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Managing Patients With Moderate-to-Severe Alzheimer’s Disease: Expectations, Treatments, and Prognosis

William J. Burke, MD

Stead Family Memory Center, Banner Alzheimer’s Institute, and the Department of Psychiatry, University of Arizona College of Medicine, Phoenix

Alzheimer’s disease (AD) places a heavy burden on caregivers and the health care community as the disease progresses and individuals lose the ability to live independently and perform activities of daily living (ADL). Although no cure is available, clinicians can use available therapies to try to help individuals with AD maintain their quality of life to the extent possible, maximize function in daily activities, and enhance cognition, mood, and behavior. Providing information and support to caregivers can help them foster a safe environment and promote social engagement, as appropriate, for patients with AD. Effective management of AD involves giving patients and their caregivers realistic expectations regarding the prognosis and goals of treatment (which change over time), providing appropriate treatments, and managing troublesome behavioral and psychological symptoms of dementia (BPSD).

Patient and Caregiver Expectations

The diagnosis of probable AD is often devastating for patients and family members to receive. When they learn that treatments are available, they may have unrealistic expectations about what these therapies can achieve and how the disease may progress. By informing patients and caregivers about the disease stages, required monitoring, and treatment options, clinicians can improve adherence to the treatment regimen and elicit the support of caregivers for monitoring patients’ symptoms, behaviors, and safety.

AV 1. Progression of AD and MMSE Scores (0:47)

AV 1. Progression of AD and MMSE Scores

Disease stages. While the course of AD varies in individual patients, symptoms tend to follow the same general stages (AV 1). The preclinical stage has no symptoms, followed by mild cognitive impairment, when subjective memory concerns and cognitive deficits begin but no functional impairment exists. When symptoms lead to functional impairment, AD dementia begins.1 AD stages are labeled mild, moderate, or severe depending on the severity of symptoms and functional impairment.2 At the mild stage, patients typically have impairment in memory along with impairment in at least one other cognitive domain, such as language, visual spatial skills, or executive functioning. Some social or occupational ability is also affected.

Individuals in the moderate stage require assistance in instrumental activities of daily living (IADL), such as doing housework, taking medication, managing finances, or shopping, and usually need a family member or caregiver to help with these activities. They have impairments in multiple cognitive domains and often develop significant behavioral symptoms, which can be difficult for caregivers to manage.

When patients reach the severe stage, they experience marked deficits in cognition and are dependent on others for ADL, including bathing, dressing, and eating.2 People with severe AD require either intensive caregiving at home or nursing home care. Knowing these stages can help patients and family members make informed and timely decisions regarding financial, medical, and legal issues, such as durable power of attorney and advanced directives.

Required monitoring. As patients gradually decline, clinicians must manage co-occurring medical conditions, watch for delirium and changes in BPSD, and monitor safety issues, such as driving ability. They should also assess the caregivers’ health status and offer relevant community or online resources and support, such as the Alzheimer’s Association.

Treatment expectations. Clinicians should let patients and caregivers know that, while current pharmacotherapies for AD may help lessen cognitive and functional decline, they are not disease-modifying or curative. Symptom improvement can occur but is rare.3 The treatment goal is to slow disease progression in the long-term.4 Clinicians should explain that patients who are treated early and consistently with medication will show less deterioration over time than is expected without medication.4 Discontinuing treatment may lead to rapid decline.3 When patients and caregivers understand the typical progression of AD and the benefits as well as the limitations of treatment, they tend to be less frustrated with treatment and more willing to comply with recommendations.5

AD Treatments

Pharmacologic treatments for AD include 3 cholinesterase inhibitors and the NMDA receptor antagonist memantine (Table 1).6 The cholinesterase inhibitors galantamine, donepezil, and rivastigmine are FDA-approved for the treatment of mild-to-moderate AD, while the 10- and 23-mg dosages of donepezil and the 13.3-mg patch formulation of rivastigmine are approved for severe AD.3 Memantine is approved for treating symptoms of moderate-to-severe AD.

Table 1. Pharmacologic Treatments for AD

Table 1. Pharmacologic Treatments for AD

Cholinesterase inhibitors have similar efficacy with proven benefits for cognition, global functioning, and ADL,7 and potential benefits for certain BPSD, such as depression and anxiety.3 Common side effects of cholinesterase inhibitors include nausea, vomiting, diarrhea, weight loss, appetite loss, and muscle weakness.6

Donepezil. A 23-mg/d tablet of donepezil is now available for patients with moderate or severe AD, but only if they have tolerated the 10-mg/d dose for at least 3 months.8 The 23-mg/d dose was developed based on several observations: (1) the 10-mg/d dose inhibits cortical AChE activity in vivo by only 20% to 40%, (2) cholinergic deficits are greater in patients with more advanced AD, and (3) trials comparing 5 mg/d and 10 mg/d of donepezil with placebo showed a dose-response relationship in favor of the 10-mg/d dose, with more benefits in patients with advanced AD.8 Due to the risk of increased side effects, the 23-mg/d dose may not be appropriate for patients with very low weight, poor appetite, bradycardia, or a history of gastrointestinal bleeding.8 Before starting the 23-mg/d formulation of donepezil, clinicians should describe expected adverse effects to caregivers, and, after initiation, monitor side effects carefully.

Rivastigmine. Rivastigmine is available in capsule, oral solution, and patch formulations, with the patch formulations approved for severe AD.6 The patch formulations provide similar drug exposure to the oral formulations but at a lower plasma concentration and slower absorption rate, which maintains the medication’s efficacy while improving tolerability and ease of use.9 In a 24-week, randomized controlled trial10 comparing the 4.6 mg/24 h patch with the 13.3 mg/24 h patch in patients with severe AD (N = 716), the 13.3-mg patch was significantly superior to the 4.6-mg patch on cognition and ADL function measures (P < .0001 and P = .025, respectively). Due to its superior efficacy and similar tolerability to the 4.6-mg patch, the 13.3-mg patch demonstrates a favorable risk-benefit profile in severe AD.10

Memantine. Memantine was the first agent FDA-approved for moderate-to-severe AD due to its benefits on cognition, global outcomes, ADL, and behavior, including agitation and aggression.3 Unlike the cholinesterase inhibitors, memantine has less association with gastrointestinal adverse effects but can be associated with constipation as well as dizziness, headache, and confusion.3,6 A study11 of extended-release memantine (28 mg/d) as add-on treatment with cholinesterase inhibitors compared with placebo in patients with moderate-to-severe AD (N = 677) showed that memantine-treated patients performed better than placebo-treated patients on measures of cognition, global clinical status, behavioral disturbances, and verbal fluency, but not ADL.

BPSD Management

Behavioral and psychological symptoms are cardinal features of dementia, varying by diagnosis and stage of illness. BPSD may present as observed behaviors, such as wandering, agitation, and sexually inappropriate behaviors, or psychological symptoms, including depression, anxiety, and delusions (AV 2).12 These noncognitive behaviors or symptoms tend to occur in clusters and can increase caregiver burden and lead to earlier institutionalization.12 One study13 showed that 61% of patients with dementia demonstrated one or more BPSD in the past month, with apathy (27%), depression (24%), and agitation/aggression (24%) being the most common. Instruments to monitor BPSD include the BEHAVE-AD and NPI.12 As AD progresses, BPSD become more predominant and must be treated to avoid emotional and financial repercussions for patients, caregivers, and the health care system.5 First-line treatment for BPSD includes nonpharmacologic interventions, but, if those fail, several off-label pharmacologic options are available, depending on the specific symptoms and the risk-benefit ratio.5,12

AV 2. Discussing Treatment and Problem Behaviors With A Caregiver (2:32)

AV 2. Discussing Treatment and Problem Behaviors With A Caregiver

Nonpharmacologic interventions. The benefits of nonpharmacologic interventions for BPSD are that they may address the psychosocial or environmental trigger for the behavior and they avoid the adverse effects and drug interactions associated with pharmacologic treatment.5 BPSD may be triggered by pain, illness, boredom, loneliness, and unpredictable environments. Interventions include refocusing or redirecting the patient, participating in enjoyable activities, establishing regular routines, eliminating sources of conflict and frustration, and giving rewards for success.5 CBT, CST, and IPT have also been designed to stimulate and engage people with dementia.5 Interventions for the caregiver, such as support groups or training, can also be effective in alleviating BPSD because caregivers can reduce problem behaviors and create a safe and calm environment for patients with AD.5

Pharmacologic interventions. Because no FDA-approved treatments are available for BPSD, clinicians must inform patients and caregivers about potential risks associated with pharmacologic treatment.14 Off-label treatments include antipsychotics, mood stabilizers, antidepressants, and the stimulant methylphenidate.5

Atypical antipsychotics are effective in the treatment of psychotic symptoms, agitation, and aggression, but they are off-label in elderly patients due to their increased risk of death, falls, and cerebrovascular adverse events.3 The risk of death in elderly patients treated with atypical antipsychotics is 1.6 to 1.7 times that seen in placebo-treated patients.14

Other drugs used for agitation include the antidepressant trazodone and the mood-stabilizing drugs carbamazepine and divalproex sodium.5 However, divalproex sodium was studied as a preventive treatment for agitation and psychosis in patients with moderate AD, and the treatment did not delay symptoms or functional decline. Instead, the treatment group showed brain volume loss and ventricular expansion,15 suggesting that divalproex sodium is not appropriate for patients with AD.

Antidepressants may be used to treat symptoms such as depression, mood lability, and anxiety. The SSRIs citalopram and sertraline appear to be more effective and have fewer side effects in patients with AD than other antidepressants, but no direct-comparison studies have been performed.5 In a study16 of patients with probable AD (N = 186) receiving a psychosocial intervention plus either citalopram or placebo, the citalopram group showed less agitation and caregiver burden than the placebo group.

Finally, the stimulant methylphenidate appears to demonstrate some efficacy for the treatment of apathy in elderly patients with AD, but more evidence is needed.5

Conclusion

Receiving a diagnosis of probable AD is often overwhelming for patients and their family members. They need information on how the disease progresses, what monitoring is required, what treatments are available, and what they can expect from treatment. Of the 4 treatments approved for AD, all show benefits for cognition, global status, and ADL, but side effect profiles differ between classes. Clinicians should monitor response to treatment and adverse effects as well as emerging BPSD. Treatments for BPSD include psychotherapy and caregiver training, but off-label medications may be necessary to treat unresolved symptoms. Because additional medications to treat BPSD are likely to create adverse effects, clinicians should discuss the risks and benefits with patients and caregivers. Successful management of patients with moderate-to-severe AD requires diligent monitoring and caregiver education and support.

Clinical Points
  • Provide education on the stages of AD, support services, and treatment expectations to patients and caregivers
  • Select appropriate pharmacologic treatment for patients with moderate-to-severe AD based on risk-benefit profiles
  • Manage BPSD using nonpharmacologic options including psychotherapy and caregiver training
  • Consider off-label medications for BPSD only when nonpharmacologic options fail and patients and caregivers understand the associated risks
Drug Names

carbamazepine (Carbatrol, Equetro, and others), citalopram (Celexa and others), divalproex sodium (Depakote and others), donepezil (Aricept and others), galantamine (Razadyne and others), memantine (Namenda and others), methylphenidate (Daytrana, Focalin, and others), rivastigmine (Exelon and others), sertraline (Zoloft and others), trazodone (Oleptro and others)

Abbreviations

AChE =acetylcholinesterase, AD = Alzheimer’s disease, ADL = activities of daily living, BEHAVE-AD = Behavioral Pathology in Alzheimer’s Disease rating scale, BPSD = behavioral and psychological symptoms of dementia, CBT = cognitive-behavioral therapy, CST = cognitive stimulation therapy, FDA = US Food and Drug Administration, IADL = instrumental activities of daily living, IPT = interpersonal therapy, MCI = mild cognitive impairment, MMSE = Mini Mental State Examination, NMDA = N-methyl-d-aspartate, NPI = Neuropsychiatric Inventory, SSRI = selective serotonin reuptake inhibitor

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References
  1. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):263–269. PubMed
  2. National Institute on Aging. About Alzheimer’s Disease: Symptoms. http://www.nia.nih.gov/alzheimers/topics/symptoms. Accessed July 28, 2014.
  3. Farlow MR, Miller ML, Pejovic V. Treatment options in Alzheimer’s disease: maximizing benefit, managing expectations. Dement Geriatr Cogn Disord. 2008;25(5):408–422. PubMed
  4. Geldmacher DS, Frolich L, Doody RS, et al. Realistic expectations for treatment success in Alzheimer’s disease. J Nutr Health Aging. 2006;10(5):417–429. PubMed
  5. Sadowsky CH, Galvin JE. Guidelines for the management of cognitive and behavioral problems in dementia. J Am Board Fam Med. 2012;25(3):350–366. PubMed
  6. National Institute on Aging. Alzheimer’s Disease Medications: Fact Sheet.
    http://www.nia.nih.gov/sites/default/files/ad_meds_fact_sheet-2014_update-final_2-12-14.pdf. Updated January 2014. Accessed July 28, 2014.
  7. Thompson S, Lanctôt KL, Herrmann N. The benefits and risks associated with cholinesterase inhibitor therapy in Alzheimer’s disease. Expert Opin Drug Saf. 2004;3(5):425–440. PubMed
  8. Cummings JL, Geldmacher D, Farlow M, et al. High-dose donepezil (23 mg/day) for the treatment of moderate and severe Alzheimer’s disease: drug profile and clinical guidelines. CNS Neurosci Ther. 2013;19(5):294–301. PubMed
  9. Kurz A, Farlow M, Lefèvre G. Pharmacokinetics of a novel transdermal rivastigmine patch for the treatment of Alzheimer’s disease: a review. Int J Clin Pract. 2009;63(5):799–805. PubMed
  10. Farlow MR, Grossberg GT, Sadowsky CH, et al. A 24-week, randomized, controlled trial of rivastigmine patch 13.3 mg/24 h versus 4.5 mg/24 h in severe Alzheimer’s dementia. CNS Neurosci Ther. 2013;19(10):745–752. PubMed
  11. Grossberg GT, Manes F, Allegri RF, et al. The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial of patients with moderate-to-severe Alzheimer’s disease taking cholinesterase inhibitors. CNS Drugs. 2013;27(6):469–478. PubMed
  12. Lawlor BA. Behavioral and psychological symptoms in dementia: the role of atypical antipsychotics. J Clin Psychiatry. 2004;65(suppl 11):5–10. Full Text
  13. Lyketsos GC, Steinberg M, Tschanz JT, et al. Mental and behavioral disturbances in dementia: findings from the Cache County study on memory in aging. Am J Psychiatry. 2000;157(5):708–714. PubMed
  14. Cascade E, Kalali AH, Cummings JL. Use of atypical antipsychotics in the elderly. Psychiatry (Edgmont). 2008;5(7):28–31. PubMed
  15. Tariot PN, Schneider LS, Cummings J, et al. Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Arch Gen Psychiatry. 2011;68(8):853–861. PubMed
  16. Porsteinsson AP, Drye LT, Pollock BG, et al, for the CitAD Research Group. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014;311(7):682–691. PubMed
From the Series:
Treating and Caring for the Patient With Moderate-to-Severe Alzheimer’s Disease

Supported by an educational grant from Forest Laboratories, Inc.

CME Background Information

Supported by an educational grant from Forest Laboratories, Inc.

Participants may receive credit by reading the activity, correctly answering the posttest question, and completing the evaluation.

Objective

After completing this educational activity, you should be able to:

  • Plan an appropriate treatment regimen for a patient with moderate-to-severe Alzheimer’s disease

Financial Disclosure

The faculty for this CME activity and the CME Institute staff were asked to complete a statement regarding all relevant personal and financial relationships between themselves or their spouse/partner and any commercial interest. The CME Institute has resolved any conflicts of interest that were identified. No member of the CME Institute staff reported any relevant personal financial relationships. Faculty financial disclosure is as follows:

Dr Burke is a consultant for Otsuka and has received grant/research support from Eli Lilly, Pfizer, Takeda, NeoSync, Elan, Accera, and Lundbeck.

Accreditation Statement

The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation

The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

The American Academy of Physician Assistants (AAPA) accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 0.5 hours of Category I credit for completing this program.

To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.

Release, Review, and Expiration Dates

This Neurology Report was published in December 2014 and is eligible for AMA PRA Category 1 Credit™ through December 31, 2017. The latest review of this material was July 2014.

Statement of Need and Purpose

Of US adults over the age of 70 years, almost 15% have a form of dementia, most commonly due to Alzheimer’s disease (AD). As the population ages, the prevalence and economic burden of this disorder are expected to significantly increase. AD has the following stages of progression: preclinical, mild, moderate, and severe. Patients with AD generally begin to require the help of a caregiver during the moderate stage, and then the disease progresses into the severe stage, requiring around-the-clock care, which can be a stressful and hefty burden for caregivers. AD is difficult to diagnose in the early stages, and physicians may mistake the disease for general signs of aging or stress, have time constraints for accurate assessment, have concerns about stigmatizing the patient, or lack the necessary skills to explain a dementia diagnosis to patients and their caregivers. After diagnosing AD, treatment guidelines recommend prescribing one of several FDA-approved agents to slow cognitive, functional, and behavioral decline; however, only about 25% of patients with AD receive these medications. Physicians may perceive that treatment options are limited or are not effective for AD since progression of the disease is inevitable. Additionally, physicians may not effectively communicate treatment options to caregivers, many of whom have reported that physicians have not told them about potential treatment options that could temporarily stabilize AD or given them adequate information on the course of the disease and its effect on function and memory, where to find help and services, and how to manage abnormal/difficult behavior. Physicians need education on managing and treating patients with moderate-to-severe AD, including communicating effectively with patients and caregivers on the diagnosis and prognosis of AD, as well as treatment options and goals. This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on AD.

Disclosure of Off-Label Usage

Dr Burke has determined that carbamazepine, citalopram, divalproex sodium, donepezil, galantamine, memantine, methylphenidate, rivastigmine, sertraline, and trazodone are not approved by the US Food and Drug Administration for the treatment of behavioral and psychological symptoms of dementia.

Review Process

The entire faculty of the series discussed the content at a peer-reviewed planning session, the Chair reviewed the activity for accuracy and fair balance, and a member of the External Advisory CME Board who is without conflict of interest reviewed the activity to determine whether the material is evidence-based and objective.

Acknowledgment

This Neurology Report is derived from the planning teleconference series “Treating and Caring for the Patient With Moderate-to-Severe Alzheimer’s Disease,” which was held in May 2014 and supported by an educational grant from Forest Laboratories, Inc. The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter.

 
 

 Content Editor ‭[2]‬

 
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Managing Patients With Moderate-to-Severe Alzheimer’s Disease: Expectations, Treatments, and Prognosis

William J. Burke, MD

Stead Family Memory Center, Banner Alzheimer’s Institute, and the Department of Psychiatry, University of Arizona College of Medicine, Phoenix

Alzheimer’s disease (AD) places a heavy burden on caregivers and the health care community as the disease progresses and individuals lose the ability to live independently and perform activities of daily living (ADL). Although no cure is available, clinicians can use available therapies to try to help individuals with AD maintain their quality of life to the extent possible, maximize function in daily activities, and enhance cognition, mood, and behavior. Providing information and support to caregivers can help them foster a safe environment and promote social engagement, as appropriate, for patients with AD. Effective management of AD involves giving patients and their caregivers realistic expectations regarding the prognosis and goals of treatment (which change over time), providing appropriate treatments, and managing troublesome behavioral and psychological symptoms of dementia (BPSD).

Patient and Caregiver Expectations

The diagnosis of probable AD is often devastating for patients and family members to receive. When they learn that treatments are available, they may have unrealistic expectations about what these therapies can achieve and how the disease may progress. By informing patients and caregivers about the disease stages, required monitoring, and treatment options, clinicians can improve adherence to the treatment regimen and elicit the support of caregivers for monitoring patients’ symptoms, behaviors, and safety.

AV 1. Progression of AD and MMSE Scores (0:47)

AV 1. Progression of AD and MMSE Scores

Disease stages. While the course of AD varies in individual patients, symptoms tend to follow the same general stages (AV 1). The preclinical stage has no symptoms, followed by mild cognitive impairment, when subjective memory concerns and cognitive deficits begin but no functional impairment exists. When symptoms lead to functional impairment, AD dementia begins.1 AD stages are labeled mild, moderate, or severe depending on the severity of symptoms and functional impairment.2 At the mild stage, patients typically have impairment in memory along with impairment in at least one other cognitive domain, such as language, visual spatial skills, or executive functioning. Some social or occupational ability is also affected.

Individuals in the moderate stage require assistance in instrumental activities of daily living (IADL), such as doing housework, taking medication, managing finances, or shopping, and usually need a family member or caregiver to help with these activities. They have impairments in multiple cognitive domains and often develop significant behavioral symptoms, which can be difficult for caregivers to manage.

When patients reach the severe stage, they experience marked deficits in cognition and are dependent on others for ADL, including bathing, dressing, and eating.2 People with severe AD require either intensive caregiving at home or nursing home care. Knowing these stages can help patients and family members make informed and timely decisions regarding financial, medical, and legal issues, such as durable power of attorney and advanced directives.

Required monitoring. As patients gradually decline, clinicians must manage co-occurring medical conditions, watch for delirium and changes in BPSD, and monitor safety issues, such as driving ability. They should also assess the caregivers’ health status and offer relevant community or online resources and support, such as the Alzheimer’s Association.

Treatment expectations. Clinicians should let patients and caregivers know that, while current pharmacotherapies for AD may help lessen cognitive and functional decline, they are not disease-modifying or curative. Symptom improvement can occur but is rare.3 The treatment goal is to slow disease progression in the long-term.4 Clinicians should explain that patients who are treated early and consistently with medication will show less deterioration over time than is expected without medication.4 Discontinuing treatment may lead to rapid decline.3 When patients and caregivers understand the typical progression of AD and the benefits as well as the limitations of treatment, they tend to be less frustrated with treatment and more willing to comply with recommendations.5

AD Treatments

Pharmacologic treatments for AD include 3 cholinesterase inhibitors and the NMDA receptor antagonist memantine (Table 1).6 The cholinesterase inhibitors galantamine, donepezil, and rivastigmine are FDA-approved for the treatment of mild-to-moderate AD, while the 10- and 23-mg dosages of donepezil and the 13.3-mg patch formulation of rivastigmine are approved for severe AD.3 Memantine is approved for treating symptoms of moderate-to-severe AD.

Table 1. Pharmacologic Treatments for AD

Table 1. Pharmacologic Treatments for AD

Cholinesterase inhibitors have similar efficacy with proven benefits for cognition, global functioning, and ADL,7 and potential benefits for certain BPSD, such as depression and anxiety.3 Common side effects of cholinesterase inhibitors include nausea, vomiting, diarrhea, weight loss, appetite loss, and muscle weakness.6

Donepezil. A 23-mg/d tablet of donepezil is now available for patients with moderate or severe AD, but only if they have tolerated the 10-mg/d dose for at least 3 months.8 The 23-mg/d dose was developed based on several observations: (1) the 10-mg/d dose inhibits cortical AChE activity in vivo by only 20% to 40%, (2) cholinergic deficits are greater in patients with more advanced AD, and (3) trials comparing 5 mg/d and 10 mg/d of donepezil with placebo showed a dose-response relationship in favor of the 10-mg/d dose, with more benefits in patients with advanced AD.8 Due to the risk of increased side effects, the 23-mg/d dose may not be appropriate for patients with very low weight, poor appetite, bradycardia, or a history of gastrointestinal bleeding.8 Before starting the 23-mg/d formulation of donepezil, clinicians should describe expected adverse effects to caregivers, and, after initiation, monitor side effects carefully.

Rivastigmine. Rivastigmine is available in capsule, oral solution, and patch formulations, with the patch formulations approved for severe AD.6 The patch formulations provide similar drug exposure to the oral formulations but at a lower plasma concentration and slower absorption rate, which maintains the medication’s efficacy while improving tolerability and ease of use.9 In a 24-week, randomized controlled trial10 comparing the 4.6 mg/24 h patch with the 13.3 mg/24 h patch in patients with severe AD (N = 716), the 13.3-mg patch was significantly superior to the 4.6-mg patch on cognition and ADL function measures (P < .0001 and P = .025, respectively). Due to its superior efficacy and similar tolerability to the 4.6-mg patch, the 13.3-mg patch demonstrates a favorable risk-benefit profile in severe AD.10

Memantine. Memantine was the first agent FDA-approved for moderate-to-severe AD due to its benefits on cognition, global outcomes, ADL, and behavior, including agitation and aggression.3 Unlike the cholinesterase inhibitors, memantine has less association with gastrointestinal adverse effects but can be associated with constipation as well as dizziness, headache, and confusion.3,6 A study11 of extended-release memantine (28 mg/d) as add-on treatment with cholinesterase inhibitors compared with placebo in patients with moderate-to-severe AD (N = 677) showed that memantine-treated patients performed better than placebo-treated patients on measures of cognition, global clinical status, behavioral disturbances, and verbal fluency, but not ADL.

BPSD Management

Behavioral and psychological symptoms are cardinal features of dementia, varying by diagnosis and stage of illness. BPSD may present as observed behaviors, such as wandering, agitation, and sexually inappropriate behaviors, or psychological symptoms, including depression, anxiety, and delusions (AV 2).12 These noncognitive behaviors or symptoms tend to occur in clusters and can increase caregiver burden and lead to earlier institutionalization.12 One study13 showed that 61% of patients with dementia demonstrated one or more BPSD in the past month, with apathy (27%), depression (24%), and agitation/aggression (24%) being the most common. Instruments to monitor BPSD include the BEHAVE-AD and NPI.12 As AD progresses, BPSD become more predominant and must be treated to avoid emotional and financial repercussions for patients, caregivers, and the health care system.5 First-line treatment for BPSD includes nonpharmacologic interventions, but, if those fail, several off-label pharmacologic options are available, depending on the specific symptoms and the risk-benefit ratio.5,12

AV 2. Discussing Treatment and Problem Behaviors With A Caregiver (2:32)

AV 2. Discussing Treatment and Problem Behaviors With A Caregiver

Nonpharmacologic interventions. The benefits of nonpharmacologic interventions for BPSD are that they may address the psychosocial or environmental trigger for the behavior and they avoid the adverse effects and drug interactions associated with pharmacologic treatment.5 BPSD may be triggered by pain, illness, boredom, loneliness, and unpredictable environments. Interventions include refocusing or redirecting the patient, participating in enjoyable activities, establishing regular routines, eliminating sources of conflict and frustration, and giving rewards for success.5 CBT, CST, and IPT have also been designed to stimulate and engage people with dementia.5 Interventions for the caregiver, such as support groups or training, can also be effective in alleviating BPSD because caregivers can reduce problem behaviors and create a safe and calm environment for patients with AD.5

Pharmacologic interventions. Because no FDA-approved treatments are available for BPSD, clinicians must inform patients and caregivers about potential risks associated with pharmacologic treatment.14 Off-label treatments include antipsychotics, mood stabilizers, antidepressants, and the stimulant methylphenidate.5

Atypical antipsychotics are effective in the treatment of psychotic symptoms, agitation, and aggression, but they are off-label in elderly patients due to their increased risk of death, falls, and cerebrovascular adverse events.3 The risk of death in elderly patients treated with atypical antipsychotics is 1.6 to 1.7 times that seen in placebo-treated patients.14

Other drugs used for agitation include the antidepressant trazodone and the mood-stabilizing drugs carbamazepine and divalproex sodium.5 However, divalproex sodium was studied as a preventive treatment for agitation and psychosis in patients with moderate AD, and the treatment did not delay symptoms or functional decline. Instead, the treatment group showed brain volume loss and ventricular expansion,15 suggesting that divalproex sodium is not appropriate for patients with AD.

Antidepressants may be used to treat symptoms such as depression, mood lability, and anxiety. The SSRIs citalopram and sertraline appear to be more effective and have fewer side effects in patients with AD than other antidepressants, but no direct-comparison studies have been performed.5 In a study16 of patients with probable AD (N = 186) receiving a psychosocial intervention plus either citalopram or placebo, the citalopram group showed less agitation and caregiver burden than the placebo group.

Finally, the stimulant methylphenidate appears to demonstrate some efficacy for the treatment of apathy in elderly patients with AD, but more evidence is needed.5

Conclusion

Receiving a diagnosis of probable AD is often overwhelming for patients and their family members. They need information on how the disease progresses, what monitoring is required, what treatments are available, and what they can expect from treatment. Of the 4 treatments approved for AD, all show benefits for cognition, global status, and ADL, but side effect profiles differ between classes. Clinicians should monitor response to treatment and adverse effects as well as emerging BPSD. Treatments for BPSD include psychotherapy and caregiver training, but off-label medications may be necessary to treat unresolved symptoms. Because additional medications to treat BPSD are likely to create adverse effects, clinicians should discuss the risks and benefits with patients and caregivers. Successful management of patients with moderate-to-severe AD requires diligent monitoring and caregiver education and support.

Clinical Points
  • Provide education on the stages of AD, support services, and treatment expectations to patients and caregivers
  • Select appropriate pharmacologic treatment for patients with moderate-to-severe AD based on risk-benefit profiles
  • Manage BPSD using nonpharmacologic options including psychotherapy and caregiver training
  • Consider off-label medications for BPSD only when nonpharmacologic options fail and patients and caregivers understand the associated risks
Drug Names

carbamazepine (Carbatrol, Equetro, and others), citalopram (Celexa and others), divalproex sodium (Depakote and others), donepezil (Aricept and others), galantamine (Razadyne and others), memantine (Namenda and others), methylphenidate (Daytrana, Focalin, and others), rivastigmine (Exelon and others), sertraline (Zoloft and others), trazodone (Oleptro and others)

Abbreviations

AChE =acetylcholinesterase, AD = Alzheimer’s disease, ADL = activities of daily living, BEHAVE-AD = Behavioral Pathology in Alzheimer’s Disease rating scale, BPSD = behavioral and psychological symptoms of dementia, CBT = cognitive-behavioral therapy, CST = cognitive stimulation therapy, FDA = US Food and Drug Administration, IADL = instrumental activities of daily living, IPT = interpersonal therapy, MCI = mild cognitive impairment, MMSE = Mini Mental State Examination, NMDA = N-methyl-d-aspartate, NPI = Neuropsychiatric Inventory, SSRI = selective serotonin reuptake inhibitor

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References
  1. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):263–269. PubMed
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From the Series:
Treating and Caring for the Patient With Moderate-to-Severe Alzheimer’s Disease

Supported by an educational grant from Forest Laboratories, Inc.

CME Background Information

Supported by an educational grant from Forest Laboratories, Inc.

Participants may receive credit by reading the activity, correctly answering the posttest question, and completing the evaluation.

Objective

After completing this educational activity, you should be able to:

  • Plan an appropriate treatment regimen for a patient with moderate-to-severe Alzheimer’s disease

Financial Disclosure

The faculty for this CME activity and the CME Institute staff were asked to complete a statement regarding all relevant personal and financial relationships between themselves or their spouse/partner and any commercial interest. The CME Institute has resolved any conflicts of interest that were identified. No member of the CME Institute staff reported any relevant personal financial relationships. Faculty financial disclosure is as follows:

Dr Burke is a consultant for Otsuka and has received grant/research support from Eli Lilly, Pfizer, Takeda, NeoSync, Elan, Accera, and Lundbeck.

Accreditation Statement

The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation

The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

The American Academy of Physician Assistants (AAPA) accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 0.5 hours of Category I credit for completing this program.

To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.

Release, Review, and Expiration Dates

This Neurology Report was published in December 2014 and is eligible for AMA PRA Category 1 Credit™ through December 31, 2017. The latest review of this material was July 2014.

Statement of Need and Purpose

Of US adults over the age of 70 years, almost 15% have a form of dementia, most commonly due to Alzheimer’s disease (AD). As the population ages, the prevalence and economic burden of this disorder are expected to significantly increase. AD has the following stages of progression: preclinical, mild, moderate, and severe. Patients with AD generally begin to require the help of a caregiver during the moderate stage, and then the disease progresses into the severe stage, requiring around-the-clock care, which can be a stressful and hefty burden for caregivers. AD is difficult to diagnose in the early stages, and physicians may mistake the disease for general signs of aging or stress, have time constraints for accurate assessment, have concerns about stigmatizing the patient, or lack the necessary skills to explain a dementia diagnosis to patients and their caregivers. After diagnosing AD, treatment guidelines recommend prescribing one of several FDA-approved agents to slow cognitive, functional, and behavioral decline; however, only about 25% of patients with AD receive these medications. Physicians may perceive that treatment options are limited or are not effective for AD since progression of the disease is inevitable. Additionally, physicians may not effectively communicate treatment options to caregivers, many of whom have reported that physicians have not told them about potential treatment options that could temporarily stabilize AD or given them adequate information on the course of the disease and its effect on function and memory, where to find help and services, and how to manage abnormal/difficult behavior. Physicians need education on managing and treating patients with moderate-to-severe AD, including communicating effectively with patients and caregivers on the diagnosis and prognosis of AD, as well as treatment options and goals. This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on AD.

Disclosure of Off-Label Usage

Dr Burke has determined that carbamazepine, citalopram, divalproex sodium, donepezil, galantamine, memantine, methylphenidate, rivastigmine, sertraline, and trazodone are not approved by the US Food and Drug Administration for the treatment of behavioral and psychological symptoms of dementia.

Review Process

The entire faculty of the series discussed the content at a peer-reviewed planning session, the Chair reviewed the activity for accuracy and fair balance, and a member of the External Advisory CME Board who is without conflict of interest reviewed the activity to determine whether the material is evidence-based and objective.

Acknowledgment

This Neurology Report is derived from the planning teleconference series “Treating and Caring for the Patient With Moderate-to-Severe Alzheimer’s Disease,” which was held in May 2014 and supported by an educational grant from Forest Laboratories, Inc. The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter.