Evidence-Based Reviews

Cognitive enhancers for dementia: Do they work?

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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.


 

References

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

DIAGNOSTIC CRITERIA FOR ALZHEIMER’S DEMENTIA
  1. The development of multiple cognitive deficits manifested by both:
    1. Memory impairment (impaired ability to learn new information or to recall previously learned information) and
    2. One (or more) of the following cognitive disturbances:
      1. Aphasia (language disturbance)
      2. Apraxia (impaired ability to carry out motor activities despite intact motor function)
      3. Agnosia (failure to recognize or identify objects despite intact sensory function)
      4. Disturbance in executive functioning (i.e., planning, organization, sequencing, abstracting)
  2. 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.
  3. 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 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

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

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