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Frank W. Brown: Chapter 41. Cognitive Enhancers, in The American Psychiatric Publishing Textbook of

Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American

Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.441242. Printed 5/10/2009 from

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Textbook of Psychopharmacology >

Chapter 41. Cognitive Enhancers

COGNITIVE ENHANCERS: INTRODUCTION

Disruption of cholinergic neurotransmission and excitatory amino acids is correlated with the

development of cognitive impairment and, specifically, Alzheimer’s disease (Mesulam 2004).

Multiple mechanisms exist that may account for the progression of cognitive impairment, including

those related to cholinesterase, N-methyl-D-aspartate, vascular disease, and oxidative damage

(Aisen and Davis 1994; Bartus et al. 1982; Behl 1999; Behl et al. 1992; Jick et al. 2000; Kalaria et

1. 1996; Selkoe 2000; Terry and Buccafusco 2003; Wolozin et al. 2000). An outcome of the

disruption of many neurotransmitter systems, cognitive impairment may occur at any time during

the disease process as synaptic plasticity becomes impaired, degrading the efficiency of neuronal

transmission (Malik et al. 2007). It is intuitive that the earliest intervention prior to irreversible

disease progression is optimal. Currently, it is unknown when the irreversible disease processes

begin; no specific markers have been identified that could guide clinicians to initiate prophylactic

treatment prior to the development of cognitive or behavioral manifestations.

Cognitive enhancer is a general term that denotes a pharmacological or nutraceutical intervention

that improves cognitive functioning in an impaired or normal brain by reversing or delaying

underlying neuropathological changes within the brain or by modulating the existing

neurochemistry to facilitate a desired performance differential. The molecular pathogenesis of

cognitive impairment is not fully understood; thus, an ideal pharmacological agent has been

difficult to develop. No single agent developed to date is ideally suited for this task; however,

several agents have shown beneficial results. In this chapter, I review the established and the most

promising potential cognitive enhancers.

CHOLINESTERASE-RELATED THERAPIES

Impairment of cholinergic neurotransmission, especially in the hippocampus and cerebral cortex,

has been clearly established over the last 30 years as a significant factor in the clinical signs of

cognitive impairment, including those of Alzheimer’s disease (Davies and Maloney 1976; Mesulam

2004; Whitehouse et al. 1982). Butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) are

the two main types of cholinesterase present in the brain. The development of AChE inhibitors

(AChEIs) to increase acetylcholine levels in the brain for enhanced synaptic transmission has been

successful, with marginal positive clinical outcomes to date (Birks 2006; Thompson et al. 2004).

Four AChEIs have been marketed in the United States for cognitive therapy: tacrine, donepezil,

rivastigmine, and galantamine. These pharmaceuticals are primarily for symptomatic relief and

have limited current value in stopping or reversing the disease process, although research into

subtle neurotrophic and neuroprotective effects of these agents proceeds (Murphy et al. 2006). A

significant number of AChEI nonresponders exists (Jones 2003). Improvements in cognitive

functioning have been shown with AChEIs without major differences in their efficacy (Birks 2006;

Seltzer 2006; Thompson et al. 2004). The major side effects of AChEIs are gastrointestinal.

Recommendations

Tacrine is no longer recommended for routine clinical use. Donepezil, rivastigmine, and

galantamine are recommended with or without other cognitive enhancers (e.g., memantine) (Table

41–1). Tolerability is improved by slow dosage titration. All cholinesterase inhibitors have

significant potential for side effects; it is difficult to determine whether one AChEI has a

significantly better side-effect profile than another AChEI given individual patients’ variability.Print: Chapter 41. Cognitive Enhancers http://www.psychiatryonline.com/popup.aspx?aID=441246&print=yes…

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Switching AChEIs can be a reasonable treatment strategy if lack of efficacy or tolerability is an

issue.

TABLE 41–1. Recommended cholinesterase inhibitors

Donepezil (Aricept) Rivastigmine (Exelon) Galantamine (Razadyne)

Cholinesterase

inhibition

AChE >> BChE AChE and BChE AChE > BChE

Elimination

half-life

70 hours 2 hours 6–8 hours

AChE inhibitor

type

Piperidine based Carbamyl derivative Tertiary alkaloid

Type of

inhibition

Reversible, noncompetitive Reversible (slow) Reversible, competitive,

nicotinic modulation

Titration

schedule

5 mg/day for 4–6 weeks; 10

mg/day thereafter

1.5 mg twice daily, increasing

by 1.5 mg every 2 weeks, or

4.6 mg skin patch daily for at

least 4 weeks, then 9.5-mg skin

patch daily

4 mg twice daily, increasing

by 4 mg per dose every 4

weeks up to 24 mg daily

total; extended-release form

available for once-daily

dosing

Target dose

per day

5 or 10 mg 6, 9, or 12 mg, divided dose, or

9.5-mg skin patch daily

16 or 24 mg, divided dose

Major side

effects

Nausea, vomiting, diarrhea,

anorexia, headache,

bradycardia, abdominal

pain, nightmares; consider 5

mg/day in patients with

moderate to severe renal

disease

Nausea, vomiting, diarrhea,

anorexia, headache, abdominal

pain, weight loss; consider

lower dose (6 mg daily orally or

4.6-mg skin patch daily) in

patients with moderate to

severe renal or hepatic disease

Same as rivastigmine; 16

mg/day maximum in patients

with moderate renal or

hepatic disease;

contraindicated with severe

renal or hepatic disease

Formulations Tablets (oral, disintegrating) Tablets, oral solution, skin

patch

Tablets, oral suspension,

extended-release tablets

Note. > = greater than; >>> = much greater than; AChE = acetylcholinesterase; BChE =

butyrylcholinesterase.

Tacrine

Tacrine, a first-generation AChEI and BChE inhibitor (BChEI), is rarely used today due to its

(reversible) hepatotoxicity, drug–drug interactions, and the four-times-daily dosing schedule

required to achieve adequate central nervous system concentrations for cognitive enhancement.

Tacrine is available in an oral tablet formulation. Dosing begins with 40 mg/day given in four

10-mg doses, with titration upward every 4 weeks by 10 mg per dose to a maximal dosage of 160

mg/day (four 40-mg doses). The use of tacrine requires monitoring of liver enzymes.

Indole-tacrine heterodimers are being developed as dual-site AChEIs that would also inhibit

-amyloid peptide aggregation. Early studies indicated a net reduction of -peptide plaque formation

in an animal model (Muñoz-Ruiz et al. 2005). The simultaneous targeting of multiple receptor sites,

reduction of amyloid burden, and other neuroprotective modulations are the major mechanisms of

combination therapy. Combination therapy approaches likely represent the future for the field of

cognitive enhancers.

Donepezil

Donepezil, a piperidine-based, reversible, noncompetitive AChEI with a plasma half-life of about 70Print: Chapter 41. Cognitive Enhancers http://www.psychiatryonline.com/popup.aspx?aID=441246&print=yes…

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hours, was approved for the treatment of mild to moderate Alzheimer’s disease in the United States

in 1996 and for severe Alzheimer’s disease in 2006. Donepezil is given once daily in 5-mg or 10-mg

doses; 5-mg therapy is only slightly less effective than 10-mg therapy and can be an appropriate

regimen, especially when tolerability is an issue (Birks and Harvey 2006).

Donepezil has shown benefit in treating mild, moderate, and severe Alzheimer’s disease (Birks and

Harvey 2006; Wallin et al. 2007) and is currently being studied for efficacy in patients with mild

cognitive impairment (Chen et al. 2006; Seltzer 2007). A recent meta-analysis of pooled data on the

use of donepezil indicated caution is warranted in its use to treat mild cognitive impairment due to

modest treatment effects with significant side effects (Birks and Flicker 2006).

In addition to Alzheimer’s disease patients, Parkinson’s disease, multiple sclerosis, and vascular

dementia patients have benefited from donepezil therapy (Aarsland et al. 2002; Black et al. 2003;

Blasko et al. 2004; Christodoulou et al. 2006; Leroi et al. 2004; Rowan et al. 2007; Seltzer 2007;

Wilkinson et al. 2003). The use of donepezil as pretreatment in electroconvulsive therapy (ECT) has

also been studied; patients who received donepezil prior to ECT have shown significantly faster

recovery of cognitive deficits in the post-ECT period (Jyoti et al. 2006).

Rivastigmine

Rivastigmine, a carbamyl derivative, is a slowly reversible AChEI and BChEI with an elimination

half-life of about 2 hours. It was approved in 2000 for use in the United States to treat mild to

moderate dementia of Alzheimer’s disease and Parkinson’s disease. Rivastigmine inhibits the G1

isoenzyme of AChE selectively up to four times more potently than it does the G4 isoenzyme (Enz et

1. 1993). This unique compound with its BChEI properties has been postulated to be of greater

benefit than other AChEIs in the treatment of Alzheimer’s disease because BChE activity increases

in the hippocampus and cortex while AChE activity diminishes (Tasker et al. 2005); to date, this has

not been conclusively shown to be of clinical significance. However, as a therapy involving multiple

target receptor sites, this agent does have a theoretical advantage over single-target approaches. A

rivastigmine skin patch received U.S. Food and Drug Administration approval in 2007;

gastrointestinal side effects are reduced in frequency with this drug delivery system.

Rivastigmine is initiated at 1.5 mg taken twice daily; the dosage is increased by 1.5 mg every 2

weeks to a daily maximum of 6–12 mg divided into two doses. Transdermal therapy is initiated at

one 4.6-mg skin patch applied daily for at least 4 weeks, at which time the dosage may be

increased to the 9.5-mg daily patch.

Galantamine

Galantamine hydrobromide, a tertiary alkaloid, is a specific, competitive, and reversible AChEI with

a plasma half-life of 6–8 hours that was first marketed in the United States in 2001 as a treatment

of mild to moderate dementia of Alzheimer’s disease. Galantamine is unique in that it modulates

neuronal nicotinic receptors (Coyle and Kershaw 2001). Whether this nicotinic receptor modulation

imparts any significant clinical benefit in disease modification remains unknown. The optimal

dosage range is 16–24 mg/day. The extended-release formulation for once-daily dosing has similar

efficacy and side effects as the twice-daily dosing formulation. Pooled data from trials in patients

with mild cognitive impairment have shown significantly higher rates of death due to bronchial

carcinoma/sudden death, cerebrovascular disorder/syncope, myocardial infarction, and suicide in

the galantamine treatment groups (Cusi et al. 2007; Loy and Schneider 2006); follow-up studies are

under way to clarify these findings. One double-blind, placebo-controlled trial of galantamine with

antipsychotic medication in the treatment of subjects with schizophrenia did not show significant

benefit, although the trend was toward improvement in several cognitive domains (Lee et al. 2007).

Other Agents

Physostigmine

Physostigmine, a reversible inhibitor of BChE and AChE, is poorly tolerated due to multiplePrint: Chapter 41. Cognitive Enhancers http://www.psychiatryonline.com/popup.aspx?aID=441246&print=yes…

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gastrointestinal side effects, especially nausea and vomiting, and has a very short half-life.

Physostigmine is inactivated within approximately 2 hours due to hydrolysis. An evaluation of 15

studies using physostigmine showed only marginal clinical efficacy and significant adverse side

effects even with controlled-release formulations (Coelho and Birks 2001).

Huperzine Alpha

Huperzine alpha (more commonly known as huperzine A) is sold in the United States as a dietary

supplement for cognitive enhancement. It was first isolated from club moss (Huperzia serrata) as a

sesquiterpene alkaloid and is a slow, reversible inhibitor of AChE. Huperzine A has been shown to

significantly improve memory in Alzheimer’s disease patients with only limited side effects to date

(Zangara 2003; Z. Zhang et al. 2002). It is believed to have neuroprotective effects by reducing

neuronal cell death caused by glutamate (Ved et al. 1997). The combination of other AChEIs with

huperzine A may exacerbate gastrointestinal side effects; patients’ usage of this over-the-counter

supplement should be monitored, especially if other AChEIs are considered for treatment.

Metrifonate

Metrifonate, a long-acting irreversible cholinesterase inhibitor, was tested in clinical trials, but

further development was discontinued after a higher-than-expected incidence of neuromuscular

dysfunction and respiratory paralysis was found. Metrifonate recipients with Alzheimer’s disease

showed significant cognitive improvement compared with placebo recipients at most dosages

(50–80 mg/day) (Lopez-Arrieta and Schneider 2006).

Nicotinic Receptor Agonists

Selective and nonselective neuronal nicotinic receptor agonists have shown statistically significant

cognitive enhancement in young, healthy subjects and in subjects with Alzheimer’s disease (Dunbar

et al. 2007; Newhouse et al. 1997, 2001; Potter et al. 1999; Sunderland et al. 1988). Some prior

research using nicotine skin patches to improve attention in Alzheimer’s disease patients has been

conducted with limited efficacy shown (White and Levin 1999). Other studies have shown that

chronic administration of nicotine using skin patches did improve cognitive functioning in

Alzheimer’s disease patients (Rusted et al. 2000). The use of selective neuronal nicotinic receptor

agonists is an intuitive combination therapy with AChEIs for cognitive enhancement; research

continues in this developing area.

N-METHYL-D-ASPARTATE–RELATED THERAPY

Glutamate is an agonist of kainate, N-methyl-D-aspartate (NMDA), and

-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Neuronal plasticity of

memory and learning is influenced by glutamate’s direct modulation of the NMDA postsynaptic

receptor; glutamate acts as an excitatory neurotransmitter activating the NMDA receptor.

Glutamate excess results in neurotoxicity affecting cognitive functioning (Koch et al. 2005).

Recommendations

Memantine appears to reduce the level of cognitive impairment in patients with moderate to severe

Alzheimer’s disease. Memantine in combination with an AChEI is an appropriate consideration for

improvement in cognition and behavior.

Memantine

Memantine is a noncompetitive NMDA receptor antagonist approved in the United States for

treating moderate to severe Alzheimer’s disease. The NMDA receptor modulates memory function.

Memantine may prevent neurotoxicity due to its low-affinity antagonism of glutamate, which has

been linked to neurodegeneration and excitotoxicity (Lipton and Rosenberg 1994). Memantine has

been shown to be effective in reducing the level of cognitive impairment in patients with moderate

to severe Alzheimer’s disease (Bullock 2006; Reisberg et al. 2003). Memantine is available in

tablets and as an oral solution; dosing should be adjusted for patients with moderate or severe

renal impairment. It is recommended that memantine be initiated at a dosage of 5 mg/day for 1Print: Chapter 41. Cognitive Enhancers http://www.psychiatryonline.com/popup.aspx?aID=441246&print=yes…

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week, increasing weekly by 5 mg/day up to a target dosage of 20 mg/day. Memantine is generally

given in twice-daily doses, although the elimination half-life ranges from 60 to 80 hours.

Memantine Combination Therapy

Memantine in combination with an AChEI has been shown to improve cognitive domains

significantly and to improve behavioral dyscontrol (agitation/aggression, eating/appetite,

irritability/lability) (Cummings et al. 2006; Tariot et al. 2004). Given the disruption of multiple

neurotransmitter systems and pathways in Alzheimer’s disease and other cognitive disorders, the

use of adjunctive cognition-enhancing medications is understandable (Grossberg et al. 2006). The

specific neurobiological deficit(s) that any pharmacological or nutraceutical intervention may

impact should be considered.

VASCULAR AND INFLAMMATION-RELATED THERAPIES

Major known modifiable risk factors for vascular cognitive impairment (with or without dementia)

include diabetes mellitus, hypertension, cardiac ischemia, atrial fibrillation, smoking,

hyperlipidemia, and peripheral vascular disease (Desmond et al. 1993; Rockwood et al. 1997).

Controversial risk factors include hyperhomocysteinemia. Established vascular treatment

interventions have included low-dose aspirin and other antiplatelet agents, anticoagulation agents,

antihypertensives, aggressive management of diabetes mellitus, carotid endarterectomy for

selected patients, and the treatment of hyperlipidemia. There is a significant overlap of patients

with vascular cognitive impairment and those with Alzheimer’s disease (Gearing et al. 1995;

O’Brien 1994). Cholinergic receptors (muscarinic and nicotinic) are known modulators of cerebral

blood flow (Schwarz et al. 1999; W. Zhang et al. 1998). Ischemia-induced NMDA stimulation may

further cognitive impairment.

A meta-analysis of four randomized, placebo-controlled studies of AChEIs to treat vascular

dementia—two with donepezil and two with galantamine—showed statistically significant cognitive

enhancement even though the treatment effect was less than what has been observed in

Alzheimer’s disease patients (Birks and Flicker 2007). In addition, the authors analyzed pooled

results from memantine studies and found statistically significant improvement of cognitive

functioning with memantine treatment in patients with vascular impairment similar to that seen

with the AChEIs (Birks and Flicker 2007). A Cochrane review indicated that donepezil in doses of

either 5 mg or 10 mg improves both functional ability and cognitive symptoms in patients with mild

to moderate vascular cognitive impairment; donepezil was well tolerated in this analysis (Malouf

and Birks 2004). A more recent Cochrane review of the use of galantamine to treat vascular

cognitive impairment showed statistically significant results in terms of cognition and executive

function with galantamine versus placebo in one study but not in a second study that had fewer

subjects; gastrointestinal side effects were noted to be higher in galantamine recipients (Craig and

Birks 2006).

Recommendations

AChEIs appear to have a valid role in the treatment of vascular cognitive impairment. Combination

therapy is an important consideration, especially with other known vascular risk modifiers including

aspirin, other NSAIDs, and CDP-choline. Randomized, controlled trials do not currently support the

use of aspirin or other NSAIDs for the treatment of vascular cognitive impairment. The active use of

statins for the prevention and treatment of vascular cognitive impairment is currently not well

supported by the literature; however, research with statins remains very active in this pursuit.

Statins

-Amyloid formation and accumulation may be modulated by cholesterol. The Cardiovascular Health

Study results indicated that the use of statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA]

reductase inhibitors) was associated with a decrease in cognitive decline that was not attributed to

the lowering of serum cholesterol levels (Bernick et al. 2005). Some epidemiological investigations

also suggest that the progression of cognitive decline decreases with statin use (Rockwood et al.Print: Chapter 41. Cognitive Enhancers http://www.psychiatryonline.com/popup.aspx?aID=441246&print=yes…

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2002; Wolozin et al. 2000). Studies to date are not conclusive about the benefit of statins for the

long-term treatment of vascular cognitive impairment, however. In a post hoc analysis of pooled

data from three placebo-controlled, double-blind studies of patients with Alzheimer’s disease who

were treated with galantamine or galantamine plus a statin, galantamine was associated with

significant benefits in cognitive functioning, whereas the use of statins and galantamine did not

result in a significant improvement, only a small positive improvement (Winblad et al. 2007).

CDP-Choline

Cytidine 5′-diphosphocholine (CDP-choline), or citicoline, has shown mixed results regarding its

potential benefit in the treatment of cognitive impairment (Cohen et al. 2003; Secades and Lorenzo

2006). CDP-choline is an intermediate in the production of phospholipids of cell membranes.

Impairment in phospholipids leads to cell function loss and has been shown to be a factor in

cerebral ischemia (Klein 2000). A Cochrane review of 14 studies indicated a positive benefit of

CDP-choline on memory and behavior (Fioravanti and Yanagi 2005). CDP-choline may have

antiplatelet aggregation effects and cholinergic modulation effects and may increase dopamine

synthesis in selected brain regions (Secades and Lorenzo 2006).

Aspirin

Strong data have not yet emerged supporting the cognitive benefits of aspirin usage to treat

vascular cognitive impairment (Kang et al. 2007; Whalley and Mowat 2007). Aspirin remains a

cornerstone first-line intervention for decreasing potential cardiovascular comorbidity. As such,

aspirin may have a future role as a combination therapy with cognitive enhancers; future

longitudinal research will help clarify this position.

Other Nonsteroidal Anti-Inflammatory Drugs

Other nonsteroidal anti-inflammatory drugs (NSAIDs) provide a neuroprotective effect and affect

amyloid pathology (H. Hao et al. 2005; Siskou et al. 2007; Weggen et al. 2001). A specific role for

their use in the treatment of cognitive impairment has not been well established. Significant

gastrointestinal side effects remain a concern for long-term usage. Active research continues on

novel anti-inflammatory derivatives that have desired properties with limited side effects (Siskou et

1. 2007).

ANTIOXIDANT-RELATED THERAPIES

Antioxidant-related treatment for cognitive impairment remains poorly supported by

placebo-controlled, double-blind studies. Although this may be a potential combination therapy

modality, further research is required before endorsing specific treatment recommendations with

current antioxidants.

Ginkgo Biloba

Ginkgo biloba could be classified within several potential treatment categories, including

antioxidants, nutraceuticals, cholinergic agents, and vasodilators. Ginkgo biloba extract is currently

marketed in the United States as a food supplement. Studies have shown potential benefit in using

ginkgo to delay the progression of cognitive impairment or to enhance survival rates in humans and

animal models (Andrieu et al. 2003; Dartigues et al. 2007; Naik et al. 2006). A review based on

Cochrane meta-analyses showed a significant cognitive benefit of ginkgo only with pooled results

(Kurz and Van Baelen 2004). Although the use of ginkgo appears to have a definite positive benefit

in patients with cognitive impairment, most studies have shown marginal significance. The

recommended dosage range is 120–240 mg/day.

Vitamins and Carotenoids

Vitamin E (including tocopherols and tocotrienols), vitamin C, and carotenoids are accepted agents

with known antioxidant properties. Vitamin E is believed to act as a peroxyl radical scavenger.

Reports of its benefit in treating patients with cognitive impairment are mixed, with some studies

showing a delay in the progression of Alzheimer’s disease symptoms (Engelhart et al. 2002; Sano etPrint: Chapter 41. Cognitive Enhancers http://www.psychiatryonline.com/popup.aspx?aID=441246&print=yes…

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1. 1997). Vitamin E can affect blood coagulation and has potential cardiovascular side effects. The

research on the efficacy of vitamin C as an antioxidant for treating cognitive impairment is

currently less supportive. Carotenoids have a potential role as free radical scavengers; however,

current research has not shown a significant time delay in the progression of cognitive impairment

with their use. Combination therapy for cognitive impairment may well incorporate judicious

amounts of vitamins and carotenoids as future research delineates the specific role of these agents

in managing free radicals.

OTHER AGENTS

Currently, no recommendations for use of the following agents as monotherapy or combination

therapy can be made.

Secretase Inhibitors

The use of secretase inhibitors is one of the approaches to reduce the -amyloid protein load in the

aging brain. The -amyloid precursor protein is cleaved by proteases; the major proteases are

-secretase and -secretase and, to a lesser extent, -secretase (Hamaguchi et al. 2006).

Mice models using a -secretase inhibitor have shown reduced levels of -amyloid protein (Asai et

1. 2006). Inhibition of -secretase can have an impact on the familial expression of Alzheimer’s

disease through the genetic influence of presenilin and presenilin-2. However, each of these

secretases may impact multiple protein substrates, in which case a nonspecific – or -secretase

inhibitor may yield major unwanted side effects (Hamaguchi et al. 2006). Secretase inhibition

remains an active area of research and has the potential to have a major impact on the treatment of

cognitive impairment.

Tramiprosate

Tramiprosate is a small-molecule glycosaminoglycan compound that inhibits the development of

-amyloid plaque formation, thus reducing neurotoxic effects (Geerts 2004, Molecule of the month

2006). Tramiprosate failed to show significantly better efficacy than placebo in phase III clinical

trails. Agents that prevent amyloid production or amyloid aggregation would have great utility in

preventing the progression of Alzheimer’s disease. Research targeting neuropathological substrates

is exploring tau phosphorylation, apoptosis, formation of neurofibrillary tangles, amyloid

production, and amyloid aggregation to develop pharmaceuticals with the potential to prevent and

treat cognitive impairment, especially Alzheimer’s disease.

Modafinil

Modafinil is marketed in the United States as a wakefulness-promoting drug. Minimal

cognition-enhancing effects have been noted in low-dose (100-mg) treatment in

non-sleep-deprived, middle-age subjects (Randall et al. 2004). Clinicians have used modafinil for

the treatment of apathy associated with Alzheimer’s disease. Modafinil is not recommended as

monotherapy or in combination therapy for cognitive enhancement based on the current literature.

Hormone Replacement Therapy

Hormone replacement with estrogen-related compounds is not recommended at this time. For

women in early perimenopause, hormone replacement therapy may provide an initial benefit for

preventing cognitive decline. Once the clinical symptoms of Alzheimer’s disease are present,

however, studies have shown that estrogen replacement may have negative effects on sustained

cognitive performance (Thal et al. 2003). However, recent research in elderly primates indicates

that early intervention with estrogen replacement can significantly benefit the structural and

functional integrity of key brain sites by enabling synaptic plasticity (J. Hao et al. 2007). Research

on the use of hormone replacement therapy for the prevention and treatment of cognitive

impairment in perimenopausal women remains active.

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To date, randomized, placebo-controlled studies of nutraceutical and herbal treatments for

cognitive impairment are limited. Animal studies and limited human studies are of interest but yet

not conclusive about the treatments’ benefits in humans. Agents of interest include Rubia cordifolia

root, sage (Salvia lavandulaefolia), rosemary (Rosmarinus officinalis), and lemon balm (Melissa

officinalis) (Kennedy and Scholey 2006; Patil et al. 2006). Sage has been shown to improve

immediate word recall in healthy young adults (Tildesley et al. 2003). Various compounds found in

these agents have been shown to have AChE and BChE inhibitory properties, possess

anti-inflammatory and antioxidant properties, and modulate muscarinic and nicotinic receptors

(Kennedy and Scholey 2006). L-theanine, an amino acid found in green tea, has shown limited

cognition-enhancing effects (Nathan et al. 2006). If further randomized, placebo-controlled studies

show even a modest beneficial effect, these agents would have potential in combination therapy for

the prevention and treatment of Alzheimer’s disease and other types of cognitive impairment. Prior

to recommending any of these agents, clarity with regard to the expected target system is

important because combination therapy with existing AChEIs could cause profound exacerbation of

side effects.

Dehydro-3-Epiandrosterone

Dehydro-3-epiandrosterone (DHEA), including the sulfated ester form, is an adrenal hormone with

potential neuroprotective effects and the ability to enhance glutamate’s effects. Research results

are mixed concerning the potential benefit of DHEA for the treatment of cognitive impairment. Case

reports suggest improvement in cognition with DHEA usage. DHEA supplementation has been

suggested to have a direct negative effect on cognition (Parsons et al. 2006). A recent Cochrane

review of three studies did not find a beneficial effect of DHEA supplementation in a population

without dementia; however, the authors noted a need for long-term studies with an adequate

number of subjects (Evans et al. 2006). DHEA may have a transient effect on cognitive functioning

but not provide sustained cognitive improvement (Wolkowitz et al. 2003).

General Compounds

Aniracetam has been shown to improve cognitive impairment from traumatic brain injury to a rat

model even after a delay of up to 11 days (Baranova et al. 2006). Piracetam, a cyclic derivative of

-aminobutyric acid, has mild beneficial cognitive effects on memory and learning (Winnicka et al.

2005). In animal models, unifiram has been shown to induce acetylcholine release and act as a

cognition-enhancing agent (Martini et al. 2005).

Immunomodulatory Agents

Antiamyloid immunization may provide one of the greatest opportunities to prevent -amyloid

deposition. Immunization strategies generally focus on active or passive immunization and direct

central nervous system delivery of anti–amyloid beta antibodies. Active immunization with

-amyloid antibodies can reduce plaque formation (Lemere et al. 2006; Solomon 2006). Passive

immunization with monoclonal antibodies or preparations of immunoconjugates shows promise for

treating cognitive impairment due to Alzheimer’s disease and may be safer than active

immunization (Geylis and Steinitz 2006; Solomon 2007). Active and passive immunization may

cause microhemorrhages, and further research continues to seek safer vaccines. Reversal of plaque

load occurred in mutant mice after active immunization with -peptide (Games et al. 2000; Schenk

et al. 1999). However, during early human trials, meningoencephalitis occurred in up to 5% of the

subjects, causing the study to be halted. The occurrence of meningoencephalitis may have been

caused by excessive cell-mediated immunity (Asuni et al. 2006). Further research into the potential

use of vaccine-driven immunomodulatory approaches is warranted.

CONCLUSION

The molecular pathogenesis of nerve cell death remains elusive, especially as it relates to the onset

and progression of cognitive impairment. Alzheimer’s disease and other types of cognitive

impairment represent a wide spectrum of neurosystem dysfunction, and no single treatment

modality yet found is sufficient to address the global apoptosis and degeneration that occur. Due toPrint: Chapter 41. Cognitive Enhancers http://www.psychiatryonline.com/popup.aspx?aID=441246&print=yes…

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the multiple types of neurochemical and substructure dysfunction occurring in cognitive

impairment, multiple-drug interventions will likely be required (Siskou et al. 2007; Sunderland et

1. 1992).

Future studies will explore second-messenger modulation, inhibition of the synthesis of -amyloid

using a mimic of the prion protein to inhibit -secretase cleavage of the amyloid precursor protein,

amyloid plaque sheet breakers, AMPA receptor modulators, and the role of 1-receptor agonists and

selective neuronal nicotinic receptor agonists (Parkin et al. 2007; Rose et al. 2005; Sarter 2006).

Currently, the AChEIs and memantine are appropriate choices for slowing the progression of

cognitive impairment. Several other promising agents are likely to become available within the next

few years.

REFERENCES

Aarsland D, Laake K, Larsen JP, et al: Donepezil for cognitive impairment in Parkinson’s disease: a

randomized controlled study. J Neurol Neurosurg Psychiatry 72:708–712, 2002 [PubMed]

Aisen PS, Davis KL: Inflammatory mechanisms in Alzheimer’s disease: implications for therapy. Am

J Psychiatry 151:1105–1113, 1994 [Full Text] [PubMed]

Andrieu S, Gillette S, Amouyal K, et al: Association of Alzheimer’s disease onset with ginkgo biloba

and other symptomatic cognitive treatments in a population of women aged 75 years and older

from the EPIDOS study. J Gerontol A Biol Sci Med Sci 58A:M372–M377, 2003

Asai M, Hattori C, Iwata N, et al: The novel beta-secretase inhibitor KMI-429 reduces amyloid B

peptide production in amyloid precursor protein transgenic and wild-type mice. J Neurochem

96:533–540, 2006 [PubMed]

Asuni AA, Boutajangout A, Scholtzova H, et al: Vaccination of Alzheimer’s model mice with Abeta

derivative in alum adjuvant reduces Abeta burden without microhemorrhages. Eur J Neurosci

24:2530–2542, 2006 [PubMed]

Baranova AI, Whiting MD, Hamm RJ: Delayed, post-injury treatment with aniracetam improves

cognitive performance after traumatic brain injury in rats. J Neurotrauma 23:1233–1240, 2006

[PubMed]

Bartus RT, Dean RL, Beer B, et al: The cholinergic hypothesis of geriatric memory dysfunction.

Science 217:408–414, 1982 [PubMed]

Behl C: Vitamin E and other antioxidants in neuroprotection. Int J Vitam Nutr Res 69:213–219, 1999

[PubMed]

Behl C, Davis J, Cole GM, et al: Vitamin E protects nerve cells from amyloid beta protein toxicity.

Biochem Biophys Res Commun 186:944–950, 1992 [PubMed]

Bernick C, Katz R, Smith NL, et al: Statins and cognitive function in the elderly: the Cardiovascular

Health Study. Neurology 65:1388–1394, 2005 [PubMed]

Birks J: Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev

(1):CD005593, 2006

Birks J, Flicker L: Donepezil for mild cognitive impairment. Cochrane Database Syst Rev

(3):CD006104, 2006

Birks J, Flicker L: Investigational treatment for vascular cognitive impairment. Expert Opin Investig

Drugs 16:647–658, 2007 [PubMed]

Birks J, Harvey RJ: Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev

(1):CD001190, 2006

Black S, Roman GC, Geldmacher DS, et al: Efficacy and tolerability of donepezil in vascular

dementia: positive results of a 24 week, multicenter, international, randomized, placebo-controlled

clinical trial. Stroke 34:2323–2330, 2003 [PubMed]Print: Chapter 41. Cognitive Enhancers http://www.psychiatryonline.com/popup.aspx?aID=441246&print=yes…

10 of 14

10/05/2009 16:21

Blasko I, Bodner T, Knaus G, et al: Efficacy of donepezil treatment in Alzheimer patients with and

without subcortical vascular lesions. Pharmacology 72:1–5, 2004 [PubMed]

Bullock R: Efficacy and safety of memantine in moderate-to-severe Alzheimer disease: the evidence

to date. Alzheimer Dis Assoc Disord 20:23–29, 2006 [PubMed]

Chen X, Magnotta VA, Duff K, et al: Donepezil effects on cerebral blood flow in older adults with

mild cognitive deficits. J Neuropsychiatry Clin Neurosci 18:178–185, 2006 [Full Text] [PubMed]

Christodoulou C, Melville P, Scherl WF, et al: Effects of donepezil on memory and cognition in

multiple sclerosis. J Neurol Sci 245:127–136, 2006 [PubMed]

Coelho F, Birks J: Physostigmine for Alzheimer’s disease. Cochrane Database Syst Rev

(2):CD001499, 2001

Cohen RA, Browndyke JN, Moser DJ, et al: Long-term citicoline (cytidine diphosphate choline) use

in patients with vascular dementia: neuroimaging and neuropsychological outcomes.

Cerebrovascular Dis 16:199–204, 2003 [PubMed]

Coyle J, Kershaw P: Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic

receptors: effects on the course of Alzheimer’s disease. Biol Psychiatry 49:289–299, 2001 [PubMed]

Craig D, Birks J: Galantamine for vascular cognitive impairment. Cochrane Database Syst Rev

(1):CD004746, 2006

Cummings JL, Schneider E, Tariot PN, et al: Behavioral effects of memantine in Alzheimer disease

patients receiving donepezil treatment. Neurology 67:57–63, 2006 [PubMed]

Cusi C, Cantisani T, Celani M, et al: Galantamine for Alzheimer’s disease and mild cognitive

impairment. Neuroepidemiology 28:116–117, 2007 [PubMed]

Dartigues JF, Carcaillon L, Helmer C, et al: Vasodilators and nootropics as predictors of dementia

and mortality in the PAQUID cohort. J Am Geriatr Soc 55:395–399, 2007 [PubMed]

Davies P, Maloney AFJ: Selective loss of central cholinergic neurons in Alzheimer’s disease (letter).

Lancet 2:1403, 1976 [PubMed]

Desmond DW, Tatemichi TK, Paik M, et al: Risk factors for cerebrovascular disease as correlates of

cognitive function in a stroke-free cohort. Arch Neurol 50:162–166, 1993 [PubMed]

Dunbar G, Boeijinga PH, Demazieres A, et al: Effects of TC-1734 (AZD3480), a selective neuronal

nicotinic receptor agonist, on cognitive performance and the EEG of young healthy male volunteers.

Psychopharmacology (Berl) 191:919–929, 2007 [PubMed]

Engelhart MJ, Geerlings MI, Ruitenberg A, et al: Dietary intake of antioxidants and risk of Alzheimer

disease. JAMA 287:3223–3229, 2002 [PubMed]

Enz A, Amstutz R, Boddeke H, et al: Brain selective inhibition of acetylcholinesterase: a novel

approach to therapy for Alzheimer’s disease. Prog Brain Res 98:431–438, 1993 [PubMed]

Evans JG, Malouf R, Huppert F, et al: Dehydroepiandrosterone (DHEA) supplementation for

cognitive function in healthy elderly people. Cochrane Database Syst Rev (4):CD006221, 2006

Fioravanti M, Yanagi M: Cytidinediphosphocholine (CDP-choline) for cognitive and behavioral

disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database Syst Rev

(2):CD000269, 2005

Games D, Bard F, Grajeda H, et al: Prevention and reduction of AD-type pathology in PDAPP mice

immunized with A beta 1–42. Ann N Y Acad Sci 920:274–284, 2000 [PubMed]

Gearing M, Mirra SS, Hedreen JC, et al: The Consortium to Establish a Registry for Alzheimer’s

Disease (CERAD): part X: neuropathology confirmation of the clinical diagnosis of Alzheimer’s

disease. Neurology 45:461–466, 1995 [PubMed]Print: Chapter 41. Cognitive Enhancers http://www.psychiatryonline.com/popup.aspx?aID=441246&print=yes…

11 of 14

10/05/2009 16:21

Geerts H: NC-531 (Neurochem). Curr Opin Investig Drugs 5:95–100, 2004 [PubMed]

Geylis V, Steinitz M: Immunotherapy of Alzheimer’s disease (AD): from murine models to

anti-amyloid beta (Abeta) human monoclonal antibodies. Autoimmun Rev 5:33–39, 2006 [PubMed]

Grossberg GT, Edwards KR, Zhao Q: Rationale for combination therapy with galantamine and

memantine in Alzheimer’s disease. J Clin Pharmacol 46:17S–26S, 2006

Hamaguchi T, Ono K, Yamada M: Anti-amyloidogenic therapies: strategies for prevention and

treatment of Alzheimer’s disease. Cell Mol Life Sci 63:1538–1552, 2006 [PubMed]

Hao H, Wang G, Sun J: Enantioselective pharmacokinetics of ibuprofen and involved mechanisms.

Drug Metab Rev 37:215–234, 2005 [PubMed]

Hao J, Rapp PR, Janssen WG, et al: Interactive effects of age and estrogen on cognition and

pyramidal neurons in monkey prefrontal cortex. Proc Natl Acad Sci U S A 104:11465–11470, 2007

[PubMed]

Jick H, Zornberg GL, Jick SS, et al: Statins and the risk of dementia. Lancet 356:1627–1631, 2000

[PubMed]

Jones RW: Have cholinergic therapies reached their clinical boundary in Alzheimer’s disease? Int J

Geriatr Psychiatry 18:S7–S13, 2003

Jyoti P, Kotwai A, Prabhu HRA: Therapeutic and prophylactic utility of the memory-enhancing drug

donepezil hydrochloride on cognition of patients undergoing electroconvulsive therapy: a

randomized controlled trial. J ECT 22:163–168, 2006

Kalaria RN, Cohen DL, Premkumar DR: Cellular aspects of the inflammatory response in Alzheimer’s

disease. Neurodegeneration 5:497–503, 1996 [PubMed]

Kang JH, Cook N, Manson JA, et al: Low dose aspirin and cognitive function in the Women’s Health

Study cognitive cohort. BMJ 334:987, 2007 [PubMed]

Kennedy DO, Scholey AB: The psychopharmacology of European herbs with cognition-enhancing

properties. Curr Pharm Des 12:4613–4623, 2006 [PubMed]

Klein J: Membrane breakdown in acute and chronic neurodegeneration: focus on choline-containing

phospholipids. J Neural Transm 107:1027–1063, 2000 [PubMed]

Koch HJ, Uyanik G, Fischer-Barnicol D: Memantine: a therapeutic approach in treating Alzheimer’s

and vascular dementia. Curr Drug Targets CNS Neurol Disord 4:499–506, 2005 [PubMed]

Kurz A, Van Baelen B: Ginkgo biloba compared with cholinesterase inhibitors in the treatment of

dementia: a review based on meta-analyses by the Cochrane collaboration. Dement Geriatr Cogn

Disord 18:217–226, 2004 [PubMed]

Lee SW, Lee JG, Lee BJ, et al: A 12-week, double-blind, placebo-controlled trial of galantamine

adjunctive treatment to conventional antipsychotics for the cognitive impairments in chronic

schizophrenia. Int Clin Psychopharmacol 22:63–68, 2007 [PubMed]

Lemere CA, Maier M, Jiang L, et al: Amyloid-beta immunotherapy for the prevention and treatment

of Alzheimer disease: lessons from mice, monkeys, and humans. Rejuvenation Res 9:77–84, 2006

[PubMed]

Leroi I, Brandt J, Reich SG, et al: Randomized placebo-controlled trial of donepezil in cognitive

impairment in Parkinson’s disease. Int J Geriatr Psychiatry 19:1–8, 2004 [PubMed]

Lipton SA, Rosenberg PA: Excitatory amino acids as a final common pathway for neurologic

disorders. N Engl J Med 330:613–622, 1994 [PubMed]

Lopez-Arrieta JM, Schneider L: Metrifonate for Alzheimer’s disease. Cochrane Database Syst Rev

(2):CD003155, 2006 Print: Chapter 41. Cognitive Enhancers http://www.psychiatryonline.com/popup.aspx?aID=441246&print=yes…

12 of 14

10/05/2009 16:21

Loy C, Schneider L: Galantamine for Alzheimer’s disease and mild cognitive impairment. Cochrane

Database Syst Rev (1):CD001747, 2006

Malik R, Sangwan A, Saihgal R, et al: Towards better brain management: nootropics. Curr Med Chem

14:123–131, 2007 [PubMed]

Malouf R, Birks J: Donepezil for vascular cognitive impairment. Cochrane Database Syst Rev

(1):CD004395, 2004

Martini E, Ghelardini C, Bertucci C, et al: Enantioselective synthesis and preliminary

pharmacological evaluation of the enantiomers of unifiram (DM232), a potent cognition-enhancing

agent. Med Chem 1:473–480, 2005 [PubMed]

Mesulam M: The cholinergic lesion of Alzheimer’s disease: pivotal factor or side show? Learn Mem

11:43–49, 2004 [PubMed]

Molecule of the month: tramiprosate. Drug News Perspect 19:64, 2006

Muñoz-Ruiz P, Rubio L, Garcia-Palomero E, et al: Design, synthesis, and biological evaluation of dual

binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer’s disease.

J Med Chem 48:7223–7233, 2005 [PubMed]

Murphy KJ, Foley AG, O’Connell AW, et al: Chronic exposure of rats to cognition enhancing drugs

produces a neuroplastic response identical to that obtained by complex environment rearing.

Neuropsychopharmacology 31:90–100, 2006 [PubMed]

Naik SR, Pilgaonkar VW, Panda VS: Neuropharmacological evaluation of Ginkgo biloba phytosomes

in rodents. Phytother Res 20:901–905, 2006 [PubMed]

Nathan PJ, Lu K, Gray M, et al: The neuropharmacology of L-theanine (N-ethyl-L-glutamine): a

possible neuroprotective and cognitive enhancing agent. J Herb Pharmacother 6:21–30, 2006

[PubMed]

Newhouse PA, Potter A, Levin ED: Nicotinic system involvement in Alzheimer’s and Parkinson’s

diseases: implications for therapeutics. Drugs Aging 11:206–228, 1997 [PubMed]

Newhouse PA, Potter A, Kelton M, et al: Nicotinic treatment of Alzheimer’s disease. Biol Psychiatry

49:268–278, 2001 [PubMed]

O’Brien MD: How does cerebrovascular disease cause dementia? Dementia 5:133–136, 1994

[PubMed]

Parkin ET, Watt NT, Hussain I, et al: Cellular prion protein regulates beta-secretase cleavage of the

Alzheimer’s amyloid precursor protein. Proc Natl Acad Sci U S A 104:11062–11067, 2007 [PubMed]

Parsons TD, Kratz KM, Thompson E, et al: DHEA supplementation and cognition in postmenopausal

women. Int J Neurosci 116:141–155, 2006 [PubMed]

Patil RA, Jagdale SC, Kasture SB: Antihyperglycemic, antistress and nootropic activity of roots of

Rubia cordifolia Linn. Indian J Exp Biol 44:987–992, 2006 [PubMed]

Potter A, Corwin J, Lang J, et al: Acute effects of the selective cholinergic channel activator

(nicotinic agonist) ABT-418 in Alzheimer’s disease. Psychopharmacology (Berl) 142:334–342, 1999

[PubMed]

Randall DC, Fleck NL, Shneerson JM, et al: The cognitive-enhancing properties of modafinil are

limited in non-sleep-deprived middle-aged volunteers. Pharmacol Biochem Behav 77:547–555,

2004 [PubMed]

Reisberg B, Doody R, Stoffler A, et al: Memantine in moderate-to-severe Alzheimer’s disease. N Engl

J Med 348:1333–1341, 2003 [PubMed]

Rockwood K, Ebly E, Hachinski V, et al: Presence and treatment of vascular risk factors in patients

with vascular cognitive impairment. Arch Neurol 54:33–39, 1997 [PubMed]Print: Chapter 41. Cognitive Enhancers http://www.psychiatryonline.com/popup.aspx?aID=441246&print=yes…

13 of 14

10/05/2009 16:21

Rockwood K, Kirkland S, Hogan DB, et al: Use of lipid-lowering agents, indication bias, and the risk

of dementia in community-dwelling elderly people. Arch Neurol 59:223–227, 2002 [PubMed]

Rose GM, Hopper A, De Vivo M, et al: Phosphodiesterase inhibitors for cognitive enhancement. Curr

Pharm Des 11:3329–3334, 2005 [PubMed]

Rowan E, McKeith IG, Saxby BK, et al: Effects of donepezil on central processing speed and

attentional measures in Parkinson’s disease with dementia and dementia with Lewy bodies. Dement

Geriatr Cogn Disord 23:161–167, 2007 [PubMed]

Rusted JM, Caulfield D, King L, et al: Moving out of the laboratory: does nicotine improve everyday

attention? Behav Pharmacol 11:621–629, 2000 [PubMed]

Sano M, Ernesto C, Thomas RG, et al: A controlled trial of selegiline, alpha-tocopherol, or both as

treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N Engl J Med

336:1216–1222, 1997 [PubMed]

Sarter M: Preclinical research into cognition enhancers. Trends Pharmacol Sci 27:602–608, 2006

[PubMed]

Schenk D, Barbour R, Dunn W, et al: Immunization with amyloid-beta attenuates

Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177, 1999 [PubMed]

Schwarz RD, Callahan MJ, Coughenour LL, et al: Milameline (CI-979/RU35926): a muscarinic

receptor agonist with cognition-activating properties: biochemical and in vivo characterization. J

Pharmacol Exp Ther 29:812–822, 1999

Secades JJ, Lorenzo JL: Citicoline: Pharmacological and clinical review, 2006 update. Methods Find

Exp Clin Pharmacol 27:S1–S56, 2006

Selkoe DJ: Toward a comprehensive theory for Alzheimer’s disease: hypothesis: Alzheimer’s

disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y

Acad Sci 924:17–25, 2000 [PubMed]

Seltzer B: Cholinesterase inhibitors in the clinical management of Alzheimer’s disease: importance

of early and persistent treatment. J Int Med Res 34:339–347, 2006 [PubMed]

Seltzer B: Donepezil: an update. Expert Opin Pharmacother 8:1011–1023, 2007 [PubMed]

Siskou IC, Rekka EA, Kourounakis AP, et al: Design and study of some novel ibuprofen derivatives

with potential nootropic and neuroprotective properties. Bioorg Med Chem 15:951–961, 2007

[PubMed]

Solomon B: Alzheimer’s disease immunotherapy: from in vitro amyloid immunomodulation to in

vivo vaccination. J Alzheimers Dis 9:433–438, 2006 [PubMed]

Solomon B: Clinical immunologic approaches for the treatment of Alzheimer’s disease. Expert Opin

Investig Drugs 16:819–828, 2007 [PubMed]

Sunderland T, Tariot PN, Newhouse PA: Differential responsivity of mood, behavior, and cognition

to cholinergic agents in elderly neuropsychiatric populations. Brain Res 472:371–389, 1988

[PubMed]

Sunderland T, Molchan S, Lawlor B, et al: A strategy of “combination chemotherapy” in Alzheimer’s

disease: rationale and preliminary results with physostigmine plus deprenyl. Int Psychogeriatr

4:291–309, 1992 [PubMed]

Tariot PN, Farlow MR, Grossberg GT, et al: Memantine treatment in patients with moderate to

severe Alzheimer’s disease already receiving donepezil: a randomized controlled trial. JAMA

291:317–324, 2004 [PubMed]

Tasker A, Perry EK, Ballard CG: Butyrylcholinesterase: impact on symptoms and progression of

cognitive impairment. Expert Rev Neurother 5:101–106, 2005 [PubMed]Print: Chapter 41. Cognitive Enhancers http://www.psychiatryonline.com/popup.aspx?aID=441246&print=yes…

14 of 14

10/05/2009 16:21

Terry AV, Buccafusco JJ: The cholinergic hypothesis of age and Alzheimer’s disease-related

cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol

Exp Ther 306:821–827, 2003 [PubMed]

Thal LJ, Thomas RG, Mulnard R, et al: Estrogen levels do not correlate with improvement in

cognition. Arch Neurol 60:209–212, 2003 [PubMed]

Thompson S, Lanctot KL, Herrmann N: The benefits and risks associated with cholinesterase

inhibitor therapy in Alzheimer’s disease. Expert Opin Drug Saf 3:425–440, 2004 [PubMed]

Tildesley NT, Kennedy DO, Perry EK, et al: Salvia lavandulaefolia (Spanish sage) enhances memory

in healthy young volunteers. Pharmacol Biochem Behav 75:669–674, 2003 [PubMed]

Ved HS, Koenig ML, Dave JR, et al: Huperzine A, a potential therapeutic agent for dementia, reduces

neuronal cell death caused by glutamate. Neuroreport 8:963–968, 1997 [PubMed]

Wallin AK, Andreasen N, Eriksson S, et al: Donepezil in Alzheimer’s disease: what to expect after 3

years of treatment in a routine clinical setting. Dement Geriatr Cogn Disord 23:150–160, 2007

[PubMed]

Weggen S, Eriksen JL, Das P, et al: A subset of NSAIDs lower amyloidogenic Abeta42 independently

of cyclooxygenase activity. Nature 414:212–216, 2001 [PubMed]

Whalley LJ, Mowat DH: Aspirin and cognitive function. BMJ 334:961–962, 2007 [PubMed]

White HK, Levin ED: Four-week nicotine skin patch treatment effects on cognitive performance in

Alzheimer’s disease. Psychopharmacology (Berl) 143:158–165, 1999 [PubMed]

Whitehouse PJ, Price DL, Struble RG, et al: Alzheimer’s disease and senile dementia: loss of

neurons in the basal forebrain. Science 215:1237–1239, 1982 [PubMed]

Wilkinson D, Doody R, Helme R, et al: Donepezil in vascular dementia: a randomized,

placebo-controlled study. Neurology 61:479–486, 2003 [PubMed]

Winblad B, Jelic V, Kershaw P, et al: Effects of statins on cognitive function in patients with

Alzheimer’s disease in galantamine clinical trials. Drugs Aging 24:57–61, 2007 [PubMed]

Winnicka K, Tomasiak M, Bielawska A: Piracetam—an old drug with novel properties? Acta Pol

Pharm 62:405–409, 2005 [PubMed]

Wolkowitz OM, Kramer JH, Reus VI, et al: DHEA treatment of Alzheimer’s disease: a randomized,

double-blind, placebo-controlled study. Neurology 60:1071–1076, 2003 [PubMed]

Wolozin B, Kellman W, Ruosseau P, et al: Decreased prevalence of Alzheimer disease associated

with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 57:1439–1443, 2000

[PubMed]

Zangara A: The psychopharmacology of huperzine A: an alkaloid with cognitive enhancing and

neuroprotective properties of interest in the treatment of Alzheimer’s disease. Pharmacol Biochem

Behav 75:675–686, 2003 [PubMed]

Zhang W, Edvinsson L, Lee TJ: Mechanism of nicotine-induced relaxation in the porcine basilar

artery. J Pharmacol Exp Ther 284:790–797, 1998 [PubMed]

Zhang Z, Wang X, Chen Q, et al: Clinical efficacy and safety of huperzine alpha in treatment of mild

to moderate Alzheimer disease, a placebo-controlled, double-blind, randomized trial [in Chinese].

Zhonghua Yi Xue Za Zhi 82:941–944, 2002 [PubMed]

Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.