Cognitive enhancers for dementia: Do they work?
Three cholinesterase inhibitors—donepezil, rivastigmine, and galantamine—are commonly used to treat Alzheimer’s disease. How effective are they in improving or maintaining a patient’s cognition, functioning, or behavior? What is their impact on costs and caregiver burden? Read on for answers.
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
DIAGNOSTIC CRITERIA FOR ALZHEIMER’S DEMENTIA
- The development of multiple cognitive deficits manifested by both:
- Memory impairment (impaired ability to learn new information or to recall previously learned information) and
- One (or more) of the following cognitive disturbances:
- Aphasia (language disturbance)
- Apraxia (impaired ability to carry out motor activities despite intact motor function)
- Agnosia (failure to recognize or identify objects despite intact sensory function)
- Disturbance in executive functioning (i.e., planning, organization, sequencing, abstracting)
- The cognitive deficits in Criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning.
- The course is characterized by gradual onset and continuing cognitive decline.
Source: American Psychatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington DC: American Psychiatric Press., 1994.
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 treatment 9 (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.
WHAT IS THE PATHOPHYSIOLOGY OF AD?
The pathophysiologic processes implicated in Alzheimer’s disease (AD)include amyloid precursor protein metabolism, tau phosphorylation, apolipoprotein E, inflammation, oxidative stress, and apoptosis. Neuropathological features include amyloid plaques, neurofibrillary tangles, neuronal and synaptic loss, microgliosis, and astrocytosis. The resulting clinical syndrome of dementia is associated with neurotransmitter deficits and intracortical disconnection.
The central cholinergic neurotransmitter system is impaired in AD. This system is involved in learning and memory. The limbic system and neocortex receive projections from the cholinergic system in the septal nuclei and substantia innominata. This includes the medial septal nucleus, diagonal band, and nucleus basalis. 2 Literature on animals has demonstrated that basal forebrain lesions impair learning and memory. Cholinergic agonists can improve this. Furthermore, cholinergic antagonists such as scopolamine and atropine can impair learning and memory in humans and animals. 3 In AD, a 58% to 93% reduction in choline acetyltransferase levels (and other cholinergic markers) in the cortex and hippocampus can be observed and this correlates with dementia severity. 4 Early AD is characterized by neuronal loss and tangles in the cholinergic nucleus basalis of Meynert. 5
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
BASIC PROPERTIES OFTHEAChE INHIBITORS
Donepezil is a second-generation, piperidine-class, selective and reversible acetylcholinesterase (AChE) inhibitor. It is structurally dissimilar from other established AChE inhibitors.
Experimentally, donepezil inhibits AChE activity in human erythrocytes and increases extracellular acetylcholine levels in the cerebral cortex and the hippocampus of the rat. Pharmacologically, donepezil has a half-life of approximately 70h, lending itself to once-daily administration. 11
Rivastigmine (ENA 713, or carbamoylatine) is an AChE inhibitor with brain-region selectivity and a long duration of action. Both preclinical studies and studies in human volunteers have shown that rivastigmine induces substantially greater inhibition of AChE in the central nervous system compartment than it does in the periphery (40% inhibition of central AChE compared with 10% inhibition of plasma butylcholinesterase in healthy volunteers). Rivastigmine also preferentially inhibits the G1 enzymatic form of AChE, which predominates in the brains of patients with Alzheimer’s disease (AD).
Evidence from animal studies also suggests that rivastigmine is a more potent inhibitor of AChE in the cortex and hippocampus, the brain regions most affected by AD. The principal metabolite of rivastigmine has at least 10-fold lower activity against AChE compared with the parent drug.
Rivastigmine is completely metabolized; the major route of elimination of the metabolites is renal. Rivastigmine is inactivated during the process of interacting with and inhibiting AChE, and, in contrast to other AChE inhibitors, the hepatic cytochrome P-450 (CYP-450) system is not involved in the metabolism of rivastigmine. 12
Galantamine is an allosterically potentiating ligand that modulates nicotinic cholinergic receptors (nAChR) to increase acetylcholine release as well as acting as an AChE inhibitor. In preclinical experiments, the drug significantly improves learning, reduces AChE levels, and increases nicotinic receptor binding. Action of galantamine is on the most abundant nAChR in the human brain, the alpha4/beta2subtype. 13
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.
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 al 23 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.
COMPARING THEAChE INHIBITORS
1.5 mg bid
4 mg bid
Total recommended dosage
Adapted from Conn DK. Cholinesterase inhibitors: Comparing the options for mild-to-moderate dementia. Geriatrics56: 56-57, 2001.
An open-label study by Weiner et al 24 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 al 20 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 al 25 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.