Cognitive enhancers for dementia: Do they work?

No psychiatrist likes to see the month-by-month deterioration in an Alzheimer’s patient—the losses in cognition, the declining ability to function, the behavioral aberrations that upset family and friends.

The problem will accelerate in the decades ahead as the proportion of elderly in the population increase. More than 4 million people in the United States are afflicted with this disorder. Prevalence rates as high as 10% have been estimated for individuals older than 65. Patients with the disease have estimated direct costs of $20,000 to $61,000 per year if the duration lasts 7 to 8 years.¹

Although behavioral and functional deficits account for the high costs associated with Alzheimer’s disease (AD), the disorder is defined by cognitive criteria (Box 1). The majority of medication trials have been aimed at symptomatic treatment. More recently, studies have been designed to prevent or delay the onset of AD. Early on, initial therapies directed toward AD were aimed at reversing the cholinergic deficit (Box 2). Clinical trials utilizing lecithin (25-100 g/d) and choline (<16 g/d) as precursors of acetylcholine did not lead to significant benefit.⁶ Augmenting central cholinergic levels with acetylcholinesterase (AChE) inhibitors has consistently detected symptomatic improvement.

In recent years, the Food and Drug Administration has approved 4 AChE inhibitors—tacrine, donepezil, rivastigmine, and galantamine—for the treatment of AD. I will discuss only the latter 3, since tacrine, the first to Nshow benefit, has a high rate of adverse effects and is of limited use.⁷ The AChE inhibitors may improve cognition and behavioral symptoms and delay progression of the illness. They can also have beneficial effects on activities of daily living (ADL) and can reduce costs and improve caregiver burden.⁸

Box 1

The three AChE inhibitors have unique basic properties (Box 3). In order to maximize and prolong positive drug effects, it is important to start early and adjust dosage during the treatment⁹ (Table 1). Side effects are tolerable; the most common include nausea, vomiting, and diarrhea. Titrating the dosage slowly can reduce these. The cholinergic quality of these medications dictate that they be prescribed with caution in patients with bradycardic arrhythmias such as sick sinus syndrome, asthma, or chronic obstructive pulmonary disease.¹⁰

Effects on cognition and global assessments

Numerous efficacy studies examining cognition and global assessments in AD patients have been performed with the AChE inhibitors. Their major therapeutic effect is to maintain cognitive function at a constant level during a 6- to 12-month period of treatment, as compared to placebo. Comparison of clinical effects of all 3 agents demonstrates a similar magnitude of improvement. For some drugs, this may represent an upper limit, whereas for others it may still be possible to further increase the benefit.

Box 2

Results of 4 double-blind, placebo-controlled clinical trials of donepezil, involving more than 1,900 individuals with mild to moderate AD, have been published recently. In all, significant improvements in cognition were observed consistently for both therapeutic doses of donepezil (5 mg/d and 10 mg/d), relative to placebo. Similar benefits were reported for global functioning.

The long-term clinical efficacy and safety of donepezil versus placebo across 1 year in patients with mild to moderate AD was investigated.¹⁴ The Gottfries-Brane-Steen global assessment for rating dementia symptoms demonstrated the benefit of donepezil over placebo at weeks 24, 36, and 52, and at the study end point. Advantages of donepezil were also observed in cognition and ADL.

Donepezil also appears to work for patients with moderate to severe AD. In a recent 24-week study,¹⁵ patients receiving donepezil showed benefits on the Clinician’s Interview-Based Impression of Change with Caregiver Input (CIBIC+), compared with placebo, at all visits up to week 24 and at the study’s end point. All other secondary measures showed significant differences between the groups in favor of donepezil at the end of the study. These data suggest that donepezil’s benefits extend into more advanced stages of AD than those previously investigated, with good tolerability.

Clinical trials of rivastigmine (1.5-6 mg twice daily PO) have also demonstrated benefits on cognitive and global measures.¹⁶ The efficacy of rivastigmine tartrate (ENA 713) in patients with mild to moderately severe Alzheimer’s disease was evaluated in a 26-week open-label extension of a 26-week, double-blind, placebo-controlled study. By 52 weeks, patients originally treated with rivastigmine 6 to 12 mg/d had significantly better cognitive function than did patients originally treated with placebo.^{17- 19}

Box 3

Clinical trials of galantamine (4-12 mg/bid PO) have demonstrated similar benefits.²⁰ Following a 4-week placebo run-in, patients were randomized to 1 of 4 treatment arms: placebo or galantamine escalated to final maintenance dosages of 8, 16, or 24 mg/d for a 5-month treatment phase. At study’s end, the galantamine-place-bo differences on the cognitive subscale of the AD Assessment Scale were 3.3 points for the 16 mg/d group and 3.6 points for the 24 mg/d group. Treatment discontinuations due to adverse events were low in all galantamine groups (6% to 10%) and comparable with that in the placebo group (7%). The incidence of adverse events in the galantamine groups, notably gastrointestinal symptoms, was low and most adverse events were mild.

Other studies examining galantamine have demonstrated similar clinical benefits.^{8, 21}

When using AChE inhibitors, the slope of cognitive decline is similar in treated and untreated patients after the initial improvement. These drugs essentially do not reverse the disorder’s course but shift upward the curve describing the time course of cognitive decline. This applies also to behavioral and functional benefits. Thus the benefit obtained is symptomatic and not neuroprotective, and is lost after discontinuing the medications.

Effects on functioning and behavior

In a 24-week multinational clinical trial, patients receiving donepezil (10 mg/d) were more able than placebo-treated patients to perform complex daily functioning tasks.²² Similar effects have been observed with rivastigmine and galantamine.^{16, 20}

All 3 AChE inhibitors have demonstrated improvements in the behavioral changes associated with AD. Cummings et al²³ tested the hypothesis that behavioral disturbances are reported at significantly lower rates by caregivers of AD patients receiving donepezil, compared with a group of patients not receiving a drug for treatment of dementia. Donepezil patients were described as significantly less likely to be threatening, destroy property, and talk loudly, and significantly fewer were treated with sedatives.

Table 1

COMPARING THEAChE INHIBITORS

An open-label study by Weiner et al²⁴ examined the effects of donepezil on emotional and behavioral symptoms using the CERAD Behavior Rating Scale for Dementia and its subscales. In a group of 25 AD patients treated with donepezil, scores returned to baseline levels at 12 months. In contrast, the scores of the reference group worsened minimally.

Galantamine has also proved effective in treating behavioral symptoms associated with AD. In the Tariot et al²⁰ study, galantamine at 16 mg/d and 24 mg/d had a significantly better outcome on CIBIC+, ADL, and behavioral symptoms versus placebo.

Rosler et al²⁵ assessed the ability of rivastigmine to improve behavioral symptoms in AD. Using the behavioral component of the CIBIC+, results showed that long-term treatment with rivastigmine could slow the progression of symptoms. Symptoms showing stabilization included aggressiveness, activity disturbances, hallucinations, and paranoid features. The results also suggest that patients treated earlier with rivastigmine may attain a greater benefit than those whose treatment is delayed 6 months.

Rivastigmine also has significant effects on controlling behavioral symptoms in patients with Lewy body dementia.²⁶ A placebo-controlled, double-blind, multicenter study was performed in 120 patients with Lewy body dementia. Individuals were given up to 12 mg/d rivastigmine or placebo for 20 weeks, followed by 3 weeks rest. Assessment by neuropsychiatric inventory was made at baseline, and again at weeks 12, 20, and 23.

Patients taking rivastigmine were significantly less apathetic and anxious than those on placebo, and had fewer delusions and hallucinations. Almost twice as many patients on rivastigmine as on placebo (37, 63% versus 18, 30%) showed at least a 30% improvement from baseline. In a computerized cognitive assessment system and neuropsychological tests, patients were significantly faster and better than those on placebo, particularly when performing tasks with a substantial attentional component.

Cost effectiveness

Numerous studies have demonstrated that AChE inhibitors are cost savers in AD treatment. Fillit et al²⁷ examined the impact of donepezil in a multisite managed care organization for 2 years using claims data for 70 individuals with AD and related dementias. The median per diem medical costs were $1.22 lower post treatment than they were in the pretreatment phase. Moreover, posttreatment costs were reduced in 6 of 7 service settings, with median per diem savings of $0.77 in outpatient care and $0.65 in office visits.

Neumann et al²⁸ utilized cost-effectiveness analysis to predict that for mild AD, donepezil would pay for itself in cost offsets if the drug’s effect exceeds 2 years. Donepezil costs were partially offset by a reduction in the costs of care due to enhanced cognitive functioning and the delay in placing the patient in more costly disease stages and settings.

One study used the disease-progression model to estimate potential per-patient savings resulting from the treatment of AD in Canada.²⁹ Rivastigmine was estimated to delay the transition to more severe stages of AD by up to 188 days for patients with mild AD after 2 years of treatment. For patients with mild-to-moderate and moderate disease, this delay was estimated to be 106 and 44 days, respectively.

The Assessment of Health Economics in Alzheimer’s Disease model uses algorithms to predict the time until patients with AD require full-time care. A study, performed in Canada, compared treatment with galantamine to treatment without pharmacological interventions.³⁰ Galantamine was predicted to reduce the duration of full-time care by almost 10%. Approximately 5.6 patients with mild-to-moderate disease must be placed on treatment to avoid 1 year of full-time care, resulting in savings averaging $528 per patient. For patients with moderate disease, 3.9 patients must be placed on treatment to avoid 1 year of full-time care, with savings predicted at $2,533 per patient.

Caregiving burden

Fillit et al addressed caregiver well-being in a self-administered, nationwide survey of AD caregivers. Caregivers of patients treated with donepezil (n = 274) were compared with caregivers of patients not treated with donepezil (n = 274).³¹ The Caregiver Burden Scale measured time demands and distress linked to commonly performed caregiving tasks. Donepezil caregivers reported significantly lower scores on difficulty of caregiving. Similar findings have been observed with galantamine.³²

Related resources

• Bullock R. New drugs for Alzheimer’s disease and other dementias. Br J Psychiatry. 2002;180(2):135-139.
• Brodaty H, Ames D, et al. Pharmacological treatment of cognitive deficits in Alzheimer’s disease. Med J Aust. 2001;175(6):324-329.
• Ahmed MB. Alzheimer’s disease: recent advances in etiology, diagnosis, and management. Tex Med. 2001;97(12):50-58.
• Frisoni GB. Treatment of Alzheimer’s disease with acetyl-cholinesterase inhibitors: bridging the gap between evidence and practice. J Neurol. 2001;248(7):551-7.

Drug brand names

• Tacrine • Cognex
• Donepezil • Aricept
• Rivastigmine • Exelon
• Galantamine • Reminyl

Disclosure

The author reports that he receives grant/research support from, serves as a consultant to, and is on the speaker’s bureau of Janssen Pharmaceutica and Pfizer Inc., and serves as consultant to and is on the speaker’s bureau of Novartis Pharmaceuticals Corp.

No psychiatrist likes to see the month-by-month deterioration in an Alzheimer’s patient—the losses in cognition, the declining ability to function, the behavioral aberrations that upset family and friends.

The problem will accelerate in the decades ahead as the proportion of elderly in the population increase. More than 4 million people in the United States are afflicted with this disorder. Prevalence rates as high as 10% have been estimated for individuals older than 65. Patients with the disease have estimated direct costs of $20,000 to $61,000 per year if the duration lasts 7 to 8 years.¹

Although behavioral and functional deficits account for the high costs associated with Alzheimer’s disease (AD), the disorder is defined by cognitive criteria (Box 1). The majority of medication trials have been aimed at symptomatic treatment. More recently, studies have been designed to prevent or delay the onset of AD. Early on, initial therapies directed toward AD were aimed at reversing the cholinergic deficit (Box 2). Clinical trials utilizing lecithin (25-100 g/d) and choline (<16 g/d) as precursors of acetylcholine did not lead to significant benefit.⁶ Augmenting central cholinergic levels with acetylcholinesterase (AChE) inhibitors has consistently detected symptomatic improvement.

In recent years, the Food and Drug Administration has approved 4 AChE inhibitors—tacrine, donepezil, rivastigmine, and galantamine—for the treatment of AD. I will discuss only the latter 3, since tacrine, the first to Nshow benefit, has a high rate of adverse effects and is of limited use.⁷ The AChE inhibitors may improve cognition and behavioral symptoms and delay progression of the illness. They can also have beneficial effects on activities of daily living (ADL) and can reduce costs and improve caregiver burden.⁸

Box 1

The three AChE inhibitors have unique basic properties (Box 3). In order to maximize and prolong positive drug effects, it is important to start early and adjust dosage during the treatment⁹ (Table 1). Side effects are tolerable; the most common include nausea, vomiting, and diarrhea. Titrating the dosage slowly can reduce these. The cholinergic quality of these medications dictate that they be prescribed with caution in patients with bradycardic arrhythmias such as sick sinus syndrome, asthma, or chronic obstructive pulmonary disease.¹⁰

Effects on cognition and global assessments

Numerous efficacy studies examining cognition and global assessments in AD patients have been performed with the AChE inhibitors. Their major therapeutic effect is to maintain cognitive function at a constant level during a 6- to 12-month period of treatment, as compared to placebo. Comparison of clinical effects of all 3 agents demonstrates a similar magnitude of improvement. For some drugs, this may represent an upper limit, whereas for others it may still be possible to further increase the benefit.

Box 2

Results of 4 double-blind, placebo-controlled clinical trials of donepezil, involving more than 1,900 individuals with mild to moderate AD, have been published recently. In all, significant improvements in cognition were observed consistently for both therapeutic doses of donepezil (5 mg/d and 10 mg/d), relative to placebo. Similar benefits were reported for global functioning.

The long-term clinical efficacy and safety of donepezil versus placebo across 1 year in patients with mild to moderate AD was investigated.¹⁴ The Gottfries-Brane-Steen global assessment for rating dementia symptoms demonstrated the benefit of donepezil over placebo at weeks 24, 36, and 52, and at the study end point. Advantages of donepezil were also observed in cognition and ADL.

Donepezil also appears to work for patients with moderate to severe AD. In a recent 24-week study,¹⁵ patients receiving donepezil showed benefits on the Clinician’s Interview-Based Impression of Change with Caregiver Input (CIBIC+), compared with placebo, at all visits up to week 24 and at the study’s end point. All other secondary measures showed significant differences between the groups in favor of donepezil at the end of the study. These data suggest that donepezil’s benefits extend into more advanced stages of AD than those previously investigated, with good tolerability.

Clinical trials of rivastigmine (1.5-6 mg twice daily PO) have also demonstrated benefits on cognitive and global measures.¹⁶ The efficacy of rivastigmine tartrate (ENA 713) in patients with mild to moderately severe Alzheimer’s disease was evaluated in a 26-week open-label extension of a 26-week, double-blind, placebo-controlled study. By 52 weeks, patients originally treated with rivastigmine 6 to 12 mg/d had significantly better cognitive function than did patients originally treated with placebo.^{17- 19}

Box 3

Clinical trials of galantamine (4-12 mg/bid PO) have demonstrated similar benefits.²⁰ Following a 4-week placebo run-in, patients were randomized to 1 of 4 treatment arms: placebo or galantamine escalated to final maintenance dosages of 8, 16, or 24 mg/d for a 5-month treatment phase. At study’s end, the galantamine-place-bo differences on the cognitive subscale of the AD Assessment Scale were 3.3 points for the 16 mg/d group and 3.6 points for the 24 mg/d group. Treatment discontinuations due to adverse events were low in all galantamine groups (6% to 10%) and comparable with that in the placebo group (7%). The incidence of adverse events in the galantamine groups, notably gastrointestinal symptoms, was low and most adverse events were mild.

Other studies examining galantamine have demonstrated similar clinical benefits.^{8, 21}

When using AChE inhibitors, the slope of cognitive decline is similar in treated and untreated patients after the initial improvement. These drugs essentially do not reverse the disorder’s course but shift upward the curve describing the time course of cognitive decline. This applies also to behavioral and functional benefits. Thus the benefit obtained is symptomatic and not neuroprotective, and is lost after discontinuing the medications.

Effects on functioning and behavior

In a 24-week multinational clinical trial, patients receiving donepezil (10 mg/d) were more able than placebo-treated patients to perform complex daily functioning tasks.²² Similar effects have been observed with rivastigmine and galantamine.^{16, 20}

All 3 AChE inhibitors have demonstrated improvements in the behavioral changes associated with AD. Cummings et al²³ tested the hypothesis that behavioral disturbances are reported at significantly lower rates by caregivers of AD patients receiving donepezil, compared with a group of patients not receiving a drug for treatment of dementia. Donepezil patients were described as significantly less likely to be threatening, destroy property, and talk loudly, and significantly fewer were treated with sedatives.

Table 1

COMPARING THEAChE INHIBITORS

An open-label study by Weiner et al²⁴ examined the effects of donepezil on emotional and behavioral symptoms using the CERAD Behavior Rating Scale for Dementia and its subscales. In a group of 25 AD patients treated with donepezil, scores returned to baseline levels at 12 months. In contrast, the scores of the reference group worsened minimally.

Galantamine has also proved effective in treating behavioral symptoms associated with AD. In the Tariot et al²⁰ study, galantamine at 16 mg/d and 24 mg/d had a significantly better outcome on CIBIC+, ADL, and behavioral symptoms versus placebo.

Rosler et al²⁵ assessed the ability of rivastigmine to improve behavioral symptoms in AD. Using the behavioral component of the CIBIC+, results showed that long-term treatment with rivastigmine could slow the progression of symptoms. Symptoms showing stabilization included aggressiveness, activity disturbances, hallucinations, and paranoid features. The results also suggest that patients treated earlier with rivastigmine may attain a greater benefit than those whose treatment is delayed 6 months.

Rivastigmine also has significant effects on controlling behavioral symptoms in patients with Lewy body dementia.²⁶ A placebo-controlled, double-blind, multicenter study was performed in 120 patients with Lewy body dementia. Individuals were given up to 12 mg/d rivastigmine or placebo for 20 weeks, followed by 3 weeks rest. Assessment by neuropsychiatric inventory was made at baseline, and again at weeks 12, 20, and 23.

Patients taking rivastigmine were significantly less apathetic and anxious than those on placebo, and had fewer delusions and hallucinations. Almost twice as many patients on rivastigmine as on placebo (37, 63% versus 18, 30%) showed at least a 30% improvement from baseline. In a computerized cognitive assessment system and neuropsychological tests, patients were significantly faster and better than those on placebo, particularly when performing tasks with a substantial attentional component.

Cost effectiveness

Numerous studies have demonstrated that AChE inhibitors are cost savers in AD treatment. Fillit et al²⁷ examined the impact of donepezil in a multisite managed care organization for 2 years using claims data for 70 individuals with AD and related dementias. The median per diem medical costs were $1.22 lower post treatment than they were in the pretreatment phase. Moreover, posttreatment costs were reduced in 6 of 7 service settings, with median per diem savings of $0.77 in outpatient care and $0.65 in office visits.

Neumann et al²⁸ utilized cost-effectiveness analysis to predict that for mild AD, donepezil would pay for itself in cost offsets if the drug’s effect exceeds 2 years. Donepezil costs were partially offset by a reduction in the costs of care due to enhanced cognitive functioning and the delay in placing the patient in more costly disease stages and settings.

One study used the disease-progression model to estimate potential per-patient savings resulting from the treatment of AD in Canada.²⁹ Rivastigmine was estimated to delay the transition to more severe stages of AD by up to 188 days for patients with mild AD after 2 years of treatment. For patients with mild-to-moderate and moderate disease, this delay was estimated to be 106 and 44 days, respectively.

The Assessment of Health Economics in Alzheimer’s Disease model uses algorithms to predict the time until patients with AD require full-time care. A study, performed in Canada, compared treatment with galantamine to treatment without pharmacological interventions.³⁰ Galantamine was predicted to reduce the duration of full-time care by almost 10%. Approximately 5.6 patients with mild-to-moderate disease must be placed on treatment to avoid 1 year of full-time care, resulting in savings averaging $528 per patient. For patients with moderate disease, 3.9 patients must be placed on treatment to avoid 1 year of full-time care, with savings predicted at $2,533 per patient.

Caregiving burden

Fillit et al addressed caregiver well-being in a self-administered, nationwide survey of AD caregivers. Caregivers of patients treated with donepezil (n = 274) were compared with caregivers of patients not treated with donepezil (n = 274).³¹ The Caregiver Burden Scale measured time demands and distress linked to commonly performed caregiving tasks. Donepezil caregivers reported significantly lower scores on difficulty of caregiving. Similar findings have been observed with galantamine.³²

Related resources

• Bullock R. New drugs for Alzheimer’s disease and other dementias. Br J Psychiatry. 2002;180(2):135-139.
• Brodaty H, Ames D, et al. Pharmacological treatment of cognitive deficits in Alzheimer’s disease. Med J Aust. 2001;175(6):324-329.
• Ahmed MB. Alzheimer’s disease: recent advances in etiology, diagnosis, and management. Tex Med. 2001;97(12):50-58.
• Frisoni GB. Treatment of Alzheimer’s disease with acetyl-cholinesterase inhibitors: bridging the gap between evidence and practice. J Neurol. 2001;248(7):551-7.

Drug brand names

• Tacrine • Cognex
• Donepezil • Aricept
• Rivastigmine • Exelon
• Galantamine • Reminyl

Disclosure

The author reports that he receives grant/research support from, serves as a consultant to, and is on the speaker’s bureau of Janssen Pharmaceutica and Pfizer Inc., and serves as consultant to and is on the speaker’s bureau of Novartis Pharmaceuticals Corp.

No psychiatrist likes to see the month-by-month deterioration in an Alzheimer’s patient—the losses in cognition, the declining ability to function, the behavioral aberrations that upset family and friends.

The problem will accelerate in the decades ahead as the proportion of elderly in the population increase. More than 4 million people in the United States are afflicted with this disorder. Prevalence rates as high as 10% have been estimated for individuals older than 65. Patients with the disease have estimated direct costs of $20,000 to $61,000 per year if the duration lasts 7 to 8 years.¹

Although behavioral and functional deficits account for the high costs associated with Alzheimer’s disease (AD), the disorder is defined by cognitive criteria (Box 1). The majority of medication trials have been aimed at symptomatic treatment. More recently, studies have been designed to prevent or delay the onset of AD. Early on, initial therapies directed toward AD were aimed at reversing the cholinergic deficit (Box 2). Clinical trials utilizing lecithin (25-100 g/d) and choline (<16 g/d) as precursors of acetylcholine did not lead to significant benefit.⁶ Augmenting central cholinergic levels with acetylcholinesterase (AChE) inhibitors has consistently detected symptomatic improvement.

In recent years, the Food and Drug Administration has approved 4 AChE inhibitors—tacrine, donepezil, rivastigmine, and galantamine—for the treatment of AD. I will discuss only the latter 3, since tacrine, the first to Nshow benefit, has a high rate of adverse effects and is of limited use.⁷ The AChE inhibitors may improve cognition and behavioral symptoms and delay progression of the illness. They can also have beneficial effects on activities of daily living (ADL) and can reduce costs and improve caregiver burden.⁸

Box 1

The three AChE inhibitors have unique basic properties (Box 3). In order to maximize and prolong positive drug effects, it is important to start early and adjust dosage during the treatment⁹ (Table 1). Side effects are tolerable; the most common include nausea, vomiting, and diarrhea. Titrating the dosage slowly can reduce these. The cholinergic quality of these medications dictate that they be prescribed with caution in patients with bradycardic arrhythmias such as sick sinus syndrome, asthma, or chronic obstructive pulmonary disease.¹⁰

Effects on cognition and global assessments

Numerous efficacy studies examining cognition and global assessments in AD patients have been performed with the AChE inhibitors. Their major therapeutic effect is to maintain cognitive function at a constant level during a 6- to 12-month period of treatment, as compared to placebo. Comparison of clinical effects of all 3 agents demonstrates a similar magnitude of improvement. For some drugs, this may represent an upper limit, whereas for others it may still be possible to further increase the benefit.

Box 2

Results of 4 double-blind, placebo-controlled clinical trials of donepezil, involving more than 1,900 individuals with mild to moderate AD, have been published recently. In all, significant improvements in cognition were observed consistently for both therapeutic doses of donepezil (5 mg/d and 10 mg/d), relative to placebo. Similar benefits were reported for global functioning.

The long-term clinical efficacy and safety of donepezil versus placebo across 1 year in patients with mild to moderate AD was investigated.¹⁴ The Gottfries-Brane-Steen global assessment for rating dementia symptoms demonstrated the benefit of donepezil over placebo at weeks 24, 36, and 52, and at the study end point. Advantages of donepezil were also observed in cognition and ADL.

Donepezil also appears to work for patients with moderate to severe AD. In a recent 24-week study,¹⁵ patients receiving donepezil showed benefits on the Clinician’s Interview-Based Impression of Change with Caregiver Input (CIBIC+), compared with placebo, at all visits up to week 24 and at the study’s end point. All other secondary measures showed significant differences between the groups in favor of donepezil at the end of the study. These data suggest that donepezil’s benefits extend into more advanced stages of AD than those previously investigated, with good tolerability.

Clinical trials of rivastigmine (1.5-6 mg twice daily PO) have also demonstrated benefits on cognitive and global measures.¹⁶ The efficacy of rivastigmine tartrate (ENA 713) in patients with mild to moderately severe Alzheimer’s disease was evaluated in a 26-week open-label extension of a 26-week, double-blind, placebo-controlled study. By 52 weeks, patients originally treated with rivastigmine 6 to 12 mg/d had significantly better cognitive function than did patients originally treated with placebo.^{17- 19}

Box 3

Clinical trials of galantamine (4-12 mg/bid PO) have demonstrated similar benefits.²⁰ Following a 4-week placebo run-in, patients were randomized to 1 of 4 treatment arms: placebo or galantamine escalated to final maintenance dosages of 8, 16, or 24 mg/d for a 5-month treatment phase. At study’s end, the galantamine-place-bo differences on the cognitive subscale of the AD Assessment Scale were 3.3 points for the 16 mg/d group and 3.6 points for the 24 mg/d group. Treatment discontinuations due to adverse events were low in all galantamine groups (6% to 10%) and comparable with that in the placebo group (7%). The incidence of adverse events in the galantamine groups, notably gastrointestinal symptoms, was low and most adverse events were mild.

Other studies examining galantamine have demonstrated similar clinical benefits.^{8, 21}

When using AChE inhibitors, the slope of cognitive decline is similar in treated and untreated patients after the initial improvement. These drugs essentially do not reverse the disorder’s course but shift upward the curve describing the time course of cognitive decline. This applies also to behavioral and functional benefits. Thus the benefit obtained is symptomatic and not neuroprotective, and is lost after discontinuing the medications.

Effects on functioning and behavior

In a 24-week multinational clinical trial, patients receiving donepezil (10 mg/d) were more able than placebo-treated patients to perform complex daily functioning tasks.²² Similar effects have been observed with rivastigmine and galantamine.^{16, 20}

All 3 AChE inhibitors have demonstrated improvements in the behavioral changes associated with AD. Cummings et al²³ tested the hypothesis that behavioral disturbances are reported at significantly lower rates by caregivers of AD patients receiving donepezil, compared with a group of patients not receiving a drug for treatment of dementia. Donepezil patients were described as significantly less likely to be threatening, destroy property, and talk loudly, and significantly fewer were treated with sedatives.

Table 1

COMPARING THEAChE INHIBITORS

An open-label study by Weiner et al²⁴ examined the effects of donepezil on emotional and behavioral symptoms using the CERAD Behavior Rating Scale for Dementia and its subscales. In a group of 25 AD patients treated with donepezil, scores returned to baseline levels at 12 months. In contrast, the scores of the reference group worsened minimally.

Galantamine has also proved effective in treating behavioral symptoms associated with AD. In the Tariot et al²⁰ study, galantamine at 16 mg/d and 24 mg/d had a significantly better outcome on CIBIC+, ADL, and behavioral symptoms versus placebo.

Rosler et al²⁵ assessed the ability of rivastigmine to improve behavioral symptoms in AD. Using the behavioral component of the CIBIC+, results showed that long-term treatment with rivastigmine could slow the progression of symptoms. Symptoms showing stabilization included aggressiveness, activity disturbances, hallucinations, and paranoid features. The results also suggest that patients treated earlier with rivastigmine may attain a greater benefit than those whose treatment is delayed 6 months.

Rivastigmine also has significant effects on controlling behavioral symptoms in patients with Lewy body dementia.²⁶ A placebo-controlled, double-blind, multicenter study was performed in 120 patients with Lewy body dementia. Individuals were given up to 12 mg/d rivastigmine or placebo for 20 weeks, followed by 3 weeks rest. Assessment by neuropsychiatric inventory was made at baseline, and again at weeks 12, 20, and 23.

Patients taking rivastigmine were significantly less apathetic and anxious than those on placebo, and had fewer delusions and hallucinations. Almost twice as many patients on rivastigmine as on placebo (37, 63% versus 18, 30%) showed at least a 30% improvement from baseline. In a computerized cognitive assessment system and neuropsychological tests, patients were significantly faster and better than those on placebo, particularly when performing tasks with a substantial attentional component.

Cost effectiveness

Numerous studies have demonstrated that AChE inhibitors are cost savers in AD treatment. Fillit et al²⁷ examined the impact of donepezil in a multisite managed care organization for 2 years using claims data for 70 individuals with AD and related dementias. The median per diem medical costs were $1.22 lower post treatment than they were in the pretreatment phase. Moreover, posttreatment costs were reduced in 6 of 7 service settings, with median per diem savings of $0.77 in outpatient care and $0.65 in office visits.

Neumann et al²⁸ utilized cost-effectiveness analysis to predict that for mild AD, donepezil would pay for itself in cost offsets if the drug’s effect exceeds 2 years. Donepezil costs were partially offset by a reduction in the costs of care due to enhanced cognitive functioning and the delay in placing the patient in more costly disease stages and settings.

One study used the disease-progression model to estimate potential per-patient savings resulting from the treatment of AD in Canada.²⁹ Rivastigmine was estimated to delay the transition to more severe stages of AD by up to 188 days for patients with mild AD after 2 years of treatment. For patients with mild-to-moderate and moderate disease, this delay was estimated to be 106 and 44 days, respectively.

The Assessment of Health Economics in Alzheimer’s Disease model uses algorithms to predict the time until patients with AD require full-time care. A study, performed in Canada, compared treatment with galantamine to treatment without pharmacological interventions.³⁰ Galantamine was predicted to reduce the duration of full-time care by almost 10%. Approximately 5.6 patients with mild-to-moderate disease must be placed on treatment to avoid 1 year of full-time care, resulting in savings averaging $528 per patient. For patients with moderate disease, 3.9 patients must be placed on treatment to avoid 1 year of full-time care, with savings predicted at $2,533 per patient.

Caregiving burden

Fillit et al addressed caregiver well-being in a self-administered, nationwide survey of AD caregivers. Caregivers of patients treated with donepezil (n = 274) were compared with caregivers of patients not treated with donepezil (n = 274).³¹ The Caregiver Burden Scale measured time demands and distress linked to commonly performed caregiving tasks. Donepezil caregivers reported significantly lower scores on difficulty of caregiving. Similar findings have been observed with galantamine.³²

Related resources

• Bullock R. New drugs for Alzheimer’s disease and other dementias. Br J Psychiatry. 2002;180(2):135-139.
• Brodaty H, Ames D, et al. Pharmacological treatment of cognitive deficits in Alzheimer’s disease. Med J Aust. 2001;175(6):324-329.
• Ahmed MB. Alzheimer’s disease: recent advances in etiology, diagnosis, and management. Tex Med. 2001;97(12):50-58.
• Frisoni GB. Treatment of Alzheimer’s disease with acetyl-cholinesterase inhibitors: bridging the gap between evidence and practice. J Neurol. 2001;248(7):551-7.

Drug brand names

• Tacrine • Cognex
• Donepezil • Aricept
• Rivastigmine • Exelon
• Galantamine • Reminyl

Disclosure

The author reports that he receives grant/research support from, serves as a consultant to, and is on the speaker’s bureau of Janssen Pharmaceutica and Pfizer Inc., and serves as consultant to and is on the speaker’s bureau of Novartis Pharmaceuticals Corp.