-10 Study Group. A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology. 2000;54:2269-2276. 40. Lane R, Tekin S, Mesenbrink R The efficacy of rivastigmine on behavioral symptoms of activity disturbances in patients with Alzheimer's disease. Poster presented at: American Association for Geriatric Psychiatry Annual Meeting; March 1-4, 2003; Honolulu, Hawaii. 41. Lane R, Spiegel R, Tel
49. Bullock R, Moulias R, Steinwachs KC, et al. Effects of rivastigmine on behavioural symptoms in nursing home patients with Alzheimer's disease. Int Psychogeriatr. 2001;13(Suppl 2):242. Abstract P248. 50. Cummings J, Koumaras B, Rabinowicz A, et al. Effects of rivastigmine (Exelon®) treatment on the neuropsychiatric and behavioral disturbances of nursing home residents with moderate to severe Alzheimer's disease. Am d Geriatr Psychiatry. In press. 51. Cummings J, Anand R, Koumaras B, et al. Rivastigmine treatment on the psychiatric and behavioral disturbances of nursing home residents with moderate to severe Alzheimer's disease (final results). Poster presented at: International Psychogeriatric Association; August 17-21, 2003; Chicago, Ill. 52. Messina J, Koumaras B, Hartman R. Treatment with rivastigmine reduces the need for psychotropic medications in patients with Alzheimer's disease residing in long-term care facilities. Poster presented at: 3rd Annual International Meeting of the College of Psychiatric Neurological Pharmacists; April 6-9, 2000; Washington, DC. 53. Edwards K, Goodman W, Anand R, et al. Effect of Alzheimer's disease severity on psychotropic drug use and behavior in nursing home patients treated with rivastigmine. Poster presented at: 8th International Conference on Alzheimer's Disease and Related Disorders; July 17-22, 2002; Stockholm, Sweden. 54. Donepezil: Suspected adverse reactions. CMAJ. 1998; 159:81,85. 55. Dunn NR, Pearce GL, Shakir SA. Adverse effects associated with the use of donepezil in general practice in England. d Psychopharmacol. 2000;14:406-408. 56. Ito T, Yamadera H. The efficacy of donepezil in Alzheimer's disease [in Japanese]. d Nippon Med Sch. 2002;69:379-382. 57. Wilkinson D, Doody R, Helme R, et al, for the Donepezil 308 Study Group. Donepezil in vascular dementia: A randomized, placebo-controlled study Neurology. 2003 ;61:479-486. 58. Exelon [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2001. 59. Sultzer DL, Brown CV, Mandelkern MA, et al. Delusional thoughts and regional frontal/temporal cortex metabolism in Alzheimer's disease. Am d Psychiatry. 2003;160:341-349.
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60. Vennerica A, Shanks MF, Staff RT, et al. Cerebral blood flow and cognitive responses to rivastigmine treatment in Alzheimer's disease. NeuroReport. 2002; 13:83-87.
61. Rombouts SA, Barkhof F, Van Meel CS, Scheltens P Alterations in brain activation during cholinergic enhancement with rivastigmine m Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2002;73:665-671.
Address correspondence to: Sanford I. Finkel, MD, 3127 Greenleaf Avenue, Wilmette, IL 60091. E-mail: sandy, [email protected]
990
Effects of Rivastigmine on Behavioral and Psychological Symptoms of Dementia in Alzheimer's Disease Sanford I. Finkel, MD
Department of Psychiatry, University of Chicago Medical School, Chicago, Illinois
ABSTRACT
Background: The presence of certain behavioral and psychological symptoms (eg, paranoia, hallucinations, aggression, activity disturbances) in Alzheimer's disease (AD) may predict faster cognitive and functional decline; therefore, such symptoms represent an important treatment target. Behavioral and psychological symptoms of dementia (BPSD) may be caused at least in part by cholinergic deficits. Regulatory studies of rivastigmine in AD were not designed to evaluate effects on BPSD, but further investigation of rivastigmine in AD was prompted by later studies demonstrating behavioral benefits in other types of dementia. Objective: The primary aim of this article was to review available data on the behavioral benefits of rivastigmine in patients with AD. Methods: Relevant data were identified through a MEDLINE search for studies published in peer-reviewed journals through January 2004. The search terms were Alzheimer, behavior, psychosis, and rivastigmine. Data presented at international scientific congresses were also reviewed to ensure that the most recent data were considered. Results: A meta-analysis of three 6-month, placebo-controlled trials of rivastigmine in mild to moderate AD indicated that rivastigmine 6 to 12 mg/d may improve or prevent disruptive BPSD (P < 0.05 vs placebo). In patients with more advanced AD, 2 open-label studies of up to 12 months' duration found that improvements in BPSD were accompanied by a decrease in the use of psychotropic medications. Rivastigmine demonstrated behavioral benefits in patients with dementia with Lewy bodies (DLB) in a double-blind, placebo-controlled study (P < 0.05). In open-label extension studies, rivastigmine provided sustained effects (up to 2 years) in patients with mild to moderate AD or DLB. Conclusions: The available data suggest that rivastigmine may be a well-tolerated treatment option for improving or preventing psychotic and nonpsychotic symptoms associated with AD. Prospective, double-blind studies are needed to evaluate these preliminary findings. (Clin 7her. 2004;26:980-990) Copyright @ 2004 Excerpta Medica, Inc. Key words: Alzheimer's disease, behavior, cholinergic deficits, psychosis, rivastigmine. AcceptedJor publication April 29, 2004. Printed in the USA. Reproduction in whole or part is not permitted.
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S.I. Finkel
INTRODUCTION
Behavioral and psychological symptoms of dementia (BPSD) are an important aspect of dementing illnesses, affecting 50% to 80% of patients with dementia. 1-~ In general, these symptoms worsen as Alzheimerg disease (AD) progresses, 5,6 but similar symptoms have been reported in patients with mild cognitive impairment] indicating that some BPSD are present across the continuum of dementia severity. Psychotic and nonpsychotic symptoms such as delusions, agitation, aggression, and aberrant motor behavior (eg, wandering, rummaging) are among the most common symptoms in patients with AD. 7 Studies have shown that patients exhibiting these symptoms experience faster cognitive deterioration and functional decline, as well as reduced survival. 8-12 For example, certain behavioral problems (eg, agitation, aberrant motor behavior, sleep disturbances) have been found to predict faster progression of cognitive impairment, 8,9 whereas others (eg, paranoid behavior, hallucinations, aberrant motor behavior) appeared to predict faster functional decline. 8,1° A negative association has been reported between certain neurologic and psychiatric symptoms and survival, M although this relationship may apply to men only. 12 Taken together, these findings suggest that treatment interventions may improve the long-term prognosis of patients with AD. The treatment of BPSD is a challenge for physicians managing patients with AD. Prescribed cautiously, psychotropic drugs may enhance the physical and psychological well-being of elderly patients (age >65 years). However, this age group is particularly sensitive to undesirable drug effects, which can lead to a decline in medical and functional status or to the use of additional prescriptions and an increased risk for drug interactions. 13 In addition, some newer antipsychotic agents (eg, olanzapine, risperidone) recently have been associated with an increased risk for cerebrovascular events in the elderly. 1~ It is now widely accepted that cholinergic deficits are involved in the cognitive symptoms of AD. 15 There is accruing evidence that behavioral alterations in patients with AD may also have a cholinergic basis. 16,17 Although all layers of the cerebral cortex receive cholinergic innervation, the limbic system, which is involved in BPSD and includes such structures as the amygdala and hippocampus, has the high-
est density of cholinergic axons within the human cortex. 18 Moreover, the afferent input to the nucleus basalis is largely from limbic brain regions. 19 This has led to a "revised" cholinergic hypothesis, which proposes that the BPSD of AD, as well as the cognitive impairment, may result from cholinergic deficits. 16,2° This theory has important implications for AD treatment strategies, particularly for use of cholinesterase inhibitors. A recent meta-analysis indicated that these agents may provide modest benefits in terms of BPSD. 21 Patients randomized to receive cholinesterase inhibitors had a 1.92-point improvement in scores on the Neuropsychiatric Inventory (NPI) compared with placebo recipients (95% CI, 0.87-2.57), indicating a small but statistically significant benefit with the use of cholinesterase inhibitors.21 Two types of cholinesterase are present in the human central nervous system--acetylcholinesterase (ACHE) and butyrylcholinesterase (BuChE)--both of which are involved in the regulation of cholinergic transmission. 22 Three cholinesterase inhibitors have been approved in the United States and Europe for the symptomatic treatment of AD: rivastigmine, donepezil, and galantamine. 23,2. Whereas donepezil and galantamine are AChE selective, rivastigmine inhibits both AChE and BuChE. 25 It has been hypothesized that inhibition of both enzymes may provide additional benefits beyond those of ACHEselective i n h i b i t o r s . 26-29 In particular, the presence of high levels of BuChE in structures such as the hippocampus, amygdala, and thalamus 3°,31 suggests that inhibition of both enzymes may have an important role in the treatment of BPSD. Pivotal trials of cholinesterase inhibitors in AD were not designed to evaluate BPSD because the regulatory focus at the time was on cognitive performance. However, in more recent trials of these agents in other types of dementia, rivastigmine demonstrated promising behavioral benefits in patients with mixed dementia (improvement in NPI scores at 26 weeks, P = 0.044 vs baseline)32; subcortical vascular dementia (improvement in NPI and Behavioral Pathology in Alzheimer's Disease [BEHAVE-AD] scores at 22 months vs baseline and vs control [aspirin]; all comparisons, P < 0.05)33; and Parkinson's disease dementia (improvement in NPI scores at 14 weeks, P < 0.004 vs baseline). 3. One 6-month study of donepezil in patients with moderate to severe AD demon981
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strated benefits on anxiety, depression, and apathy (P < 0.05), 35 although studies of donepezil in patients with mild to moderate AD, 36 patients with Down syndrome and AD,3r or nursing home patients with AD 38 have not shown behavioral benefits. In a 5-month, placebo-controlled study, 39 galantamine delayed the emergence of BPSD in patients with mild to moderate AD. NPI scores were significantly improved compared with placebo at 5 months (P < 0.05), but were not significantly different from baseline. The new focus on BPSD, the revised cholinergic hypothesis, and the potential behavioral effects of cholinesterase inhibitors reported in other types of dementia warranted further trials and analyses in patients with AD. METHODS
This article reviews new and current evidence for the behavioral benefits of rivastigmine in patients with AD. Data were identified through searches of MEDLINE through January 2004 and the reference lists of relevant articles. The search terms were Alzheimer, behavior, psychosis, and rivastigmine. To ensure maximum topicality, recent data presented at international scientific congresses or provided by colleagues in the field also were reviewed. RESULTS Mild to M o d e r a t e Alzheimer's Disease
Meta-analyses evaluating the effects of rivastigmine on behaviors associated with mild to moderate AD have been performed and presented in poster form. *°#~ Data were derived from a pooled population of 1840 patients for whom scores were available on the behavioral component of the Clinician's Interview-Based Impression of Change Plus Caregiver Input scale (CIBIC-plus, adapted from BEHAVE-AD) from three 6-month, double-blind, placebo-controlled regulatory trials of rivastigmine in patients with mild to moderate AD (mean baseline Mini-Mental State Examination [MMSE] score, 19.93). *2-** To investigate the effects of the drug in terms of improvement in existing symptoms and prevention of the emergence of new symptoms, patients were stratified by the presence or absence of disruptive BPSD at baseline. Many patients with BPSD were excluded from the original studies because receipt of antipsychotics was an exclusion criterion. Nevertheless, a large pro982
portion of patients had BPSD at study entry: 63.7% had activity disturbances, 44.8% aggressiveness, 42.8% delusions, and 20.9% hallucinations. .1,.2 These symptoms were generally mild and tended to be more frequent in patients with greater severity of disease at baseline. .2 The results after 6 months of treatment with rivastigmine 6 to 12 mg/d suggested interesting differential effects on individual symptoms. Despite a strong placebo effect, patients with symptoms at baseline had significant improvements in paranoid and delusional ideation and aggressiveness with rivastigmine compared with placebo (P = 0.002 and P = 0.046, respectively) (Figure 1). .1 With regard to the prevention of symptom emergence (defined as development of symptoms in a smaller proportion of patients who were symptom free at study entry), rivastigmine treatment appeared to prevent the emergence of activity disturbances compared with placebo (P = 0.016) (Figure 2). *°#~ Treatment differences in the effect on hallucinations were not statistically significant in the pooled population, probably reflecting the low baseline prevalence of these symptoms (20.9% of patients). However, in a cohort of patients with more advanced AD (MMSE score <12) and hallucinations at baseline (32.4% of patients), significant improvements in hallucinations (P = 0.039) and aggressiveness (P = 0.030) were observed in patients who received rivastigmine compared with those who received placebo (Figure 3). *~ The authors of these poster presentations (which have not yet undergone full peer review) suggested that rivastigmine may improve existing psychotic symptoms in patients with mild to moderate AD and may improve or prevent the emergence of nonpsychotic symptoms. These observations warrant further investigation in prospective, controlled clinical studies in patients with moderate to severe symptoms. The benefits of rivastigmine in patients with mild to moderate AD appear to be sustained over the long term. An open-label extension of a 6-month, doubleblind, placebo-controlled regulatory study of rivastigmine in patients with mild to moderate AD (N = 725; mean baseline MMSE score, 10-26) *3 reported significant sustained effects on BPSD for up to 2 years. .5 At 6 months (the end of the double-blind phase), 34 patients receiving rivastigmine had significant improvements from baseline in scores on the behavioral component of the CIBIC-plus (P = 0.02), where-
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as placebo recipients had no improvement. During the open-label extension, all patients received rivastigmine 3 to 12 mg/d for a further 18 months. At 12 months (6 months into the open-label phase), additional improvements were reported in patients who had received rivastigmine from the start of the study; at 24 months, symptoms in this group continued to be rated as mild to moderate. At all times after baseline, BPSD were significantly better in the patients who had received rivastigmine for the entire study compared with those who had received placebo for the first 6 months (P < 0.05). With regard to particular items on the BEHAVE-AD, symptoms of hallucinations, aggressiveness, activity disturbances, and paranoid and delusional ideation were improved for >2 years in patients receiving rivastigmine (Figure 4). Moreover, significant improvements from baseline in mood symptoms were reported at 12 and 24 months (P = 0.001). Significant worsening of these symptoms would have been expected in untreated patients over this time period. The failure of patients who had initially received placebo to "catch up" to patients who had received rivastigmine from the outset suggests that rivastigmine may have
prevented the emergence of symptoms in patients receiving active treatment over the longer term. This possibility suggests an effect on the underlying disease process. Rivastigmine also has demonstrated behavioral benefits in patients with dementia with Lewy bodies (DLB), including patients with both DLB and AD. In a double-blind, placebo-controlled study in patients with DLB (N = 120; mean baseline MMSE score, 17.9), .6 receipt of rivastigmine 2 to 12 mg/d was associated with improvements in psychiatric symptoms, as assessed using the NPI. More than twice as many patients receiving rivastigmine (38%) than placebo (18%) had >30% improvement on the NPI from baseline. A 30% reduction in NPI score is considered clinically relevant and comparable in magnitude to changes observed with conventional antipsychotic agents used for disruptive behavioral symptoms of dementia. *r The psychiatric features that were most improved in patients who received rivastigmine were apathy, anxiety, delusions, and hallucinations. Hallucinations and psychotic features resolved almost completely in more than half of patients receiving rivastigmine. ~6 A separate analysis 983
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Figure 3. Proportions of patients with advanced AIzheimer's disease and symptoms of hallucinations and aggressiveness at study entry who showed improvement in these symptoms after receiving rivastigmine or placebo for 6 months. 4m Logistic regression analysis: *P = 0.039; tp = 0.030.
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984
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calculated the response to rivastigmine treatment as the sum of scores for hallucinations and delusions, with response defined as improvements in those with psychotic symptoms at baseline or the prevention of symptom emergence in those without symptoms at baseline. 4~ Significantly more patients responded to rivastigmine than to placebo (P = 0.027). Moreover, the effects of rivastigmine on BPSD in patients with DLB were maintained over the long term. At the end of the study period, NPI scores remained at baseline levels in patients who had received rivastigmine for 96 weeks. Because DLB is a progressive illness, the authors had expected to see a substantial worsening of NPI scores over 96 weeks; instead, rivastigmine appeared to prevent the emergence of new behavioral and psychological symptoms. Disruptive Behaviors in More Advanced Alzheimer's Disease
The efficacy of rivastigmine in the treatment of BPSD also has been studied in patients with moderate to severe AD living in long-term care facilities. In a 6-month study in 113 patients with severe AD (mean baseline NPI-nursing home version [NPI-NH] score, 15.5; mean baseline MMSE score, 10.9), 49 >53% of patients showed improvements on all NPI-NH items, including those relating to psychotic and
nonpsychotic behaviors (Figure 5), and had a mean improvement of 0.7 point on the MMSE. More than 40°,6 of patients had >_30% improvement from baseline in NPI-NH scores. Among patients without BPSD at baseline, up to 93% developed no symptoms during active treatment. Thus, rivastigmine treatment seemed to reduce the emergence or development of BPSD in patients with advanced AD. These benefits were maintained during a 6-month extension of this study, 49 in which sustained improvements in BPSD were accompanied by a decrease in the use of psychotropic medications. In a 6-month study in 173 patients (mean baseline NPI-NH score, 16.5; mean baseline MMSE score, 9.3), ~° 59% of patients had improvements in NPI-NH scores, and improvements in disruptive BPSD were accompanied by a substantial decrease in the use of psychotropic medications. In particular, there were improvements in mean scores on the NPI-NH categories of aberrant motor behavior, agitation, delusions, hallucinations, irritability, apathy, appetite changes, and nighttime behavior. An extension of this study found that the efficacy of rivastigmine was maintained in these patients for >_12 months. 51 After 12 months of treatment, 57% of patients who had exhibited BPSD at baseline demonstrated improvements on the NPI-NH, with -50% of these patients
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having >30% improvement. These behavioral benefits were associated with a reduction in the use of drugs for the treatment of behavioral symptoms (Figure 6). 52 Further analyses indicated that these benefits occurred both in patients with moderate AD (baseline MMSE score >10) and in those with severe AD (baseline MMSE score <10). 53 At 52 weeks, patients with moderate AD maintained a mean 3.1point improvement in NPI-NH score from baseline, whereas patients with severe AD maintained a mean improvement of 0.2 point. Neuroleptic use decreased by 68% and 62% in the subgroups with moderate and severe AD, respectively. As a result, significantly more patients with moderate AD were able to discontinue all psychotropic use compared with those with severe AD (P = 0.04). Because these were open-label studies, it is not possible to quantify any placebo (psychosocial) effects.
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It is important that drugs do not cause behavioral problems while improving or preventing the emergence of BPSD. Some reports have indicated that use of some cholinesterase inhibitors may be associated with treatment-emergent neuropsychiatric events. 35S,5~-5r NPI scores were reported to be better in placebo recipients compared with donepezil recipients in studies involving patients with Down syndrome (2.5point difference; P < 0.05) 3r and patients with AD residing in a nursing home (3.0-point difference; P = NS)J 8 possibly reflecting a potential for donepezil to cause treatment-emergent events. Dunn et a155 recommended that donepezil not be given to patients with such problems as insomnia or agitation. It is not known whether the more frequent reports of treatment-emergent neuropsychiatric events with donepezil compared with other cholinesterase inhibitors 29 reflect a problem particular to this agent or simply the fact that donepezil is the most commonly prescribed agent in this class. As stated in the product informationj 8 rivastigmine has been studied in >3300 patients. Adverse events associated with rivastigmine generally have been mild to moderate, transient, and dose dependent, the most common being nausea, vomiting, dizziness, anorexia, asthenia, and somnolence. 23 Because of the cholinomimetic nature of this drug, special care may be necessary when prescribing rivastigmine for patients with
986
Figure 6. Reductions in the concomitant use of antipsychotic medications in nursing home patients receiving rivastigmine for 12 months, s2
sick-sinus syndrome or conduction defects, active gastric or duodenal ulcers or a predisposition to either, a history of asthma or obstructive pulmonary disease, a predisposition to urinary obstruction, or a predisposition to seizures. 58 Rivastigmine is unlikely to be involved in significant interactions with other medications. It is almost completely independent of metabolism and elimination by liver microsomal enzymes and does not bind significantly to plasma proteins. However, in view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic drugs and may interfere with the activity of anticholinergic medications. DISCUSSION
In addition to its effects on cognitive performance and ability to perform activities of daily living in patients with AD, 23'2"+ rivastigmine treatment may provide clinically relevant behavioral benefits across the spectrum of AD severity. Some of rivastigmine's benefit appears to be the result of improvements in existing symptoms, but its main behavioral effect seems to be in preventing the emergence of symp-
S.I. Finkel
toms. These benefits have been reflected in a reduction in the use of concomitant psychotropic drugs. 52 The positive effects of rivastigmine in patients with AD appear to be clinically relevant. In particular, in patients with DLB, ~6 which is noted for its high prevalence of BPSD, the effects of rivastigmine have been reported to be significant, meaningful, and comparable in magnitude to changes observed with conventional psychotropic a g e n t s S The reported benefits of rivastigmine therapy in patients with AD support the revised hypothesis concerning cholinergic control of behavioral symptoms. 16,2° The effects of rivastigmine on BPSD also may help clarify the specific roles of AChE and BuChE in different regions of the human brain. For example, levels of BuChE are particularly high in structures such as the hippocampus, amygdala, and thalamus3°,31--brain regions involved in aspects of behavior and emotion. Delusional thoughts have recently been linked to frontal/temporal cortex hypometabolism, 59 and rivastigmine has been shown to improve glucose metabolism in these regions of the human brain. 6°,61 Because these brain structures are believed to be involved in aspects of behavior and emotion, the ability of rivastigmine to inhibit both BuChE and AChE in these regions may predict important clinical effects. This review is limited by the fact that most of the analyses of rivastigmine in patients with mild to moderate AD were retrospective. Pivotal studies of rivastigmine in this population were not designed to prospectively evaluate effects on BPSD. Moreover, patients were excluded from studies if they had severe behavioral problems, so the present results are relevant only to the subpopulation of AD patients with minimal behavioral problems. As such, these data should be interpreted with caution. CONCLUSIONS
The findings of this review suggest a basis for further revisions to the cholinergic hypothesis, specifically the inclusion of BuChE as a rational target for the treatment of AD, particularly in patients with BPSD. Rivastigmine may provide a well-tolerated treatment option for the improvement or prevention of psychotic and nonpsychotic symptoms associated with AD. These preliminary findings require further investigation in prospective, randomized, double-blind studies.
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Address correspondence to: Sanford I. Finkel, MD, 3127 Greenleaf Avenue, Wilmette, IL 60091. E-mail: sandy, [email protected]
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