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Chapter: Essentials of Psychiatry: Cognitive Enhancers and Treatments for Alzheimer’s Disease

Cognitive Enhancers and Treatments for Alzheimer’s Disease

By the late 1980s the advent and general acceptance of research-based diagnostic criteria for the dementia of Alzheimer’s disease.

Cognitive Enhancers and Treatments for Alzheimer’s Disease

By the late 1980s the advent and general acceptance of research-based diagnostic criteria for the dementia of Alzheimer’s disease (AD) (McKhann et al., 1984), an understanding of its underlying pathology along with mechanism-based pharmacological therapeu-tics provided the framework for clinical trials to exploit a variety of new treatment strategies that might positively impact the illness.

Since AD is defined by the presence of dementia, attempts have been made to identify a predementia state of cognitive im-pairment, likely to lead to AD. This state of “mild cognitive im-pairment” (MCI) has now been the target of several clinical tri-als of medications previously used for AD. However, MCI is not merely a predementia stage of AD, since many people who fulfill criteria do not progress to dementia.


Regulatory Issues


The Food and Drug Administration (FDA) utilizes de facto guidelines for establishing that a drug has “antidementia effi-cacy” (Leber, 2002). These require, in part, that: 1) clinical tri-als be double-blind and placebo-controlled; 2) patients fulfill the now-accepted criteria for a primary dementia such as AD (e.g., using either DSM-IV-TR or NINCDS-ADRDA (National Insti-tute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association) Work Group Criteria) (McKhann et al., 1984); and 3) appropriate effi-cacy instruments be used. Although the de facto guidelines avoid specifying that only Alzheimer’s dementia can be treated, allow-ing the possibility that any recognized or accepted conditions can receive approval, at present it is the only dementia for which FDA-approved medications are available. [Note that DSM-IV-TR criteria for Dementia of the Alzheimer’s Type very closely reflect the NINCDS-ADRDA Work Group Criteria.]


Limitations to the current guidelines include the failure to recognize improvement in behavior or functional activities alone as legitimate therapeutic goals or indications in the prescribing information, despite the fact that behavioral symptoms occur in the majority of dementia patients, and that improvements in functional status may have a major effect on prolonging inde-pendence. In addition, these guidelines fail to provide for effi-cacy measures for severely impaired patients who are unable to perform standard cognitive tests.

Therapeutic Implications of Pathophysiology


Advances in understanding of plaques and tangles over the last few years underscore the biological heterogeneity of the illness, and several clues about definitive therapeutic approaches have appeared. It is likely that there are several stimuli for these ab-normal protein processes, genetically, biologically and environ-mentally determined. These processes need to be understood more fully in order to discover new drugs acting directly on the pathological processes responsible for the neurodegeneration. For example, the finding that amyloid precursor protein process-ing is in part controlled by a cholinergic mechanism suggests that cholinergically based therapeutic strategies may modify the progress of the disease as well as providing symptomatic relief (Giacobini, 1996).


Other potential interventions in development now include agents that interfere with beta-amyloid formation such as secre-tase inhibitors, modulators of APP expression, β-secretase and β-secretase inhibitors that prevent cleavage of APP into insoluble β -amyloid protein, inhibitors of β-amyloid protein aggregation or deposition, or the passive or active immunization with antibodies to β-amyloid.


The observed neurotransmitter perturbations in AD, how-ever, provide more immediate and accessible targets for thera-peutic interventions. For example, the observation of deficits in noradrenergic or serotoninergic function provide rationales for the use of antidepressants in patients with AD and symptomatic behaviors. Although not the exclusive pathological change, the cholinergic deficits represent the most consistent transmitter de-pletion and appear to be one of the early events in the disease process (Francis et al., 1985, 1999). Thus, it continues to remain a major focus of applied clinical pharmacological research.


Treatment Paradigms


Approaches to the treatment of AD can be grouped into several conceptual categories (Table 83.1). One approach attempts to treat the behavioral symptoms such as agitation, aggression, psy-chosis, depression, anxiety, apathy, and sleep or appetite distur-bances. A second approach attempts to treat the cognitive or neu-ropsychological signs symptoms of the illness such as memory, language, praxis, attention, orientation and knowledge. A third

approach attempts to slow the rate of progression of the illness, preserving patients’ quality of life or autonomy. (Slowing the rate of decline might also be related to treating symptoms.) A fourth conceptual treatment approach is primary prevention, to delay the time to onset of illness. Success at this approach could have considerable impact.

Cholinergic Agents


The primary implication of the cholinergic hypothesis is that potentiation of central cholinergic function should improve the cognitive and behavioral impairment associated with AD. This simple “neurotransmitter replacement” rationale has been made most compelling by the consistent effects of cholinesterase in-hibitors as a class of drugs across trials.


While agents with several kinds of procholinergic action have been evaluated for efficacy in AD, the ChIs (cholinesterase inhibitors) are the only agents to have consistently demonstrated efficacy in numerous multicenter, placebo-controlled trials, and thus have been approved by many national regulatory authorities Thus ChIs represent the first class of efficacious pharmacological approaches for AD, and an approach that is likely to be clinically useful for the indefinite future, especially since research on drugs with other mechanisms has not advanced as rapidly as had been hoped for.


The well-established cholinergic defects in AD include: decline of cholinergic baso-cortical projections; reduced activity of ChAT, the key acetylcholine (ACh) synthesis en-zyme, and cholinergic cell body loss in the nucleus basalis. Additionally, there are correlations between cortical ChAT reduction or nucleus basalis cell reduction and cortical plaque density. Such cholinergic deficits correlate with cognitive de-cline as measured by the Blessed-Roth Dementia Rating Scale (Blessed et al., 1968). The cholinergic hypothesis proposes that cognitive deficits of AD are related to decreases in central acetylcholinergic activity, and that increasing intrasynaptic ACh will enhance cognitive function and clinical well-being. (See Figure 83.1.)



Cholinergic Treatment Approaches


Cholinergic treatment approaches include precursor loading, cholinesterase inhibition, direct cholinergic receptor stimulation and indirect cholinergic stimulation. Unfortunately, most of these cholinergic strategies have thus far proven ineffective, effective but too toxic, or have not been completely developed.


Cholinesterase Inhibitors


ChIs have shown generally consistent symptomatic efficacy in standardized, well-controlled multicenter trials lasting from 6 months to occasionally 12 months. Cholinesterase inhibitors (Table 83.2) have been the most frequently used experimental treatment for AD and the major group of medications to yield consistently positive results in clinical trials. Current marketed ChIs include tacrine, donepezil, rivastigmine and galantamine, although tacrine is now used much less commonly due to the risk of hepatotoxicity.


Mechanisms of Cholinesterase Inhibition


Acetylcholine is inactivated when it is hydrolyzed to choline and acetate by acetylcholinesterase (AChE). By inhibiting the actions of AChE, ChIs effectively increase the amount of ACh available for intrasynaptic cholinergic receptor stimula-tion. A summary of pharmacokinetics and pharmacodynamics is in Table 83.3.

Individual Cholinesterase Inhibitors – Dosing and Adverse Effects




Tacrine is a noncompetitive reversible inhibitor of ChE. It binds near the catalytically active site of the AChE molecule to inhibit enzyme activity. It has other actions as well including blocking sodium and potassium channels, and direct activity at muscarinic receptors (Adem et al., 1990).




Tacrine’s FDA-approved dosing regimen is based on the clini-cal trials. The recommended starting dose is 10 mg q.i.d. to be maintained for 6 weeks, while serum transaminase levels are monitored every other week. If the drug is tolerated and transam-inase levels do not increase above three times the upper limit of normal, the dose is then increased to 20 mg q.i.d. After 6 weeks, dosage should be increased to 30 mg q.i.d., again with biweekly monitoring and then, if tolerated, to 40 mg q.i.d. for the next 6 weeks. Due to hepatotoxicity concerns, Tacrine’s use greatly decreased.




Donepezil (Aricept™) is a long-acting piperidine-based highly selective and reversible acetylcholinesterase inhibitor.




Donepezil is initiated at 5 mg/day and then increased to 10 mg/day after 4 to 6 weeks. Raising the dose earlier increases the risk for cholinergic adverse events. Five or 10 mg/day are effective doses; 10 mg tends to be somewhat more effective than 5 mg when the various trials as a group are evaluated.




Rivastigmine (Exelon™) is a pseudo-irreversible, selective AChE subtype inhibitor.




The recommended starting dose of rivastigmine is 1.5 mg b.i.d., taken with meals. If this dose is well tolerated after a minimum of 2 weeks of treatment, it may be increased to 3 mg b.i.d. Sub-sequent increases to 4.5 mg and then 6 mg b.i.d. should be based on good tolerability of the current dose and may be considered after a minimum of 2 weeks of treatment. Higher daily doses, averaging about 9 to 10 mg were associated with better efficacy than lower doses.




Galantamine (Reminyl™), an alkaloid originally extracted from Amaryllidaceae (Galanthus woronowi, the Caucasian snow-drop), but now synthesized, is a reversible, competitive inhibi-tor of AChE with relatively less butyrylcholinesterase activity (Harvey, 1995).



Initial dosing is 4 mg b.i.d., and should be raised to 8 mg b.i.d. after 2 to 4 weeks. For patients who are tolerating medication but not responding the dose can be raised to 12 mg b.i.d. after another 4 weeks.


Adverse Effects of Cholinesterase Inhibitors


Most adverse events from ChIs are cholinergically mediated, and are characteristically mild in severity and short-lived, lasting only a few days. Adverse events of the marketed ChIs are sum-marized in Table 83.4. Significant cholinergic side effects can oc-cur in up to about 25% of patients receiving higher doses. Often they are related to the initial titration of medication. Patients tend rapidly to become tolerant to the adverse events when they oc-cur. Hepatotoxicity with tacrine is a significant concern requiring very close monitoring if the drug is used.


Because of the actions of ChIs, these drugs require caution when used in patients with significant asthma, significant chronic obstructive pulmonary disease, cardiac conduction defects, or clinically significant bradycardia. Appropriate considerations are involved in general anesthesia as well since they may prolong the effects of succinylcholine-type drugs.

Drug interactions with medications which inhibit cy-tochrome P450 types 3A4 or 2D6 may occur with this class of medications.



Infrequent Adverse Events Worth Noting


A number of infrequent adverse events that may be of particular concern to patients, caregivers and physicians, and are common among the class of ChIs include fatigue, anorexia, weight loss and bradycardia. Myasthenia and respiratory depression occurred in a few patients treated with the higher doses of the organophos-phate drug metrifonate leading to its therapeutic demise for AD. Although myasthenia might not be expected to occur with the reversible ChI, physicians should be vigilant for complaints of fatigue and weakness.


An increased but modest incidence of anorexia appears to be a consistent finding across clinical trials and appears to be dose related. The absolute reported incidence var-ies across trials from approximately 8 to 25% at the highest dose of ChI compared with 3 to 10% in comparable placebo patients. Similarly, there is an increased rate of significant weight loss with higher doses of ChIs compared with placebo patients. The proportion of patients losing greater than 7% of their baseline weight varies from approximately 10 to 24% in the higher doses and from 2 to 10% of the placebo-treated patients in those trials reporting the statistic. Anorexia and weight loss are significant clinical problems for many elderly patients independent of medication effects, and whether or not demented.




Treatment Approach with Cholinesterese Inhibitors


The typical candidates for ChIs are outpatients with AD of mild to moderate cognitive severity. They usually live at home or in an assisted living facility. Dementia is their main clini-cal problem; concurrent illnesses are not severe or dominating the clinical picture. Nor do behavioral syndromes such as psy-chosis, agitation, or significant insomnia, apathy, or depression dominate.


As indicated above, dosing should be initiated with 5 mg/ day donepezil, 1.5 mg b.i.d. rivastigmine or 4 mg b.i.d. galan-tamine. Tacrine should be reserved as a second-line medication since it requires q.i.d. dosing and biweekly blood monitoring for elevated transaminase. After a minimum of 2 weeks, but prefer-ably 4 to 6 weeks, the dosages should be doubled although 5 mg of donepezil is an effective dose.


Optimal duration of treatment with continuing efficacy is unknown but overall efficacy extends at least 9 to 12 months based on the clinical trials and open-label extension phases.


Maintenance treatment can be continued as long as a therapeutic benefit for the patient seems apparent. Therefore, the potential clinical benefit of ChIs should be reassessed on a regu-lar basis. Discontinuation should be considered when evidence of a therapeutic effect is no longer present. Because of the great interpatient variability of response, it is not possible to predict individual patient responses to ChIs.


It is difficult to assess individual patient response because of the variability of the deteriorating course of AD, and because most of the effect of medication is due to a stabilization or lack of worsening of symptoms or cognitive function while placebo-treated patients continue to decline. Therefore, the clinical ob-servations of minimal or no clinical worsening may be sufficient reasons to continue medication treatment if patients are tolerat-ing therapy.



Monitoring Side Effects


Cholinergic side effects such as diarrhea, nausea and vomiting, when they occur, tend to occur at initiation of treatment and when titrating to higher doses. They are often transient or self-limited and can often be managed with encouragement and maintenance of the present dose level, by omitting one or more doses, or by temporarily decreasing dosage. Most cholinergic side effects are related to the dose escalation phase of treatment, just after start-ing or increasing. Patients on maintenance doses should have few and very mild cholinergic side effects if any.


However, anorexia and weight loss may be clinically sig-nificant problems over the longer term, especially in older, more medically ill and nursing home patients, so these parameters should be monitored and medication reduced or discontinued if anorexia or weight loss become clinically significant to assess if appetite returns.

Uncommonly, the vagotonic effects of ChIs may cause significant bradycardia, and this can be a particular concern to patients with supraventricular conduction impairments or sick sinus syndrome.


Because gastric acid secretion may be increased with cholinesterase inhibitors, there may be an increased risk for de-veloping ulcers or gastrointestinal bleeding. Patients receiving nonsteroidal anti-inflammatory drugs may be at a particularly additive risk. It is possible that ChIs may cause bladder out-flow obstruction, seizures and exacerbate asthma or obstruc-tive pulmonary disease, and interfere with succinylcholinelike anesthetics.



Effect on Behavior


The evidence that ChIs may improve behavior is based on case series and secondary analyses of efficacy trials (Kaufer et al., 1996; Raskind et al., 1997). Nevertheless, clinical experience suggests that they may be effective at least for mildly disturbed behavior, and in delaying the onset of troublesome behaviors, perhaps by maintaining cognitive function or perhaps through enhancing attentional processes and activation.





Cholinergic therapies may have effects beyond the short-term symptomatic improvement of cognition and may modify the pathogenetic processes of the illness (Radebaugh et al., 1996; Thal et al., 1997). For example, activation of M1 muscarinic re-ceptors can stimulate secretion of amyloid precursor proteins via the α-secretase pathway such that there is a decrease in the production of toxic and insoluble β-amyloid, thus theoretically decreasing the formation of amyloid plaques and promoting the normal processing of APP (Inestrosa et al., 1996; Muller et al., 1997; Nitsch et al., 1992). These effects remain to be proven in clinical trials (Buxbaum et al., 1992; Haroutunian et al., 1997; Lahiri et al., 2000).




L-glutamate is the main excitatory neurotransmitter in the central nervous system. Enhancement of its activity at the N-methyl-D-aspartate (NMDA) receptor may contribute to the pathogenesis of Alzheimer’s disease, a phenomenon known as excitotoxicity. Memantine is a low affinity antagonist that is believed to reduce NMDA receptor overstimulation and restore receptor signalling function to more normal levels. It is also possible that reducing excitotoxicity may be neuroprotective by preventing neuronal cal-cium overload though there is no evidence that memantine modi-fies neurodegeneration in patients with Alzheimer’s disease.


Unlike the cholinesterase inhibitors, memantine is ap-proved by the FDA for the treatment of moderate to severe Alzhe-imer’s disease (defined as an MMSE score of less than 15).




Treatment should be initiated at a dose of 5 mg/day and increased in increments of 5 mg at intervals of one week to a target dose of 20 mg/day; doses of 10 mg/day or more should be divided into two given 12 hours apart. Memantine is well tolerated and is not associated with an increase in treatment discontinuation com-pared with placebo.


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