Psychiatric Annals

CME 

Psychopharmacologic Agents to Enhance Cognition in Alzheimer’s Disease

Alireza Atri, MD, PhD; Theodore A. Stern, MD

Abstract

Cognitive dysfunction in people with Alzheimer’s disease (AD) significantly affects their interactions, independence, behavior, health, wellness, and quality of life; care providers also experience quality of life issues as a result. This review summarizes clinical data on agents associated with cognitive enhancement in AD, particularly the currently approved anti-AD medications including the acetyl cholinesterase inhibitors (ChEIs) (donepezil, galantamine, and rivastigmine) and the N-methyl-d-aspartate antagonist, memantine. Initiation and maintenance of stage-appropriate monotherapy or combination therapy with a ChEI and memantine provides the best pharmacologic approach to stem the expected inexorable course of cognitive decline. Discontinuation of agents that impair cognition and treatment of comorbid conditions (eg, sleep disorders, dehydration, depression, anxiety, pain, as well as metabolic, hormone, and vitamin derangements) may also improve cognition. The preponderance of evidence regarding ChEIs, memantine, and vitamin E strongly supports modest, but clinically relevant, “disease-course modifying” effects of cognitive enhancement (eg, improvement, stabilization, or shifting of the trajectory of cognitive or functional decline) in patients who receive appropriate and persistent treatment. [Psychiatr Ann. 2015;45(7):354–367.]

Abstract

Cognitive dysfunction in people with Alzheimer’s disease (AD) significantly affects their interactions, independence, behavior, health, wellness, and quality of life; care providers also experience quality of life issues as a result. This review summarizes clinical data on agents associated with cognitive enhancement in AD, particularly the currently approved anti-AD medications including the acetyl cholinesterase inhibitors (ChEIs) (donepezil, galantamine, and rivastigmine) and the N-methyl-d-aspartate antagonist, memantine. Initiation and maintenance of stage-appropriate monotherapy or combination therapy with a ChEI and memantine provides the best pharmacologic approach to stem the expected inexorable course of cognitive decline. Discontinuation of agents that impair cognition and treatment of comorbid conditions (eg, sleep disorders, dehydration, depression, anxiety, pain, as well as metabolic, hormone, and vitamin derangements) may also improve cognition. The preponderance of evidence regarding ChEIs, memantine, and vitamin E strongly supports modest, but clinically relevant, “disease-course modifying” effects of cognitive enhancement (eg, improvement, stabilization, or shifting of the trajectory of cognitive or functional decline) in patients who receive appropriate and persistent treatment. [Psychiatr Ann. 2015;45(7):354–367.]

Cognitive decline in the elderly leads to significant loss of independence, morbidity, and diminished quality of life. The most common cause of cognitive decline and dementia is Alzheimer’s disease (AD); it typically has a slow onset and a varied course of decline over 1 to 10 years. In people older than age 75 years, mixed vascular-AD pathologies are common and can benefit from the management of comorbid conditions (eg, anxiety, depression, diabetes, cardiac dysfunction, cerebrovascular disease) by engaging in brain health strategies (eg, physical exercise, social and mental engagement, nutrition, stress management, and sleep hygiene) and by moderation of alcohol use. Discontinuation of agents that impair cognition (Table 1) and treatment of comorbid conditions (eg, sleep disorders, dehydration, depression, anxiety, pain, as well as metabolic, hormone, and vitamin derangements) may also improve cognition.

Medications to Avoid in Older Cognitively Impaired Individuals

Table 1.

Medications to Avoid in Older Cognitively Impaired Individuals

This review summarizes clinical data on agents associated with cognitive enhancement in AD. It is unclear whether the currently approved anti-AD medications (eg, the acetyl cholinesterase inhibitors [ChEIs] donepezil, galantamine, and rivastigmine; the N-methyl-d-aspartate (NMDA) antagonist, memantine)1,2 contribute to “disease-process modification.”3–5 However, the preponderance of evidence on these agents strongly supports a modest, but clinically relevant, “disease-course modifying” effect of cognitive enhancement (eg, stabilization of cognitive decline; shifting the trajectory of cognitive, functional, and behavioral decline) in patients who receive appropriate treatment.3

Cholinesterase Inhibitors and Memantine

The only US Food and Drug Administration (FDA)-approved medications in the United States for the treatment of AD are the ChEIs (donepezil, galantamine, and rivastigmine) and the NMDA antagonist, memantine. Donepezil and rivastigmine are approved by the FDA for use in mild, moderate, and severe AD, whereas memantine is FDA-approved for use in moderate and severe AD. ChEIs and memantine appear to have complementary mechanisms of action and additive clinical effects, demonstrate good tolerability, and have acceptable safety profiles.6

Aggregate data from 6- to 12-month randomized (placebo-controlled, double-blind) clinical trials (RCTs) with anti-AD medications suggest that although responses vary greatly, cognitive performance significantly improves (Figure 1) or stabilizes in 50% to 70% of patients.7 Marked clinical worsening, defined by simultaneous significant worsening on multiple domains, is also reduced by 48% to 68% in patients on ChEI-mematine combotherapy compared to ChEI alone.6 A recent large study containing pooled data from 1,408 people with moderate to severe AD from four 6-month randomized trials used area-under-the-curve analysis to support the notion that adding memantine to donepezil results in overall clinical benefits that are additive compared with individual monotherapies; indicates a continuation to accumulate through 6 months of treatment; and are at least 50% greater than those of monotherapies.5

Clinical efficacy of donepezil-memantine (DPZL+MEM) add-on combination treatment to produce cognitive enhancement over 6 months, compared to donepezil-placebo (donepezil monotherapy) treatment. The severe impairment battery is a 100-point, clinician administered, clinical trial scale that measures cognition in people with moderate and severe dementia (higher scores reflect better performance). Observed case and last observer carried forward analysis both support improved cognitive performance at trial end-point (24 weeks) in favor of the DPZL+MEM group relative to the donepezil monotherapy group. Data from Tariot et al.88

Figure 1.

Clinical efficacy of donepezil-memantine (DPZL+MEM) add-on combination treatment to produce cognitive enhancement over 6 months, compared to donepezil-placebo (donepezil monotherapy) treatment. The severe impairment battery is a 100-point, clinician administered, clinical trial scale that measures cognition in people with moderate and severe dementia (higher scores reflect better performance). Observed case and last observer carried forward analysis both support improved cognitive performance at trial end-point (24 weeks) in favor of the DPZL+MEM group relative to the donepezil monotherapy group. Data from Tariot et al.88

Moreover, there is no evidence to support the idea that patients who do not show significant improvement or stabilization in the first few months after starting anti-AD treatment do not benefit in the longer run. Finally, discontinuation of pharmacologic treatment has been shown to be harmful (ie, patients who discontinue anti-AD medications appear to progress more rapidly than patients who continue treatments [particularly ChEIs]).8–12

Cholinesterase Inhibitors

Cholinesterase inhibitors (ChEIs) facilitate central cholinergic activity by reducing the physiologic breakdown of acetylcholine (Ach) by the enzyme acetylcholinesterase (AChE). After early observations that the use of scopolamine (a cholinergic blocker) impairs episodic memory function (see Atri et al.13 for a review) and could be reversed with ChEIs, such as physostigmine, more selectively centrally acting ChEIs were developed as anti-AD medications. With availability of tacrine (no longer used) in 1993, ChEIs became the first drug class approved for the treatment of AD.

Mechanism of Action of Acetylcholine and Cholinesterase Inhibitors in Alzheimer’s disease

The central nervous system functions of ACh include: (1) modulation of sleep, wakefulness, attention, learning, and memory; (2) suppression of pain at the spinal cord level; (3) and immunosuppression.13–17 The cholinergic hypothesis posits a central cholinergic deficit with resultant reduction in neurotransmission in AD. Low brain levels of choline acetyltransferase (ChAT) (catalyses ACh synthesis) are at least partially responsible for decreased synthesis of ACh in cholinergic neurons affected by AD. Lower ACh levels lead to reduced cholinergic neurotransmission and contribute to disordered cognition, abnormal function, and dysfunctional behavior in AD.

Pharmacokinetics and Characteristics

Currently available ChEIs (donepezil, rivastigmine, and galantamine) have mechanistic and pharmacokinetic differences (Table 2) but no significant efficacy differences. Donpezil and rivastigmine are FDA-approved for mild, moderate, and severe AD dementia; galantamine is FDA-approved for mild and moderate AD. Donepezil (introduced in 1997) remains the most frequently prescribed ChEI in the US (accounting for approximately 70% of prescriptions) and the world. Rivastigmine is a “pseudo-irreversible” ChEI (forms a labile carbamoylate complex that inactivates AChE until the covalent bond is broken). Rivastigmine is available orally (twice daily) and as a transdermal patch (once daily). Galantamine is a reversible ChEI and a nonpotentiating nicotinic receptor ligand. All three drugs exhibit linear pharmacokinetics, and prolonged time to maximum plasma concentration (tmax) values and elimination half-lives in the elderly.

Pharmacokinetic and Mechanistic Characteristics of the Anti-Alzheimer’s Disease Drugsa

Table 2.

Pharmacokinetic and Mechanistic Characteristics of the Anti-Alzheimer’s Disease Drugs

Safety and Tolerability of Cholinesterase Inhibitors

With slow titration, these medications are typically well tolerated and have an acceptable side-effect profile; their most common adverse effects (eg, nausea, vomiting, anorexia, flatulence, loose stools, diarrhea, salivation, and abdominal cramping) are related to peripheral cholinomimetic effects on the gastrointestinal (GI) tract. The adverse GI effects of oral ChEIs can be minimized by administering the drug after a meal, or in combination with memantine. Bodily secretions may be increased and mild rhinorrhea may arise. In addition, vivid dreams or mild insomnia can occur and may be mitigated by administering the drug after a morning meal. The rivastigmine transdermal patch can cause skin irritation, redness, or rash at the site of application; adverse effects can be minimized by applying the patch to different sites (usually the back, upper trunk, or shoulders). Overall, adverse effects (usually mild and transient) may develop in 5% to 20% of patients receiving ChEIs, related to the dose and the rate of the dose escalation. These medications may also decrease heart rate and increase the risk of syncope, particularly in those with sick sinus syndrome or atrioventricular block, or those who take an overdose. Use of these agents is contraindicated in patients with unstable or severe cardiac disease, uncontrolled epilepsy, unexplained syncope, or active peptic ulcer disease.

Efficacy and Effectiveness

In more than 40 short-term RCTs (in patients with mild AD) lasting longer than 24 weeks, and in meta-analyses of RCTs, all three ChEIs have demonstrated a small to medium effect-size treatment benefit—improving, stabilizing, or delaying decline in cognition, improving activities of daily living and global status, and ameliorating caregiver burden.7,11,12,18–30 Several RCTs and meta-analyses have also shown similar benefits in patients with moderate to severe AD dementia.12,31–40 In the few studies that have directly compared ChEIs to each other, no significant differences were found.41,42 In longer-term open-label trials, including extension trials from the original placebo-controlled, randomized studies, the cognitive benefits of the ChEIs appear to last for at least 2 to 4 years.35,43–45 Long-term prospective observation clinical cohort studies have also provided support for significant benefits of sustained ChEI treatment on ameliorating declines in cognition and function, and delaying institutionalization, but not altering survival.46–50

NMDA Antagonists (Memantine)

Memantine, in 2002, became the last FDA-approved treatment for AD dementia and it remains the sole medication in its class. It affects glutamatergic transmission and is an NMDA-receptor open-channel blocker (in that it modulates calcium flux through the opened channel in a voltage-dependent manner.

Glutamate and Memantine’s Mechanism of Action in Alzheimer’s Disease

Glutamate is the major excitatory neurotransmitter in the neocortex and it plays an important role in memory and learning.51 Given that the glutamatergic hypothesis links cognitive decline in patients with AD to neuronal damage that results from overactivation of NMDA receptors by glutamate52 when glutamatergic transmission is disrupted in AD, deficiencies in glutamate reuptake by astroglial cells in the synaptic cleft arise.52–54 Although synaptic NMDA-receptor activation may be neuroprotective, there is evidence to support the notion that aberrant activation of extrasynaptic NMDA receptors may be neurotoxic and lead to calcium-induced excitotoxicity, neuronal amyloid-beta release, and neurodegeneration.54,55 Memantine preferentially targets extrasynaptic NMDA-receptor signaling pathways. It has been further posited that due to aberrant glutamatergic exposure and stimulation in AD, synaptic signal-to-noise ratio is degraded, leading to failure or inefficient neural transmission.52,54

Pharmacokinetics and Characteristics

Memantine is available in immediate-release (IR), twice daily, and extended-release (XR) (once daily) preparations. The pharmacokinetic profiles and characteristics of these formulations are reviewed in Table 3. Memantine is cleared predominantly by the kidneys and does not affect the hepatic CYP450 enzyme system.

Pharmacokinetic Characteristics and Effects of the Anti-Alzheimer’s Disease Drugsa

Table 3.

Pharmacokinetic Characteristics and Effects of the Anti-Alzheimer’s Disease Drugs

Safety and Tolerability of Memantine

When titrated appropriately, memantine has a favorable safety and tolerability profile. Mild and transient treatment-emergent side effects include confusion, dizziness, constipation, headache, and somnolence; these may be encountered during (or shortly after) titration to the maximum total daily dose of 10 mg twice daily for IR memantine or 28 mg once daily for memantine XR. In patients with severe renal insufficiency (creatinine clearance <30 mL/min) a dose adjustment to 5 mg twice daily for IR memantine and 14 mg daily for memantine XR is recommended. Memantine can be taken with or without food, does not produce significant changes in heart rate or blood pressure, and does not have significant interactions with other medications, including the ChEIs. Due to its mechanism of action, however, co-administration with other medications that have antiglutamatergic effects (eg, amantadine, dextromethorphan) should be approached with caution.

Efficacy

Memantine is FDA-approved for the treatment of moderate to severe AD dementia, as monotherapy or in combination with a ChEI. In moderate and severe AD, the short-term efficacy of memantine monotherapy has been demonstrated in several RCTs of 12 to 50 weeks and has been supported by meta-analyses; treatment benefits include improvement, stabilization, or reduced decline in cognition, function (as measured by activities of daily living [ADLs]), global status, and by amelioration of caregiver burden.12, 56–70 However, therapeutic effects associated with memantine treatment (over short intervals) may not be readily detectable in mild AD.20,56,71–73 Nevertheless, the practice of using off-label prescriptions of memantine in patients with mild AD, typically in combination with a ChEI, is common, particularly in patients with early-onset AD or in those who have rapid progression.74–81

Add-On Combination Therapy with Cholinesterase Inhibitors and Memantine

Several types and grades of clinical data, including those from short-term (6–12 months) RCTs (Level I evidence), longer-term (12–36 months) open-label extensions to RCTs (Levels II and III evidence), and long-term (2–5 or more years) observational prospective clinical cohort effectiveness studies (Level II evidence) support the safety and benefits of anti-AD treatments in combination (most frequently as a memantine add-on to a stable regimen of a ChEI).74,77–81 Systematic reviews and meta-analysis also provide Level II evidence for the benefit of ChEI-memantine combination treatment in AD dementia.6,20,22,23,82–84

ChEIs and memantine work via complementary mechanisms. Under certain conditions, the combination of a ChEI and memantine may act synergistically to increase release of hippocampal Ach.85–87 Clinically, memantine add-on-to-donepezil treatment shows evidence for an additive effect.5

Efficacy in Short-Term Trials

Three 24-week, double-blind RCTs have investigated the efficacy and safety of memantine (20–28 mg/day) in combination with a ChEI (Table 4).88 Two of these trials were conducted in patients with moderate to severe AD and demonstrated efficacy on multiple prespecified outcome measures.88

Level I and Level II Evidence Grade Controlled Clinical Efficacy and Effectiveness Studies of a Cholinesterase Inhibitor and Memantine Add-On Combination TherapyLevel I and Level II Evidence Grade Controlled Clinical Efficacy and Effectiveness Studies of a Cholinesterase Inhibitor and Memantine Add-On Combination TherapyLevel I and Level II Evidence Grade Controlled Clinical Efficacy and Effectiveness Studies of a Cholinesterase Inhibitor and Memantine Add-On Combination Therapy

Table 4.

Level I and Level II Evidence Grade Controlled Clinical Efficacy and Effectiveness Studies of a Cholinesterase Inhibitor and Memantine Add-On Combination Therapy

The first RCT of combination treatment for AD assessed the efficacy of administration of memantine (10 mg twice daily) versus placebo to patients with moderate to severe AD (Mini-Mental State Examination [MMSE] 5–14; n = 404) receiving stable donepezil therapy.88 Relative to placebo, memantine produced significant benefits in all primary and secondary outcome measures and all four key symptom domains of AD: cognition (Figure 1), function, behavior, and global status.88 Several post-hoc analyses of this data have identified specific significant benefits of memantine add-on treatment relative to chronic donepezil monotherapy, including decreases in frequency, severity, and duration of existing neuropsychiatric and behavioral symptoms; a reduction in the emergence of these symptoms; lowering of caregiver distress and burden; improved daily functioning in ADLs; and better cognitive performance related to memory, language, and praxis.32,89,90

The second 24-week RCT assessed the efficacy of memantine (20 mg once daily) versus placebo in patients with mild to moderate AD (MMSE 10–22; n = 433) taking a stable dose of any approved ChEI therapy (donepezil, rivastigmine, galantamine)73 who failed to meet a priori outcome endpoints in cognition and daily functioning. There were no significant differences observed in tolerability and safety between the memantine and placebo groups.

Another short-term RCT demonstrated multidomain superiority of ChEI-memantine add-on combination treatment compared to chronic ChEI placebo add-on treatment in 661 patients with AD in the moderate to severe range (MMSE 3–14).91 This study was novel in that it used a once-daily memantine XR preparation at 28 mg daily. It also allowed baseline ChEI treatment with any oral ChEI preparation (donepezil, rivastigmine, galantamine). Significant combination treatment benefits were observed at the 24-week study endpoint on primary and secondary outcome measures in the domains of cognition, global status, neuropsychiatric symptoms and behaviors, and verbal fluency (P <.01 for all). ADLs improved, showing statistical trends in favor of combination treatment at weeks 18 (P = 0.068) and 24 (P = 0.155).

Longer-Term Trials, Open-Label Extensions, and Naturalistic Observational Clinical Cohort Studies

The preponderance of evidence from longer-term clinical studies support that the benefits of anti-AD medications, particularly in combination, for 1 year or more with ongoing treatment (Table 4). Multiple open-label extension studies of short-term RCTs have reported sustained benefits for persistent treatment (3–5 years) with ChEIs10,92–94 and memantine (1 year).95 Longer RCTs and long-term observational clinical cohort studies also support effectiveness of ChEI, memantine, and combination therapy12,74,79 (see reviews Atri et al.22 and Rountree et al.23).

Despite methodologic limitations, the United Kingdom DOMINO-AD 52-week effectiveness RTC12 in community-dwelling patients with moderate to severe AD (MMSE 5-13) showed significant treatment benefits for donepezil and memantine on cognition, function, and behavior.12,96 Memantine add-on-to-donepezil background therapy was well tolerated, and discontinuation of donepezil was detrimental to cognition and function.12,96

Long-term observational clinical cohort studies performed in naturalistic settings with prospectively collected data show similar patterns to RCTs. They provide supportive Level II grade and more generalizable evidence that combination treatment is more effective than monotherapy, and that monotherapy is better than no anti-AD medication treatment.22,23,74,79,97 Long-term ChEI-memantine combination therapy significantly reduced cognitive (Figure 2) and functional decline, and delayed time to nursing home admission, compared to ChEI monotherapy and to standard care without a ChEI or memantine.23,74,77,79,98 Furthermore, the benefits of combination therapy accumulated over time and were sustained for years.74,77

Clinical effectiveness of acetyl cholinesterase inhibitors (ChEI) plus memantine add-on combination treatment to reduce long-term progression of cognitive and functional decline in Alzheimer’s disease (AD) dementia. The estimated trajectory of cognitive decline over 4 years for groups of patients with AD dementia starting with 10 errors on the Blessed Dementia Information-Memory-Concentration subscale (BDS) (∼ Mini-Mental State Examination score of 22) is lowest in the combination treatment group. Similar graphs (not shown) illustrate significant benefits of combination treatment to reduce progression of cognitive decline in groups of patients with mild and severe AD dementia. Data from Atri et al.74

Figure 2.

Clinical effectiveness of acetyl cholinesterase inhibitors (ChEI) plus memantine add-on combination treatment to reduce long-term progression of cognitive and functional decline in Alzheimer’s disease (AD) dementia. The estimated trajectory of cognitive decline over 4 years for groups of patients with AD dementia starting with 10 errors on the Blessed Dementia Information-Memory-Concentration subscale (BDS) (∼ Mini-Mental State Examination score of 22) is lowest in the combination treatment group. Similar graphs (not shown) illustrate significant benefits of combination treatment to reduce progression of cognitive decline in groups of patients with mild and severe AD dementia. Data from Atri et al.74

Effects on Cognition

Patients with MMSE scores in the 3 to 15 range (moderate to severe AD) on combination treatment demonstrated significant benefits over ChEI monotherapy in two large 24-week RCTs.88,91 A post-hoc analysis reported beneficial treatment effects in memory, language, and praxis.90 A 12-week RCT with memantine monotherapy or ChEI combination therapy reported improvements in functional communication, as recognized by caregivers.99 In the DOMINO-AD RCT, treatment benefits of donepezil and memantine, alone or in combination, were also evident throughout 52 weeks on the MMSE.12 Benefits on cognition are also reported in observational prospective clinical cohort effectiveness studies.

Safety and Tolerability of Cholinesterase Inhibitors: Memantine Combination Treatment

Addition of memantine to stable doses of ChEIs does not generate significant increases in adverse events (AEs) (eg, with nausea, vomiting, and diarrhea, most common with oral rivastigmine). The rates for donepezil are approximately 5% for those taking 10 mg daily and ≤12% for those taking 23 mg daily.37 Meanwhile, memantine monotherapy is not associated with a significant increase in AEs compared to treatment with placebo.100

Significantly fewer AEs on donepezil-memantine (10 mg twice daily memantine IR) combination treatment were noted as compared to donepezil-placebo.88 In the recently published study with the higher dose of 28 mg once daily memantine XR, AEs that were more prevalent in the ChEI-memantine XR group than the ChEI-placebo group were diarrhea (5% vs 3.9%) and headache (5.6% vs 5.1%).91 In a meta-analysis of 520 subjects, adding memantine (20 mg daily) to donepezil (10 mg daily) did not result in an AE profile that was significantly different compared to donepezil and placebo; there were also approximately half as many reports of agitation as an adverse event in donepezil-memantine combination treatment as with the donepezil-placebo combination.6

Mild Cognitive Impairment: Early/Mild Alzheimer’s Disease

RCTs of ChEI treatment in mild cognitive impairment (MCI) have shown mixed results; although some studies suggest treatment-related preserved cognitive function,101 other data support the notion that ChEI treatment (donepezil) delays time to dementia diagnosis by 2 to 3 years in those who carry one or more apolipoprotein E epsilon4 alleles102 or in those who show symptoms of depression.103 However, systematic reviews of RCTs have yet to show clear efficacy for all MCI groups.104 The general good safety and tolerability profile of these medications, along with signals of potential efficacy and effectiveness and the generic availability of most of these medications should provoke a discussion between the clinician and the patient.

Vitamins, Medical Foods, and Supplements

Supplements (including vitamin E, fish oil, and vitamin C) may be of benefit to some patients with AD; however, controversy surrounds their efficacy and risks. Other than for vitamin E, where Level I evidence exists for treatment efficacy in AD, only Level III evidence exists for potential benefits of these compounds in primary prevention of dementia.

Vitamin E

Two large RCTs support efficacy of high-dose vitamin E in slowing functional decline in AD dementia. Unless contraindicated due to a bleeding diathesis, coronary artery disease, or another comorbidity, vitamin E (1,000 IU twice daily) should be considered. A 2-year RCT in moderately severe AD (n = 341) patients showed that, compared to placebo, vitamin E 1,000 IU twice per day slowed time to severe dementia, loss of ability to perform ADLs, institutionalization, or death.105 More recently, a RCT by Dysken et al.106 showed that over a mean (standard deviation) follow-up of 2.27 (1.22) years, patients with mild to moderate AD treated with 2,000 IU per day of vitamin E had a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period; additionally, caregiver time increased least in the vitamin E group, and there was no adverse effect on mortality.

A meta-analysis suggested that low-dose vitamin E supplementation (up to 150 IU daily) is associated with less all-cause mortality but that high-dose vitamin E may be associated with a very small increase in relative risk (RR) (approximately 1.05) of mortality. However, the subgroup of patients with AD included in this study was observed to have a lower RR of mortality associated with high-dose vitamin E supplementation. Other studies also support that high-dose vitamin E supplementation is not associated with death.107

Medical Foods

Souvenaid (Nutricia, The Netherlands) is a prescription nutritional supplement (aka medical food) containing Fortasyn Connect (Nutricia, The Netherlands) that includes precursors (uridine monophosphate, choline, phospholipids, eicosopentaenoic acid, docosahexaenoic acid) and cofactors (vitamins E, C, B12, and B6; folic acid; selenium) thought to support synapse synthesis and the formation of neuronal membranes in individuals with AD. Efficacy data from short-term studies (12–24 weeks) have been conflicting and do not support the benefits of Souvenaid in patients with AD on background therapy with anti-AD medications. Very modest signals of potential benefit were reported in two short-term (12–24 weeks) studies in drug-naïve patients with mild AD (n = 225–259 patients; mean MMSE scores of 24–25).108,109 But, more recently a 24-week study of Souvenaid added onto baseline anti-AD medications did not show benefit in affecting cognitive decline in individuals with mild-to-moderate AD.110 However, tolerability of Souvenaid in combination with standard care anti-AD medications was good.

Other Vitamins and Supplements

Large RCTs in the dementia stage of AD have failed to support any significant benefit from treatment by ginkgo biloba, high-dose vitamin B12/folic acid combinations, omega-3 fatty acid/fish oil components/preparations, nonsteroidal anti-inflammatory drugs, or statins.18,24 There is, however, epidemiologic and Level III and Level IV evidence that suggests potential signals of benefits for lower rates of dementia associated with individuals who take these supplements; therefore, it is possible that some of these compounds may confer a benefit in primary but not secondary prevention or treatment in AD dementia.

Antipsychotics for Treatment of Severe and Refractory Agitation, Aggression, and Psychosis

Although severe agitation, aggression, and psychosis are prevalent in advanced AD, they can respond to atypical antipsychotics (with a small treatment effect size of 0.2). However, the use of antipsychotics in AD is off-label in the United States and its prescribing information carries an FDA black-box warning due to at least a 1.5–1.7 increased relative risk of mortality.3 Clinicians should resist the urge to start antipsychotics in patients with dementia, and do so only after giving careful consideration to the risks, benefits, side effects, and alternatives. Antipsychotics can have detrimental effects on cognition, function, and patient safety, and should be reserved for selected patients who have a multidisciplinary behavioral plan; who are already on stable background combination therapy; who are under the supervision of a dementia specialist; or when there is an immediate or impending high risk to the safety or well-being of the patient or others.

Conclusions, Best Practices, and Recommendations

Evidence supports efficacy, effectiveness, and use of ChEIs and memantine for cognitive enhancement in AD (particularly for initiation of ChEIs in mild stage AD and adding memantine at the moderate stage). For those not diagnosed until moderate or severe stages, either a ChEI or memantine can be initiated. Data further support the added benefits of achieving ChEI-memantine add-on combination therapy in moderate and later stages of AD dementia. Level II evidence supports treatment with ChEI may be beneficial in mild stage AD and for particular subgroups of patients with MCI due to AD (ie, carriers of apolipoprotein E epsilon4 alleles,102 or those with depression or depressive symptoms).103 Such off-FDA label pharmacotherapy is not sufficiently supported by evidence to warrant an unequivocal recommendation for its blanket use in all patients. However, available benefit, risk (tolerability and safety) and cost data, individual clinical circumstances, and patient-caregiver dyad preferences warrant a discussion among clinicians, patients, and caregivers about this possibility.

ChEI therapy should be initiated and slowly titrated over several months to a maximal clinical or tolerated dose after diagnosis of AD (Table 5), unless contraindicated (due to conditions such as unstable cardiac arrhythmias, uncontrolled seizures, active peptic ulcer disease, GI bleeding, or unexplained syncope). For patients with moderate to severe AD, memantine should be initiated once stable-dose ChEI therapy has been achieved for several months without adverse effects (Table 5). Memantine monotherapy can be initiated on-label in the United States if the patient has moderate or later stage AD; conversely, a ChEI can be added after several months of stable memantine therapy. The latter may be a useful strategy for patients who are sensitive to, or who experience GI side effects, with ChEIs. In the event of adverse events, trying a low dosage and titrating it slowly may be helpful. In highly refractory cases, a trial of switching to another ChEI at a low dose should be tried.

Dosing of Anti-Alzheimer’s Disease Medications

Table 5.

Dosing of Anti-Alzheimer’s Disease Medications

AD care should be individualized based on an open discussion with the patient and caregivers, regarding prognosis, goals, and expectations of therapy. Appropriate maintenance of treatment with cognitive enhancers can meaningfully contribute to differences in the course of AD.

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Medications to Avoid in Older Cognitively Impaired Individuals

Anticholinergic Other Mechanisms
Antihistamines   Brompheniramine   Carbinoxamine   Chlorpheniramine   Clemastine   Cyproheptadine   Dimenhydrinate   Diphenhydramine   Hydroxyzine   Loratadine   Meclizine Anti-Parkinson agents   Benztropine   Trihexyphenidyl Barbiturates   Amobarbital   Butabarbital   Butalbital   Mephobarbital   Pentobarbital   Phenobarbital   Secobarbital Nonbenzodiazepine hypnotics   Eszopiclone   Zolpidem   Zaleplon   Chloral hydrate   Meprobamate
Skeletal muscle relaxants   Carisoprodol   Cyclobenzaprine   Orphenadrine   Tizanidine
Antidepressants   Amitriptyline   Amoxapine   Clomipramine   Desipramine   Doxepin   Imipramine   Nortriptyline   Paroxetine   Protriptyline   Trimipramine Antipsychotics   Chlorpromazine   Clozapine   Fluphenazine   Loxapine   Olanzapine   Perphenazine   Pimozide   Prochlorperazine   Promethazine   Thioridazine   Thiothixene   Trifluoperazine Benzodiazepines   Short- and intermediate-acting     Alprazolam     Estazolam     Lorazepam     Oxazepam     Temazepam     Triazolam   Long-acting      Chlorazepate     Chlordiazepoxide     Chlordiazepoxide-amitriptyline     Clidinium-chlordiazepoxide     Clonazepam     Diazepam     Flurazepam     Quazepam
Antimuscarinics (urinary incontinence)   Darifenacin   Fesoterodine   Flavoxate   Oxybutynin   Solifenacin   Tolterodine   Trospium Antispasmodics   Atropine products   Belladonna   Alkaloids   Dicyclomine   Homatropine   Hyoscyamine   products   Loperamide   Propantheline   Scopolamine

Pharmacokinetic and Mechanistic Characteristics of the Anti-Alzheimer’s Disease Drugsa

Drug Half-Life (h) Bioavailability (%) Tmax (h) Hepatic Metabolism Absorption Affected by Food Reversible Inhibition of AChE Other Cholinomimetic Effects
Donepezil 60–90 100 3–5 Yes No Yes Not applicable
Rivastigmine 1.5–2b 40 0.8–1.8 No Yes Noc BuChEI
Rivastigmine patch 3.4b 55–65 8–12 No No Noc BuChEI
Galantamine 5–8 85–100 0.5–1.5 Yes Yes Yes nAChR agonist
Galantamine ER 25–35 85–100 4.5–5 Yes Yes Yes nAChR agonist

Pharmacokinetic Characteristics and Effects of the Anti-Alzheimer’s Disease Drugsa

Drug Half-Life (h) Bioavailability (%) Tmax (h) Hepatic Metabolism Renal Excretion Absorption Affected by Food Effects on Other Receptors Other Notes
Memantine 60–80 95–100 9–12 Little (<10%)b Yesc No HT3 antagonist 10 mg twice daily maximum dose (20 mg totaldaily maximum)e
Memantine XR 60–80 95–100 18–25d Little (<10%)b Yesc Yesd HT3 antagonist 28 mg once daily maximum dosee

Level I and Level II Evidence Grade Controlled Clinical Efficacy and Effectiveness Studies of a Cholinesterase Inhibitor and Memantine Add-On Combination Therapy

Study Design Number of Patients Duration or Mean Follow Up Disease Stage Study Goal Primary Endpoints Results Evidence Level
Tariot et al.88 (2004) RCT, efficacy trial 404 24 weeks Moderate-severe Safety and efficacy of adding 10 mg twice daily memantine immediate-release to stable background donepezil treatment Cognition: SIB function: ADCS-ADL19 Safety and tolerability: TEAE Significantly better outcome with addition of memantine versus placebo in all primary endpoints; good safety profile and well tolerated I
Porsteinsson et al. 73 (2008) RCT, efficacy trial 433 24 weeks Mild-moderate Safety and efficacy of adding 20 mg once daily memantine immediate-release to stable background ChEI treatment (donepezil, rivastigmine, or galantamine) Cognition: ADAS-cog Global change: CIBIC-Plus Safety and tolerability: TEAE No statistical treatment differences on primary endpoints; underpowered studya; good safety profile and well tolerated II
Grossberg et al. 91 (2013) RCT, efficacy trial 677 24 weeks Moderate-severe Safety and efficacy of adding 28 mg once daily memantine extended-release to stable background ChEI treatment (donepezil, rivastigmine, or galantamine) Cognition: SIB function: ADCS-ADL19 Behavior: NPI Global Change: CIBIC-Plus Fluency: VFT Safety and tolerability: TEAE Significantly better outcome with addition of memantine versus placebo in all primary endpoints (SIB and CIBIC-Plus), and secondary endpoints of NPI and VFT, but not ADLs. Good safety profile and well tolerated I
Howard et al.12 (2012) RCT, effectiveness trial 295 52 weeks Moderate-severe Comparative effectiveness of discontinuing background donepezil and adding placebo or memantine, or continuing donepezil and adding placebo or memantine Cognition: SMMSE Function: BALDS Behavior: NPI QOL: DEMQOL-proxy Caregiver health: GHQ-12 Significantly better outcomes on SMMSE, BALDS, and NPI at 52-week end-point for all treatment groups compared to discontinuation of donepezil and starting placebo; overall, treatment groups undifferentiated at 52 weeks IIb
Atri et al.74 (2008) CLOC, effectiveness cohort study 382 Mean, 2.5 years Mild, moderate, and severe Long-term clinical effectiveness of CT versus ChEI alone versus standard care without ChEI or memantine Cognition: BDS Function: ADL Significantly slower trajectory of cognitive and functional decline for CT; slower decline in cognition for ChEI than standard care; effect sizes increase with time on CT II
Lopez et al.79 (2009) CLOC, effectiveness cohort study 943 Mean, 5.2 years Mild, moderate, and severe Effects of CT versus ChEI alone versus standard care without ChEI or memantine on time to death or nursing home admission Time to nursing home admission or death Longer time to nursing home admission for CT over ChEIs alone, and for ChEIs versus standard care. No differences in time to death II
Rountree et al.23 (2009) CLOC, effectiveness cohort study 641 Mean, 3 years Mild, moderate, and severe Clinical effectiveness of persistence of anti-Alzheimer’s disease therapies with ChEI, memantine, and CT Cognition: ADAS-cog, MMSE, BPMSE Function: PSMS and IADL Severity: CDR-sb Treatment persistenceassociated with significant benefits in outcomes (slower decline) in all domains; treatment benefits are cumulative II
Gillette-Guyonnet et al. 80 (2012) CLOC, effectiveness cohort study 686 Mean, 2.6 years Mild, moderate, and severe Delineation and comparison of rates of deterioration on clinical measures between ChEI and/or memantine treated and untreated (historical) cohorts Cognition: ADAS-cog, MMSE, Function: ADL Behavior: NPI Severity: CDR-sb Significantly lower rates of deterioration on MMSE and ADAS-cog in treatedAlzheimer’s disease patients compared to untreated patients in the Pre-ChEI era. No pre-ChEI versus post-ChEI/memantine era comparative data for ADL, NPI, and CDR II

Dosing of Anti-Alzheimer’s Disease Medications

Drug Dose
Donepezil Starting dose: 5 mg/day; can be increased to 10 mg/day after 4–6 weeks. Before starting donepezil at 23 mg/day, patients should be taking donepezil at 10 mg/day for at least 3 months
Rivastigmine Oral: Starting dose,1.5 mg twice daily. If well tolerated, the dose may be increased to 3 mg twice daily after 2 weeks. Subsequent increases to 4.5 mg and 6 mg twice daily should be attempted after 2-week minimums at previous dose. Maximum dose: 6 mg twice daily Patch: Starting dose, one 4.6-mg patch once daily for a 24-hour period Maintenance dose: one 9.5-mg or 13.3-mg patch once daily for a 24-hour period. Before initiating a maintenance dose, patients should undergo a minimum of 4 weeks of treatment at the initial dose (or at the lower patch dose of 9.5 mg) with good tolerability
Galantamine Extended-release: Start at 8 mg once daily for 4 weeks; increase to 16 mg once daily for 4 weeks; increase to 24 mg once daily Generic: Start at 4 mg twice daily for 4 weeks; increase to 8 mg twice daily for 4 weeks; increase to 12 mg twice daily
Memantine Immediate-release: Starting dose, 5 mg once daily; increase dose in 5-mg increments to a maximum of 20 mg daily (divided doses taken twice daily) with a minimum of 1 week between dose increases. The maximum recommended dose in severe renal impairment is 5 mg twice daily Extended-release: For patients new to memantine, the recommended starting dose of memantine extended-release is 7 mg once daily, and the recommended target dose is 28 mg once daily. The dose should be increased in 7-mg increments every 7 days. The minimum recommended interval between dose increases is 1 week, and only if the previous dose has been well tolerated. The maximum recommended dose in severe renal impairment is 14 mg once daily
Authors

Alireza Atri, MD, PhD, is the Ray Dolby Endowed Chair in Brain Health Research; the Director of Research and Education, Ray Dolby Brain Health Center; a Senior Scientist, California Pacific Medical Center Research Institute; an Assistant in Neurology, Memory Disorders Unit, Department of Neurology, Massachusetts General Hospital; and an Instructor of Neurology (part-time), Harvard Medical School. Theodore A. Stern, MD, is the Ned H. Cassem Professor of Psychiatry in the field of Psychosomatic Medicine/Consultation, Harvard Medical School; and the Chief of the Avery D. Weisman Psychiatry Consultation Service, and the first Director of the Office for Clinical Careers, Massachusetts General Hospital.

Address correspondence to Alireza Atri, MD, PhD, Ray Dolby Brain Health Center, CPMC Davies Campus, 45 Castro Street, Suite 220, San Francisco, CA 94114; email: atria@cpmcri.org.

Disclosure: Alireza Atri discloses royalties received from Oxford University Press; consulting fees received from Actavis/Forest Laboratories, Merck & Co., and Lundbeck; and an institutional research contract from Lundbeck. Theodore A. Stern discloses a salary received from the Academy of Psychosomatic Medicine and royalties received from Elsevier and Massachusetts General Hospital.

10.3928/00485713-20150626-07

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