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CognitiveCognitive enhancersenhancers forfor John Kasckow, MD, PhD Director of Geriatric Psychiatry University of Cincinnati College of Medicine Cincinnati, Ohio Three cholinesterase inhibitors—donepezil, rivastigmine, and galantamine—are commonly used to treat Alzheimer’s disease. How effective are they inin improvingimproving oror maintainingmaintaining aa patient’spatient’s cognition,cognition, functioning, or behavior? What is their impact on costs and caregiver burden? Read on for answers. 22 VOL. 1, NO. 3 / MARCH 2002 Currentp SYCHIATRY Currentp SYCHIATRY dementia: Do they work? o psychiatrist likes to see the month-by- show benefit, has a high rate of adverse effects and is of lim- month deterioration in an Alzheimer’s ited use.7 The AChE inhibitors may improve cognition and patient—the losses in cognition, the behavioral symptoms and delay progression of the illness. Ndeclining ability to function, the behavioral aberrations that upset family and friends. Box 1 The problem will accelerate in the decades ahead DIAGNOSTIC CRITERIA as the proportion of elderly in the population increase. More than 4 million people in the United States are FOR ALZHEIMER’S DEMENTIA afflicted with this disorder. Prevalence rates as high as A. The development of multiple cognitive deficits 10% have been estimated for individuals older than 65. manifested by both: Patients with the disease have estimated direct costs of 1. Memory impairment (impaired ability to learn $20,000 to $61,000 per year if the duration lasts 7 to 8 new information or to recall previously learned years.1 information) and Although behavioral and functional deficits 2. One (or more) of the following cognitive account for the high costs associated with Alzheimer’s disturbances: disease (AD), the disorder is defined by cognitive criteria a. Aphasia (language disturbance) (Box 1). The majority of medication trials have been b. Apraxia (impaired ability to carry out motor aimed at symptomatic treatment. More recently, studies activities despite intact motor function) have been designed to prevent or delay the onset of AD. c. Agnosia (failure to recognize or identify Early on, initial therapies directed toward AD were objects despite intact sensory function) aimed at reversing the cholinergic deficit (Box 2). d. Disturbance in executive functioning (i.e., Clinical trials utilizing lecithin (25-100 g/d) and choline planning, organization, sequencing, abstracting) (<16 g/d) as precursors of acetylcholine did not lead to B. The cognitive deficits in Criteria A1 and A2 each significant benefit.6 Augmenting central cholinergic levels cause significant impairment in social or occupational with acetylcholinesterase (AChE) inhibitors has consis- functioning and represent a significant decline from tently detected symptomatic improvement. a previous level of functioning. In recent years, the Food and Drug Administration C. The course is characterized by gradual onset and has approved 4 AChE inhibitors—tacrine, donepezil, continuing cognitive decline. rivastigmine, and galantamine—for the treatment of AD. Source: American Psychatric Association. Diagnostic and Statistical Manual of Mental I will discuss only the latter 3, since tacrine, the first to Disorders, 4th ed. Washington DC: American Psychiatric Press., 1994. VOL. 1, NO. 3 / MARCH 2002 23 Cognitive enhancers for dementia: Do they work? They can also have beneficial effects on activities of daily liv- Comparison of clinical effects of all 3 agents demonstrates a ing (ADL) and can reduce costs and improve caregiver bur- similar magnitude of improvement. For some drugs, this may den.8 represent an upper limit, whereas for others it may still be The three AChE inhibitors have possible to further increase the benefit. unique basic properties (Box 3). In order to Double-blind, placebo- Results of 4 double-blind, placebo- maximize and prolong positive drug effects, controlled trials have controlled clinical trials of donepezil, it is important to start early and adjust dosage involving more than 1,900 individuals during the treatment9 (Table 1). Side effects are demonstrated with mild to moderate AD, have been tolerable; the most common include nausea, vom- improved cognition published recently. In all, significant iting, and diarrhea. Titrating the dosage slowly can in patients taking improvements in cognition were observed reduce these. The cholinergic quality of these med- donepezil consistently for both therapeutic doses of ications dictate that they be prescribed with caution donepezil (5 mg/d and 10 mg/d), relative in patients with bradycardic arrhythmias such as to placebo. Similar benefits were reported for sick sinus syndrome, asthma, or chronic obstruc- global functioning. tive pulmonary disease.10 The long-term clinical efficacy and safety of donepezil versus placebo across 1 year in patients with mild to moder- Effects on cognition and global assessments ate AD was investigated.14 The Gottfries-Brane-Steen global Numerous efficacy studies examining cognition and assessment for rating dementia symptoms demonstrated the global assessments in AD patients have been performed with benefit of donepezil over placebo at weeks 24, 36, and 52, and the AChE inhibitors. Their major therapeutic effect is to at the study end point. Advantages of donepezil were also maintain cognitive function at a constant level during a 6- to observed in cognition and ADL. 12-month period of treatment, as compared to placebo. Donepezil also appears to work for patients with moder- ate to severe AD. In a recent 24- week study,15 patients receiving Box 2 donepezil showed benefits on WHAT IS THE PATHOPHYSIOLOGY OF AD? the Clinician's Interview-Based Impression of Change with he pathophysiologic processes implicated in Alzheimer’s disease (AD) include Caregiver Input (CIBIC+), Tamyloid precursor protein metabolism, tau phosphorylation, apolipoprotein E, compared with placebo, at all inflammation, oxidative stress, and apoptosis. Neuropathological features include visits up to week 24 and at the amyloid plaques, neurofibrillary tangles, neuronal and synaptic loss, microgliosis, study’s end point. All other sec- and astrocytosis. The resulting clinical syndrome of dementia is associated with ondary measures showed sig- neurotransmitter deficits and intracortical disconnection. nificant differences between the The central cholinergic neurotransmitter system is impaired in AD. This groups in favor of donepezil at system is involved in learning and memory. The limbic system and neocortex the end of the study. These data receive projections from the cholinergic system in the septal nuclei and suggest that donepezil's bene- substantia innominata. This includes the medial septal nucleus, diagonal band, fits extend into more advanced 2 and nucleus basalis. Literature on animals has demonstrated that basal forebrain stages of AD than those previ- lesions impair learning and memory. Cholinergic agonists can improve this. ously investigated, with good Furthermore, cholinergic antagonists such as scopolamine and atropine can tolerability. 3 impair learning and memory in humans and animals. In AD, a 58% to 93% Clinical trials of rivastig- reduction in choline acetyltransferase levels (and other cholinergic markers) in mine (1.5-6 mg twice daily PO) the cortex and hippocampus can be observed and this correlates with dementia have also demonstrated benefits 4 severity. Early AD is characterized by neuronal loss and tangles in the on cognitive and global mea- 5 cholinergic nucleus basalis of Meynert. sures.16 The efficacy of rivastig- 24 VOL. 1, NO. 3 / MARCH 2002 Currentp SYCHIATRY Currentp SYCHIATRY Box 3 BASIC PROPERTIES mine tartrate (ENA 713) in patients with mild to moder- OF THE AChE INHIBITORS ately severe Alzheimer's disease was evaluated in a 26- week open-label extension of a 26-week, double-blind, onepezil is a second-generation, piperidine-class, placebo-controlled study. By 52 weeks, patients originally Dselective and reversible acetylcholinesterase (AChE) treated with rivastigmine 6 to 12 mg/d had significantly inhibitor. It is structurally dissimilar from other established better cognitive function than did patients originally treat- 17-19 AChE inhibitors. ed with placebo. Experimentally, donepezil inhibits AChE activity in Clinical trials of galantamine (4-12 mg/bid PO) have 20 human erythrocytes and increases extracellular acetyl- demonstrated similar benefits. Following a 4-week choline levels in the cerebral cortex and the hippocampus placebo run-in, patients were randomized to 1 of 4 treat- of the rat. Pharmacologically, donepezil has a half-life of ment arms: placebo or galantamine escalated to final approximately 70h, lending itself to once-daily administra- maintenance dosages of 8, 16, or 24 mg/d for a 5-month tion.11 treatment phase. At study’s end, the galantamine-place- Rivastigmine (ENA 713, or carbamoylatine) is an bo differences on the cognitive subscale of the AD AChE inhibitor with brain-region selectivity and a long Assessment Scale were 3.3 points for the 16 mg/d group duration of action. Both preclinical studies and studies in and 3.6 points for the 24 mg/d group. Treatment discon- human volunteers have shown that rivastigmine induces tinuations due to adverse events were low in all galanta- substantially greater inhibition of AChE in the central ner- mine groups (6% to 10%) and comparable with that in vous system compartment than it does in the periphery the placebo group (7%). The incidence of adverse events (40% inhibition of