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Services & Info

BPUC offers many services and benefits to your Assisted Living Community.

Weekly visits to the facility with the same provider

At BPUC, the same physician will visit your community every week, allowing for a deeper and more reliable patient/physician/community relationship.  We have providers stationed all over the state so you’ll be getting local care in the comfort of your own room.

24/7 on call customer service and physician

Rest easy knowing we’re always a phone call away. We provide 24/7 on call services with a physician, as well as our customer service, at no cost to your community or your residents.

Electronic Medical Record Database

We have our very own EMR system that is available for your use when you partner up with BPUC. Again, at zero cost to your community or residents this system will introduce yet another level of convenience to your daily practices. Within our EMR program you can view patient charts, create visit schedules, view and print visit notes, correspond with your provider, and store all necessary documents for each resident.

Quick and easy start up

Getting started with BPUC is a quick and smooth process. In addition to the easy sign up process, we have two marketing directors trained to help you get all the necessary paperwork in order. At no cost to you, we can send someone to help gather all of the information on each resident, enter them into the EMR, and schedule the first round of visits. We know how busy Assisted Living Communities get, and we aim to make the process of partnering with BPUC smooth and enjoyable.

Long term support 

In addition to start up support, the marketing directors and customer service team is always available to help you. We offer on-campus EMR training, as well as helping the facilities “close the back door” should state come in. This means ensuring all necessary paperwork is in order and offering a helping hand in any area we are able to assist in.

Partner ships with other convenient services 

BPUC is also partnered with several labs and other services that enable us to provide well rounded care in a timely manner. For more information on these services, please contact our marketing department.

Excellent Recommendations

While BPUC provides only primary care, our excellent reputation has allowed us the opportunity to build valuable connections with other providers that we happily pass on to our residents.

These services provide many different benefits to both the family/resident as well as the community. To read more about these benefits more, click on each link.

Benefits to the family

Benefits to the facility

 

Controlling Influenza Outbreaks

Controlling Influenza Outbreaks

CDC Guidelines:

Interim Guidance for Influenza Outbreak Management in Long-Term Care

Recommended Dosage and Duration of Treatment or Chemoprophylaxis for Influenza Antiviral Medications.

Standard Precautions

Droplet Precautions

When the flu strikes

a facility, it is a potentially life threatening event for the elderly and immunocompromised residents that we care for.  The care team needs to move into a heightened sense of alertness and activity.

Ask the staff to immediately start cleaning all horizontal surfaces and door knobs every 8 hours with a CDC approved cleaning agent.  The least expensive and most effective is a

Dilute Clorox Solution:

Mix 1 cup (240 mL) of bleach in 1 gallon of water.
Wash surfaces with the bleach mixture.
If surfaces are rough, scrub them with a stiff brush.
Rinse surfaces with clean water.
Allow to air dry.

 

Once two confirmed cases have a occurred start chemo prophylaxis on all affected residents.  Tamiflu 75 mg daily x 10 days is commonly used.  Watch news and CDC reports for resistant strains that may need a different drug.

If the resident becomes symptomatic increase to full dose anti-viral (such as Tamiflu 75 mf BID x 5 days).

Check oxygen saturation levels on symptomnatic residents.  Residents with normal oxygen levels can be treated symptomatically. Residents with hypoxemia (88% or less) should be referred for evaluation at the local emergency department.

 

Implement Standard and Droplet Precautions for all residents with suspected or confirmed influenza.

CDC’s guidance titled Prevention Strategies for Seasonal Influenza in Healthcare Settings contains details on the prevention strategies for all health care settings. Specific recommendations are highlighted below.

Standard Precautions are intended to be applied to the care of all patients in all health care settings, regardless of the suspected or confirmed presence of an infectious agent. Implementation of Standard Precautions constitutes the primary strategy for the prevention of healthcare-associated transmission of infectious agents among patients and health care personnel.

Examples of standard precautions include:

  • Wearing gloves if hand contact with respiratory secretions or potentially contaminated surfaces is anticipated.
  • Wearing a gown if soiling of clothes with a resident’s respiratory secretions is anticipated.
  • Changing gloves and gowns after each resident encounter and performing hand hygiene
  • Perform hand hygiene before and after touching the resident, after touching the resident’s environment, or after touching the resident’s respiratory secretions, whether or not gloves are worn. Gloves do not replace the need for performing hand hygiene.

Droplet Precautions are intended to prevent transmission of pathogens spread through close respiratory or mucous membrane contact with respiratory secretions. Droplet Precautions should be implemented for residents with suspected or confirmed influenza for 7 days after illness onset or until 24 hours after the resolution of fever and respiratory symptoms, whichever is longer, while a resident is in a health care facility.

Examples of Droplet Precautions include:

  • Placing ill residents in a private room. If a private room is not available, place (cohort) residents suspected of having influenza residents with one another;
  • Wear a facemask (e.g., surgical or procedure mask) upon entering the resident’s room. Remove the facemask when leaving the resident’s room and dispose of the facemask in a waste container.
  • If resident movement or transport is necessary, have the resident wear a facemask (e.g., surgical or procedure mask), if possible.
  • Communicate information about patients with suspected, probable, or confirmed influenza to appropriate personnel before transferring them to other departments.

 

See the CDC references information above for more specific information.

Conquering the Confusion of Dementia Coding

Conquering the Confusion of Dementia Coding

Conquering the Confusion of Dementia Coding
By Danita Arrowood, RHIT, CCS
Posted on: September 14, 2012

Dementia is a common secondary diagnosis; often coders will quickly assign a “memorized” code for it and move on. However due to its commonality, are we missing something such as a co-morbid or complication code that could influence reimbursement? Or are we over-coding symptoms that are inherent to the dementia disease process?

This casual code assignment is complicated by the fact that, often, documentation related to dementia does not present a clear picture of the neurological symptoms related to dementia or those that are a result of other general medical conditions.
In this article, we will review the different codes listed in ICD-9-CM for dementia and some characteristics of each type of dementia. We will also discuss specific instructional notes associated with the dementia codes and determine when it is necessary to seek physician clarification.

Causes & Symptoms of Dementia
Dementia is not a specific disease but rather a group of symptoms related to a decrease in cognitive and social abilities that eventually interfere with a person’s cognitive efforts in work performance, relationships and social activities. These symptoms are a result of dysfunction in the cerebral cortex or other brain tissue. Dementia usually occurs in people over age 60.
Patients with dementia will develop cognitive impairments in areas of language, reasoning, judgment and problem-solving abilities. Forgetfulness, depression and clumsiness are common in early symptoms of dementia. As the condition progresses, patients often experience agitation triggered by their confusion and frustration, and they may become hostile. In later stages, behavioral disturbances, such as wandering off, physical violence and perversion, may become the most challenging issue for caretakers to handle.
To support a diagnosis of dementia, two or more brain functions must be impaired, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV). Alzheimer’s disease is the most common cause of dementia, but not the only cause. A wide variety of physiological conditions, such as alcohol and substance use, and medication reactions are all known causes leading to dementia.

In instances where dementia exists due to conditions such as traumatic or anoxic brain injury or a history of substance abuse with abstinence, dementia can be a static condition. In other cases where dementia is a manifestation of another disease process (i.e., normal pressure hydrocephalus, diabetes), proper control of the physiological condition may slow or arrest the progression of vascular dementia. Dementia associated with neurodegenerative diseases (i.e., AIDS, Lewy bodies and multiple sclerosis), is progressive and permanent. In some cases, the exact reason some patients develop dementia is not yet understood. One source lists 394 conditions associated with dementia.

Dementia Types & ICD-9 Coding
Now, we will look at how ICD-9 classifies dementia and review some of the associated instructional notes for code selection.
ICD-9-CM classifies dementia into the following subcategories:

290.0
Senile dementia, uncomplicated, NOS

290.1x
Presenile dementia

290.2x
Senile dementia with delusional or depressive features

290.3
Senile dementia with delirium

290.4x
Vascular dementia

292.82
Drug-induced persisting dementia

294.1x
Dementia in  conditions classified elsewhere, with/without behavioral disturbances

294.2x
Dementia, unspecified, with/without behavioral disturbances

331.1x
Frontotemporal dementia

331.82
Dementia with Lewy bodies

Senile & Presenile Dementia (290.0 – 290.3)
Senile dementia occurs after age 65. A diagnosis of dementia with onset prior to age 65 is presenile dementia. Although some decline in cognition and mental capacity is normal as we age, dementia is not a normal part of aging.
As always, coders should look to physician documentation to determine the type of dementia. Senile and presenile are archaic terms, not often seen in current documentation. If the physician has not stated “senile” dementia, it would be incorrect to select a code for senile dementia, simply because the patient is over age 65.

Vascular Dementia (290.40 – 290.43)
Vascular dementia is the second most common type of dementia. Incidences increase with advancing age. A buildup of plaque (atherosclerosis), amyloid protein and other debris circulating in the blood stream causes damage to the cerebrovascular system leading to vascular dementia. Multi-infarct dementia is one type of vascular dementia and develops because multiple mini-infarctions occur, scattered throughout the brain. As new, undetectable infarcts occur, symptoms of impairment associated with the affected area of the brain may change suddenly.
Ex: An 87-year-old male with a history of atherosclerosis presents with sudden onset of confusion and agitation. Workup reveals no infectious processes, labs WNL. Patient near baseline. Discharge Diagnosis: Multi-infarct dementia due to atherosclerosis, suspected mini stroke.

434.91 Cerebral artery occlusion, unspecified
290.43 Vascular dementia with delirium
437.0 Cerebral atherosclerosis

Dementia With Lewy bodies (331.82)
Lewy bodies are abnormal microscopic deposits of protein that settle in the brain and destroy nerve cells. Typical Parkinson’s type symptoms develop, such as tremors, muscle rigidity and dementia. These patients may also experience delusions and depression.
Review the instructional note at category 332 Parkinson’s disease, which excludes code 331.82 Parkinson’s with Lewy bodies. Lewy bodies with Parkinsonism is a more specific diagnosis than just Parkinson’s disease, per Coding Guidelines, assign the code for the most specific diagnosis.
When physician documentation lists Lewy bodies with Parkinson’s disease, the ICD-9 codebook instructional note directs coders to assign code 331.82 Dementia with Lewy bodies, plus an additional code to identify with or without behavioral disturbances (294.10-294.11).

Delirium, Delusional & Depressive Features
ICD-9-CM provides combination codes to identify specific types of dementia with delirium, delusional and depressive features. These codes are CCs that may affect the MS-DRG and reimbursement.
Delirium is a sudden on-set transient bout of altered consciousness and change in cognition most often attributed to a direct physiological condition. Delirium is often confused with dementia; however, delirium dissipates when the underlying general medical condition resolves, dementia is typically irreversible.
Seek clarification from the physician if documentation does not identify the type of dementia and clarify the underlying cause of acute delirium. If the cause of the delirium or type of dementia is unknown, code the conditions separately.
Delusional features are present in many psychiatric disorders including Alzheimer’s disease, personality and mood disorders. Delusions are irrational, unwavering beliefs that are clearly false and have no logical or normal basis of reasoning.
ICD-9-CM classifies the diagnosis of delusional disorders to category 297, in the Mood Disorder section. A Delusional disorder is not the same as a delusional feature.
Depressive features and depressive mood. Depression is an inherent part of the dementia disease process.
When documentation lists dementia and depression separately, without further documentation to indicate the depression is related to dementia, code them separately.

Behavioral Disturbances
Simply stated, a behavioral disturbance is any behavior that puts the patient or others at risk.
Not all patients with dementia have behavioral disturbances, but as the individual ages and dementia progresses, the likelihood increases of behavior problems manifesting and becoming the more challenging aspect of patient care.
Noted under many of the dementia codes is the instructional note “use additional code to identify behavioral disturbances.” You will also find listed under the behavioral disturbance codes, subcategory code 294.1x, the instructional note, “code first underlying physical condition.” These two notes provide code sequence instruction, directing the underlying condition to be sequenced before the 294.1x code.
Ex: An 87-year-old nursing home patient with Alzheimer’s dementia has repeatedly wandered off.
331.0 Alzheimer’s disease
294.11 Dementia in conditions classified elsewhere with behavioral disturbance
V40.31 Wandering in diseases classified elsewhere
Behavior disturbances include a wide array of disruptive behavior. It is the coder’s responsibility to watch for documentation that identifies this type of behavior. Physician documentation may not always specifically state “with behavioral disturbances.” If in doubt, query the physician for clarification.
Conclusion
In this article, we have reviewed the most common types and characteristics of dementia coded in ICD-9 and looked at many of the associated coding conventions. Documentation on dementia as a chronic, pre-existing condition can be vague and disconnected from other neurological traits the patient may have, making it difficult for the coder to select the most accurate code. As always, when documentation is not clear, query the physician for clarification.
Danita Arrowood is anAHIMA -approved ICD-10-CM/PCS trainer and an educator/medical coding educator with Precyse (www.precyse.com), which provides services and technologies that capture, organize, secure and analyze healthcare data and transform it into actionable information, supporting the delivery of quality patient care and optimizing operating performance. Danita develops content materials for ICD-9-CM and ICD-10-CM/PCS and provides clinical documentation improvement education. Danita is also adjunct faculty at Phoenix Community College.

Test your knowledge on page 2.

The use of medroxyprogesterone acetate for the treatment of sexually inappropriate behaviour in patients with dementia

The use of medroxyprogesterone acetate for the treatment of sexually inappropriate behaviour in patients with dementia

Journal of Psychiatry & Neuroscience
Canadian Medical Association

Language: English |
The use of medroxyprogesterone acetate for the treatment of sexually inappropriate behaviour in patients with dementia

Stacy Anderson Light and Suzanne Holroyd

Additional article information
Abstract

Sexually inappropriate behaviour in a patient with dementia can be a problem for caregivers. Little research has been done concerning treatment for this behavioural disorder. The hormone medroxyprogesterone acetate (MPA) is a known, but infrequently used, treatment option. We describe a series of 5 cases in which MPA was used successfully to control inappropriate sexual behaviours in men with dementia.
Medical subject headings: dementia, disinhibition, medroxyprogesterone acetate, sexual disorder
Introduction

Behavioural problems are common in dementia and present a burden to caregivers. Agitation is estimated to occur in 50%–60% of patients with dementia.1 Although much less common, sexual aggression or disinhibition can be very disruptive to family members and to care in hospitals, nursing homes or other facilities. The estimated prevalence of sexually inappropriate behaviours in patients with dementia is between 2.9% and 15%.2 In the nursing home setting, these behaviours can be a threat to the welfare of other patients. Repeated offences can lead to difficulty finding or maintaining appropriate living placement.

Studies have shown that whereas sexual activity decreases in elderly people, sexual interest does not.3 The decrease in activity may be attributed to factors including medical illness, nursing home placement and loss of opportunity.3 The diagnosis of dementia raises ethical considerations related to sexuality, including ability to give consent, advances toward unwilling participants and displays of sexual behaviours in locations or situations not deemed appropriate by society. The difficulty in managing these individuals arises from the desire to protect others, while not using undue restraint or causing significant side effects for the individual.

The literature regarding treatment is limited. A review of treatments for inappropriate sexual behaviours based on case reports including the use of antipsychotic drugs, antiandrogens, estrogens, gonadotropin-releasing hormone (Gn-RH) analogues and serotonergic agents revealed no studies comparing the efficacy of one treatment over another. However, there were more case reports regarding successful treatment of patients with dementia using antiandrogens (medroxyprogesterone acetate [MPA]) (6 cases) than serotonergic agents (1 case), clomipramine (2 cases), Gn-RH analogues (1 case) or estrogens (1 case).4 In addition, the side effects of these agents may limit their applicability in elderly patients, such as anticholinergic effects from clomipramine or cardiovascular and thromboembolic risk factors and gynecomastia due to estrogens.4 More recently, the histamine blocker cimetidine has also been identified as a possible treatment option.5

MPA is a synthetic progestin used for numerous purposes in women. When administered in males, it lowers testosterone levels, lowering sexual drive without causing feminization. MPA has been used in younger patients, including pedophiles and individuals with other mental illnesses and sexually inappropriate behaviours.6–8 Case reports suggest that MPA is a safe and efficacious treatment for symptoms specific to inappropriate sexual behaviour in men with dementia.9,10 Dosages in reported cases ranged from 100 mg taken orally daily10 to 1000 mg administered intramuscularly (IM) weekly9 based on efficacy and tolerability. The most common side effects in males are fatigue and weight gain. Impotence, hot or cold flashes, headache, mild depression, mild diabetes, loss of body hair, insomnia, nausea, phlebitis and loss of ejaculatory volume have been noted to be potential side effects.4,11 However, previous case reports to date have not revealed significant side effects in patients with dementia and have concluded that MPA is well tolerated and safe.9,10 In this report, 5 cases of treatment of inappropriate sexual behaviour in men with dementia using MPA are described to add to the literature in this area. The University of Virginia Human Investigations Committee approved this study.
Case 1

Mr. A was a 79-year-old man living in a nursing home when he began to exhibit sexually inappropriate behaviours including grabbing the breasts of female staff and residents and attempting intercourse with a male resident. His condition was diagnosed as dementia of mixed type (vascular and Alzheimer’s) with behavioural disturbance. He had no history of sexually inappropriate behaviour. The patient’s cognitive function was assessed using the Mini-Mental Status Examination (MMSE); his score was 11/30. He was already being treated with donepezil, 10 mg, each evening. Trials of buspirone and haloperidol did not improve these behaviours. MPA, 100 mg IM monthly, was prescribed, and the patient responded within 2 weeks with no further sexually inappropriate behaviours. No change in MMSE score was noted. After 4 months, the medication was stopped because of concerns expressed by a state regulator regarding “the use of chemical restraint.” Sexually inappropriate behavioural problems began almost immediately. Various medications, including trials of haloperidol, olanzapine, quetiapine, carbamazepine and buspirone, failed to improve the behaviours but did cause a variety of side effects. The patient was finally prescribed MPA again at the same dose of 100 mg monthly, which did not immediately control the behaviours, so the patient was admitted to a psychiatric facility, transferred to a state hospital and lost to follow-up.
Case 2

Mr. B was an 85-year-old man, living in a nursing home, who almost immediately from admission began exposing himself to his adult daughter and was inappropriately touching female residents and attempting oral sexual relations. The patient’s diagnosis was vascular dementia with behavioural disturbance and depression. His MMSE score was 24/30. His history was significant for sexual assault charges toward a female child many years earlier, though he was later found innocent. He had also had multiple affairs with women during his marriage. There was no history of earlier exposing or other inappropriate sexual behaviour with the daughter. There were no other earlier legal charges. The patient was prescribed sertraline for depression and MPA, 300 mg IM monthly. The sexually inappropriate behaviours stopped within 2 weeks; however, the depression remained. Sertraline was stopped, and the patient was prescribed venlafaxine instead, but he continued to have some depression. There was no change in MMSE score. About 1 year later, the MPA was discontinued because of state regulators’ concern regarding “chemical restraint.” Sexually inappropriate behavioural problems recurred within several weeks. Because the nursing home refused to allow the use of MPA secondary to state interpretations regarding chemical restraint, thioridazine was used instead. The behaviours were observed to decrease but not cease. The patient was transferred to another nursing home shortly thereafter and lost to follow-up.
Case 3

Mr. C was an 81-year-old man who repeatedly touched the breasts of his adult daughter, female staff and other female residents in the nursing home. He had no history of sexually inappropriate behaviours, and this was considered a marked behavioural change by his family. His condition was diagnosed as senile dementia of the Alzheimer’s type with depression and behavioural disturbance. His MMSE score was 14/30. Trials of sertraline for depression and quetiapine for aggression did not decrease the sexual behaviours. The patient was prescribed MPA, 100 mg every 2 weeks. The dose was slowly titrated to 500 mg weekly, and the sexual behaviours completely stopped. The patient continued to have depressive symptoms, and he was prescribed escitalopram with good results. There was no change in MMSE score following treatment with MPA. The patient remained free of further inappropriate behaviours and had no apparent side effects for over a year, when he suffered a stroke. At that point, MPA was stopped, because the patient was no longer able to physically exhibit such behaviours.
Case 4

Mr. D was a 68-year-old man admitted to the geriatric unit at the University of Virginia, Charlottesville, for inappropriate sexual behaviours including masturbating in public places, grabbing the breasts of female staff members and climbing into female residents’ beds. The diagnosis was vascular dementia with behavioural disturbance. His MMSE score was 0/30. Trials of quetiapine, trazodone, valproic acid and risperidone did not improve the sexual behaviours but did cause side effects such as sedation and gait instability. After starting MPA, 300 mg IM weekly, his sexual behaviours ceased almost immediately and all other psychotropic medications were discontinued. No change in MMSE score was noted.
Case 5

Mr. E was an 81-year-old man who showed combativeness toward caregivers and inappropriate sexual behaviour including touching female staff and residents’ breasts and engaging in sexual intercourse with a female resident. His MMSE score was 3/30. He was taking donepezil, 10 mg each evening. Quetiapine was successful in controlling combativeness but had no effect on the sexual behaviours. MPA, 300 mg IM weekly, was begun and led to a decrease in the behaviour. An increase to 500 mg weekly eliminated the sexually inappropriate behaviours entirely. The quetiapine was then discontinued without reoccurrence of combative behaviours. The patient gained 4.5 kg (10 lb) over the course of a year’s treatment, but no other side effects were noted. The MPA was discontinued after a year, because the patient’s physical status had changed in that he was no longer able to demonstrate the sexually inappropriate behaviours. After MPA was discontinued, the combative behaviours returned and quetiapine was started again to treat those behaviours.
Discussion

Our cases demonstrate the use of MPA in the treatment of inappropriate sexual behaviour in men with dementia. All the individuals’ behaviour improved with MPA treatment, after treatments with other psychiatric medications with less favourable side-effect profiles had failed. Of note, the dosage was quite variable, ranging from 100 mg each month to 500 mg each week.

The MPA appeared to be well tolerated, with the only physical side effect noted in our cases being weight gain in 1 patient. On the other hand, the use of less specific medications for the sexual behaviours resulted in more side effects. In addition, although noted to be depressed before treatment with MPA, 2 of the patients continued to experience symptoms of depression during treatment with MPA. Depression is a reported side effect of MPA therapy and could have contributed to continued symptoms in our cases. Monitoring for signs and symptoms of depression should continue throughout the time a patient is receiving MPA therapy. If patients are monitored and treated appropriately, however, depression should not be considered a contraindication for initiating or a reason for discontinuing MPA.

It is also noteworthy that in 2 cases the MPA was discontinued because of state regulatory concern regarding chemical restraint. This ethical question has been noted in the literature concerning the use of MPA and similar agents, and it is recommended that clinicians obtain fully informed written consent from the legally authorized caregiver of the individual with dementia before using MPA.9,10 However, in our opinion, MPA is less of a chemical restraint than other drugs used to control inappropriate sexual behaviours, because it is symptom specific with an antilibidinal effect, whereas other drugs such as antipsychotics are less specific and have more potential for side effects in elderly patients, such as sedation and gait instability.

These cases add to the literature on the safety and efficacy of MPA in the treatment of inappropriate sexual behaviour in male patients with dementia. Because its mechanism of action is specific to the symptom of sexual behaviour, MPA may be considered first-line therapy for this behavioural disorder.
Acknowledgments

This study was sponsored in part by the National Institute of Neurological Disorders and Stroke (grant no. NS045008-01 A1) (S.H.).
Footnotes

Contributors: Both authors contributed to the conception and design of the article, acquired and interpreted data, drafted and revised the article and gave approval for the article to be published.

Competing interests: None declared.

Correspondence to: Dr. Stacy Anderson Light, c/o Dr. Suzanne Holroyd, Department of Psychiatric Medicine, University of Virginia, Box 800623, Charlottesville VA 22908; fax 434 924-5149; ude.ainigriv@s4hs

Article information
J Psychiatry Neurosci. Mar 2006; 31(2): 132–134.
PMCID: PMC1413960
Stacy Anderson Light and Suzanne Holroyd
Department of Psychiatric Medicine, University of Virginia, Charlottesville, Va.
Copyright © 2006 CMA Media Inc. or its licensors
This article has been cited by other articles in PMC.
Articles from Journal of Psychiatry & Neuroscience : JPN are provided here courtesy of Canadian Medical Association
References
1. Geldmacher DS. Contemporary diagnosis and management of Alzheimer’s dementia. Newtown (PA): Handbooks in Health Care Company; 2003.
2. Tsai SJ, Hwang JP, Yang CH, et al Inappropriate sexual behaviors in dementia. Alzheimer Dis Assoc Disord 1999;13:60-2. [PubMed]
3. Mulligan T, Siddiqi W. Changes in male sexuality. In: Cassel CK, Leipzig RM, Cohen HJ, et al, editors. Geriatric medicine: an evidence based approach. 4th ed. New York: Springer-Verlag; 2003.
4. Levitsky AM, Owens NJ. Pharmacologic treatment of hypersexuality and paraphilias in nursing home residents. J Am Geriatr Soc 1999; 47:231-4. [PubMed]
5. Wiseman SV, McAuley JW, Friedenberg GR, et al. Hypersexuality in patients with dementia: possible response to cimetidine. Neurology 2000;54:2024. [PubMed]
6. Cooper AJ. Progestogens in the treatment of male sexual offenders: a review. Can J Psychiatry 1986;31:73-9. [PubMed]
7. Berlin FS, Meinecke CG. Treatment of sex offenders with antiandrogenic medication: conceptualization, review of treatment modalities, and preliminary findings. Am J Psychiatry 1981;138:601-7. [PubMed]
8. Gagne P. Treatment of sex offenders with medroxyprogesterone acetate. Am J Psychiatry 1981;138:644-6. [PubMed]
9. Cooper AJ. MPA acetate (MPA) treatment of sexual acting out in men suffering from dementia. J Clin Psychiatry 1987;48:368-70. [PubMed]
10. Harnett DS. Sexual disinhibition and aggression in the nursing home setting. The Clinical View: Geriatric Psychiatry in Long-Term Care 2004;2:8-10.
11. McEvoy GK, editor. Progestins. In: AHFS Drug Information. Bethesda (MD): American Society of Health-System Pharmacists; 2004.

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Donepezil and Memantine for Moderate-to-Severe Alzheimer’s Disease

Donepezil and Memantine for Moderate-to-Severe Alzheimer’s Disease

Original Article
Donepezil and Memantine for Moderate-to-Severe Alzheimer’s Disease

Robert Howard, M.D., Rupert McShane, F.R.C.Psych., James Lindesay, D.M., Craig Ritchie, M.D., Ph.D., Ashley Baldwin, M.R.C.Psych., Robert Barber, M.D., Alistair Burns, F.R.C.Psych., Tom Dening, F.R.C.Psych., David Findlay, M.B., Ch.B., Clive Holmes, Ph.D., Alan Hughes, M.B., Ch.B., Robin Jacoby, D.M., Rob Jones, M.B., Ch.B., Roy Jones, M.B., Ian McKeith, F.Med.Sc., Ajay Macharouthu, M.R.C.Psych., John O’Brien, D.M., Peter Passmore, M.D., Bart Sheehan, M.D., Edmund Juszczak, M.Sc., Cornelius Katona, M.D., Robert Hills, D.Phil., Martin Knapp, Ph.D., Clive Ballard, M.D., Richard Brown, Ph.D., Sube Banerjee, M.D., Caroline Onions, P.G.Dip., Mary Griffin, R.G.N., Jessica Adams, B.Sc., Richard Gray, M.Sc., Tony Johnson, Ph.D., Peter Bentham, M.B., Ch.B., and Patrick Phillips, Ph.D.

N Engl J Med 2012; 366:893-903March 8, 2012DOI: 10.1056/NEJMoa1106668
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Abstract
Article
References
Citing Articles (78)
Letters

Most studies evaluating cholinesterase inhibitors for the treatment of Alzheimer’s disease have focused on patients with mild-to-moderate disease. Despite questions about the methods used in the trials1 and about the clinical significance of reported benefits,1,2 guidelines advocate treatment with a cholinesterase inhibitor, although some recommend discontinuation when Alzheimer’s disease becomes severe.3 Evidence of the efficacy of memantine has been shown primarily in patients with moderate or severe Alzheimer’s disease.4 The findings of a study showing that combination therapy with memantine and a cholinesterase inhibitor was more effective than treatment with a cholinesterase inhibitor alone5 have not been replicated.6 Results from randomized, controlled trials involving patients with moderate-to-severe7,8 or severe9-12 Alzheimer’s disease suggest that cholinesterase inhibitors are associated with modest improvements in cognition and function, and these drugs are approved by the Food and Drug Administration in the United States for the treatment of severe Alzheimer’s disease. All the trials involving patients with severe Alzheimer’s disease, however, have involved nursing home residents, and none of the trials focusing on moderate-to-severe or severe Alzheimer’s disease have investigated the strategy of continuing treatment with cholinesterase inhibitors in patients already taking those drugs. There is very limited evidence to guide the difficult decision regarding continuation or discontinuation of treatment when the disease progresses, but continued treatment is associated with an increase in adverse outcomes, including syncope, the need for insertion of permanent pacemakers, and hip fractures.13

We investigated whether community-living patients with Alzheimer’s disease, who have moderate-to-severe disease and are already receiving donepezil, benefit from continuing treatment and whether initiating memantine at this point in the course of the disease is beneficial. We had three objectives: first, to test whether, over a period of 52 weeks, continuation of donepezil, as compared with discontinuation of the drug, would be associated with better cognition and function; second, to test whether memantine treatment, as compared with placebo memantine, would be associated with better cognition and function; and third, to test whether combining donepezil and memantine would provide additive or synergistic benefits.
Methods
Study Design and Participants

The Donepezil and Memantine in Moderate to Severe Alzheimer’s Disease (DOMINO) study was a multicenter, double-blind, placebo-controlled, clinical trial with a two-by-two factorial design. The outcomes were assessed for 52 weeks.14 We enrolled community residents who had caregivers who either lived with them or visited them at least daily. Eligible participants met standardized clinical criteria15 for probable or possible moderate or severe Alzheimer’s disease, had been prescribed donepezil continuously for at least 3 months and had received a dose of 10 mg for at least the previous 6 weeks, and had a score between 5 and 13 on the Standardized Mini–Mental State Examination (SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function).16 In addition, each eligible patient’s prescribing clinician was considering a change in drug treatment (i.e., stopping donepezil or introducing memantine) on the basis of National Institute for Health and Clinical Excellence (NICE) guidelines3 at the time, discussions with the patient and caregivers, and the physician’s clinical judgment. Agreement in writing to take part in the study was obtained from the participants if they were considered to have the capacity to give informed consent, and the main caregivers gave written informed consent for their own involvement and assent for the patients’ involvement.

Patients were excluded if they had severe or unstable medical conditions, were receiving memantine, or were considered to be unlikely to adhere to the study regimens. Details of the design have been published previously.14
Study Oversight

The study was overseen by King’s College London and was funded by the U.K. Medical Research Council (MRC) and the Alzheimer’s Society. Full ethical approval was received from the Scotland A Multicenter Research Ethics Committee. Pfizer-Eisai and Lundbeck donated supplies of the drugs and placebo but had no involvement in the design or conduct of the study or the analysis or reporting of the data. The study protocol, including the statistical analysis plan, is available with the full text of this article at NEJM.org. The first author vouches for the accuracy and completeness of the data and for the fidelity of the study to the protocol.
Study Procedures

Participants were randomly assigned to one of four treatments: continuation of donepezil (at a dose of 10 mg per day, with placebo memantine, starting in week 1); discontinuation of donepezil (administration of donepezil at a dose of 5 mg during weeks 1 through 4 and placebo donepezil starting in week 5, plus placebo memantine starting in week 1); discontinuation of donepezil and initiation of treatment with memantine (administration of donepezil at a dose of 5 mg during weeks 1 through 4, with placebo donepezil starting in week 5, and initiation of memantine at a dose of 5 mg in week 1, with the dose increased in 5-mg increments weekly to a dose of 20 mg from week 4 on); or continuation of donepezil and initiation of memantine (continuation of donepezil at a dose of 10 mg and initiation of memantine at a dose of 5 mg in week 1, with the dose increased in 5-mg increments weekly to a dose of 20 mg from week 4 on). Treatment assignments were made (by telephone) by the U.K. Medical Research Council Clinical Trials Unit with the use of randomized minimization17 (for full details, see the Supplementary Appendix, available at NEJM.org). The procedure involved stratifying groups according to center (among the 15 participating centers), duration of donepezil treatment before entry (3 to 6 months vs. >6 months), baseline SMMSE score (5 to 9, indicating severe disease, vs. 10 to 13, indicating moderate disease), and age (<60 years, 60 to 74 years, or ≥75 years). In addition, to maintain concealment of the treatment assignments, the first 80 participants were assigned with the use of a prepared list of simple randomized assignments.17 Donepezil (in 5-mg tablets), memantine (in 5-mg and 10-mg tablets), and matched placebo tablets were provided by the manufacturers; patients, caregivers, clinicians, outcome assessors, and investigators were unaware of the treatment assignments. Efficacy and safety data were reviewed by an independent data monitoring and ethics committee every 6 months during the course of the trial.
Outcome Measures

The coprimary outcomes were scores on the SMMSE and on the caregiver-rated Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment).18 Secondary outcomes were scores on the Neuropsychiatric Inventory19 (NPI, on which scores range from 0 to 144, with higher scores indicating increased behavioral and psychological symptoms), scores on the DEMQOL-Proxy20 (on which scores range from 31 to 134, with higher scores indicating better patient health-related quality of life), and caregiver health status, as assessed with the use of the General Health Questionnaire 1221 (GHQ-12, on which scores range from 0 to 12, with higher scores indicating increased psychological symptoms in nonprofessional caregivers).
Statistical Analysis

A sample size of 800 was planned originally, but the size was adjusted to 430 on the basis of reduced standard deviations for the outcomes from a blinded analysis of accrued data. With a sample size of 430, we estimated that the study would have 95% power to detect a 1.0-point difference between the donepezil and placebo groups or between the memantine and placebo groups in SMMSE scores and 90% power to detect a 2.0-point difference between the donepezil and placebo groups or between the memantine and placebo groups in BADLS scores at any one assessment point (objectives 1 and 2), assuming an expected rate of 20% for missed visits, at a two-sided significance level of 5%. With this sample size, we estimated that the study would also have 96% power to detect a 1.5-point difference in SMMSE scores and 80% power to detect a 2.5-point difference in BADLS scores between the combination-therapy and monotherapy groups at any one assessment point (objective 3).

Unless otherwise specified, we performed the analyses on data from all patients who underwent randomization and who received at least one dose of study drug, applying the principle of intention to treat as much as was practically possible, given any missing data. Data from participants were analyzed according to the groups to which they had been assigned, irrespective of withdrawal from the assigned study drug or initiation of open-label treatment. An analysis of variance was used to identify significant differences in continuous baseline characteristics across the four study groups, and Fisher’s exact test was used to identify differences in categorical baseline characteristics.

The primary analyses of the primary outcomes and the continuous secondary outcomes were conducted with the use of multilevel modeling repeated-measures regression,22 adjusted for baseline scores and for the four minimization factors (center, duration of donepezil treatment before entry, baseline SMMSE score, and age). All available scores at every visit, regardless of whether the patient was still taking the trial medication or had switched to open-label treatment, were included in the primary analysis, and there was no imputation of missing scores. The scheduled, rather than the actual, visit week was used in the model. For each outcome, two models were fitted — one with the interaction of donepezil with memantine, to estimate the additional benefit of combination therapy (objective 3) and to test for the interaction, and one without the interaction, to estimate the difference between the active drug (donepezil or memantine) and placebo (objectives 1 and 2). Different random-effects structures were compared with the use of Akaike’s information criterion.23 The chosen model included random effects for each visit with an unstructured covariance matrix; full details are provided in the Supplementary Appendix.

The length of time that participants in the four groups took the study drugs was compared with the use of the log-rank test for equality of survivor functions and a Cox proportional-hazards model to quantify differences among the groups. The incidence of serious adverse events was compared among the groups by means of Poisson regression. Sensitivity analyses were performed to determine the effect of missing data and of discontinuation of treatment; details are provided in the Supplementary Appendix. The analyses were conducted with the use of Stata software, version 11.2.24 Since the primary objectives were well defined and ordered, adjustment for multiple testing was not indicated in the analysis.25 For secondary outcome measures and outcomes at assessment points other than those during the 52-week study-treatment period, we defined statistical significance at the 99% confidence interval level to compensate for multiple comparisons.

Before commencing the data analysis, we published values for minimum clinically important differences for the SMMSE (1.4 points), the BADLS (3.5 points), and the NPI (8 points); these values were based on 0.4 SD of the change from baseline in the first 127 participants who completed the DOMINO trial.26
Results
Participants

During the period from February 2008 to March 2010, a total of 295 participants were enrolled. Recruitment was slower than anticipated, and it was not possible to extend the recruitment period, since the public funder of the study (MRC) believed that the disadvantages of a delay in reporting results outweighed the benefits of increasing the power of the study. The baseline characteristics of the participants in the four treatment groups were broadly similar (Table 1Table 1Baseline Characteristics of the Participants, According to Treatment Group.). Figure 1Figure 1Enrollment, Randomization, and Follow-up. shows the numbers of patients who were enrolled, were assigned to a study group, and completed follow-up. Figure 2Figure 2Kaplan–Meier Actuarial Plot of the Cumulative Probability of Withdrawal from the Assigned Study Drug. shows the number of participants in each group who were still receiving the study drug at each study visit and the cumulative probability of discontinuation of the study drug. The probability of withdrawal from the study drug among patients assigned to continue donepezil was half that among patients assigned to discontinue donepezil (hazard ratio for withdrawal among patients assigned to continued donepezil treatment, 0.51; 95% confidence interval [CI], 0.36 to 0.72; P<0.001). Patients assigned to memantine also had a lower probability of treatment withdrawal than did those assigned to placebo memantine (hazard ratio, 0.66; 95% CI, 0.47 to 0.93; P=0.02).
Primary Outcome Measures

The mean scores on the SMMSE and the BADLS in all study groups and at all visits are shown in Figure 3Figure 3Mean Scores on the Standardized Mini–Mental State Examination (SMMSE) and the Bristol Activities of Daily Living Scale (BADLS), According to Visit Week and Treatment Group.. The between-group differences in primary outcome measures at all trial visits are shown in Table 2Table 2Estimate of Treatment Differences in Primary and Secondary Outcome Measures.. Patients who were assigned to continue taking donepezil, as compared with those assigned to discontinue donepezil, had scores on the SMMSE that were higher (indicating better cognitive function) by an average of 1.9 points (95% CI, 1.3 to 2.5; P<0.001) and scores on the BADLS that were lower (indicating less functional impairment) by an average of 3.0 points (95% CI, 1.8 to 4.3; P<0.001). For both these outcomes, there was significant heterogeneity in treatment efficacy over time (P=0.002 and P=0.004, respectively), with less benefit apparent at the 6-week assessment than at later time points. From 6 weeks onward, the differences between the treatment groups were roughly parallel, and we therefore report average effects.

Patients who were assigned to receive memantine, as compared with those who were assigned to receive placebo memantine, had scores on the SMMSE that were higher by an average of 1.2 points (95% CI, 0.6 to 1.8; P<0.001) and scores on the BADLS that were lower by an average of 1.5 points (95% CI, 0.3 to 2.8; P=0.02); both these values were smaller than the minimum clinically important difference. This reflects the average effect among patients assigned to continue donepezil as well as among those assigned to discontinue donepezil. The interactions of memantine therapy with visit were not significant. For both donepezil and memantine, the benefits with respect to scores on the SMMSE and the BADLS appeared to be larger in the absence of the other agent than in the presence of the other agent (Table S4 in the Supplementary Appendix), but these differences were not significant (P=0.14 and P=0.09, respectively, for the tests for interaction). There was no significant benefit of adding memantine to donepezil, with respect to scores on the SMMSE (0.8 points higher with memantine than with placebo; 95% CI, −0.1 to 1.6; P=0.07) or with respect to scores on the BADLS (0.5 points lower with memantine than with placebo; 95% CI, −2.2 to 1.2; P=0.57).

The severity of dementia at entry significantly influenced the effect of donepezil on SMMSE scores, with larger benefits observed in patients with moderate disease (SMMSE score, 10 to 13) than in those with severe disease (SMMSE score, 5 to 9). The average difference in scores between the groups assigned to continue donepezil and the groups assigned to discontinue donepezil was 2.6 points (95% CI, 1.5 to 3.7) among patients with moderate disease (P<0.001) and 1.3 points (95% CI, 0.2 to 2.4) among patients with severe disease (P=0.02). Because we undertook several tests for interaction, this difference according to the severity of dementia, which was only moderately significant, may have arisen by chance and needs to be confirmed, particularly since the severity of dementia did not have a significant effect on the difference in the BADLS score that was observed with continued, as compared with discontinued, donepezil therapy or on the differences in SMMSE or BADLS scores observed with memantine therapy, as compared with placebo.
Secondary Outcome Measures

Patients who received memantine, as compared with those who received placebo memantine, had scores on the NPI that were lower (indicating fewer behavioral and psychological symptoms) by an average of 4.0 points (99% CI, 0.6 to 7.4; P=0.002), representing a smaller benefit than the minimum clinically important difference. We did not observe a significant difference in scores on the NPI with the continuation, as compared with the discontinuation, of donepezil therapy (2.3 points lower with continuation; 95% CI, −1.1 to 5.7; P=0.08). The addition of memantine to donepezil, as compared with the addition of placebo memantine to donepezil, resulted in a decrease in the NPI score that was greater by 5.1 points (99% CI, 0.3 to 9.8; P=0.006). In contrast with results on the SMMSE and BADLS, for both donepezil and memantine, the benefits with respect to the NPI score appeared to be larger in the presence of the other agent than in the absence of the other agent (Table S4 in the Supplementary Appendix), but these differences were not significant (P=0.42). Both continuation of donepezil therapy, as compared with discontinuation, and memantine therapy, as compared with placebo, resulted in larger average decreases (indicating fewer psychological symptoms) across trial visits in GHQ-12 scores for caregiver health status (a 0.5-point larger decrease with continuation vs. discontinuation of donepezil; 99% CI, −0.01 to 1.0; P=0.01; and a 0.5-point larger decrease with memantine vs. placebo; 95% CI, −0.1 to 0.9; P=0.03); however, the differences did not reach significance, which was defined at P<0.01 to allow for multiple secondary outcome measures.
Sensitivity Analyses

Patients who withdrew from treatment after the 18-week visit or after the 30-week visit had a lower score on the SMMSE and a higher score on the BADLS at their last visit before withdrawal than did those who continued treatment (Table S3 in the Supplementary Appendix). Patients who withdrew at any point during the study had lower SMMSE scores and higher BADLS scores after withdrawal than did those who continued to receive treatment. Of the 137 patients who withdrew from treatment before the end of the trial, 64 (47%) attended the 52-week visit (with 1 patient missing the SMMSE assessment). A number of sensitivity analyses were conducted to assess the effect of treatment withdrawal and missing outcome assessments on the results. The results of the sensitivity analyses were broadly similar to those of the primary analysis (see Table S3 in the Supplementary Appendix).
Safety

A total of 188 serious adverse events were reported, of which 6 (2 in the group receiving placebo donepezil and placebo memantine, 2 in the group receiving memantine and placebo donepezil, and 2 in the group receiving donepezil and memantine) were considered to be possibly related to the study drugs. None were considered to be unexpected serious adverse reactions. There was no evidence that the incidence of serious adverse events or death differed according to treatment group (P=0.77). Details of the serious adverse events and deaths in all treatment groups are provided in Table S5 in the Supplementary Appendix.
Discussion

This double-blind, placebo-controlled trial involving community-living patients with moderate or severe Alzheimer’s disease who were already receiving treatment with a cholinesterase inhibitor showed that there were modest cognitive and functional benefits of continuing donepezil over the course of 12 months. The difference in scores on the SMMSE between those who continued donepezil and those who discontinued it exceeded the prespecified minimum clinically important difference of 1.4 points, but the difference in scores on the BADLS was less than the minimum clinically important difference of 3.5 points. The initiation of memantine therapy was also associated with significantly better cognition and function, although the magnitude of the benefit was smaller than it was with donepezil and the differences between patients who received memantine and those who received placebo were smaller than the predefined minimum clinically important difference. Memantine, as compared with placebo, was associated with the emergence of fewer behavioral symptoms as measured by the NPI, but the difference did not reach the minimum clinically important difference. Combined treatment with donepezil and memantine was not significantly superior to treatment with donepezil alone with respect to any of the primary or secondary outcomes.

The improvements in cognition and function associated with donepezil and memantine were small relative to the overall size of the decline in cognitive and functional status that was seen in all patients. Although the cognitive benefit associated with donepezil therapy exceeded a distribution-based minimum clinically important difference,26,27 the cognitive benefits associated with memantine treatment were smaller and did not reach the minimum clinically important difference. The cognitive benefit associated with continuing donepezil was equivalent to 32%, and that associated with starting memantine was equivalent to 20%, of the total deterioration (a decrease of 5.8 SMMSE points) over the course of 12 months28,29 that was seen in the group discontinuing donepezil and receiving placebo memantine. The functional benefits of continuing donepezil were equivalent to 23%, and those of starting memantine were equivalent to 11%, of the deterioration (an increase of 12.8 BADLS points) seen over the course of 12 months in the group discontinuing donepezil and receiving placebo memantine (Figure 3). Memantine treatment was associated with a significantly smaller worsening of NPI scores, an observation that is consistent with the findings in another study,30 with a benefit that was equivalent to 83% of the 12-month deterioration (4.8 NPI points) seen in the group discontinuing donepezil and receiving placebo memantine.

In this study, patients who discontinued donepezil did not have abrupt withdrawal phenomena,31 but withdrawal from the study drug was significantly more common among participants assigned to discontinue donepezil and receive placebo donepezil than among those assigned to continue donepezil, with the majority of withdrawals occurring between week 6 and week 18 (Figure 2). Modest reductions in caregivers’ psychological symptoms that were seen with donepezil or memantine did not reach statistical significance but, considered together with lower rates of withdrawal, suggest the possibility that caregivers who live with patients perceived treatment benefits.

Participants were recruited from National Health Service clinics across England and Scotland and were representative of patients with Alzheimer’s disease who were treated with cholinesterase inhibitors. Despite difficulties with recruitment, we detected significant benefits of continued donepezil therapy with respect to cognitive and functional outcomes (P<0.001), which was the first objective of our study. With respect to our second objective, the benefits of starting memantine were smaller than the benefits of continuing donepezil, but they were significant at the P<0.05 level. With respect to our third objective, determining whether the combination of donepezil and memantine treatment showed additive benefits, we did not find significant heterogeneity in the efficacy of donepezil or memantine in the presence or absence of the other drug. Subgroup analyses, however, failed to show significant benefits of adding memantine to donepezil treatment.

Supported by the U.K. Medical Research Council and Alzheimer’s Society.

Dr. McShane reports receiving payment for work as the local principal investigator for commercial trials from Abbott, Novartis, i3 Innovus, and Medivation; Dr. Lindesay, receiving consulting fees from Novartis NEURONET and lecture fees from Janssen, Novartis, Eisai, and Pfizer; Dr. Ritchie, receiving consulting and lecture fees from Pfizer and Eisai and grant support and reimbursement for travel expenses from Eisai; Dr. Barber, receiving royalties from Arnold Press; Dr. Burns, receiving royalties from John Wiley; Dr. Findlay, receiving lecture fees and reimbursement for meeting expenses from Eisai, Pfizer, and Lundbeck; Dr. Jones, receiving consulting fees from Merz Pharmaceuticals and Janssen, grant support from Eisai, Lundbeck, and Merz Pharmaceuticals, and lecture fees from Lundbeck, Merz Pharmaceuticals, Eisai, Pfizer, and Novartis and being a board member of Merz Pharmaceuticals, Lundbeck, Eisai, Pfizer, and Lilly; Dr. McKeith, receiving lecture fees from Novartis; Dr. O’Brien, receiving consulting fees from GE Healthcare, Bayer Healthcare, and Servier and lecture fees from Pfizer, Eisai, Novartis, Lundbeck, Eli Lilly, Shire, and GE Healthcare; Dr. Passmore, receiving consulting fees from Pfizer, Lundbeck, Novartis, Shire, and Johnson & Johnson and lecture fees and reimbursement for travel expenses from Lundbeck and Pfizer; Dr. Katona, receiving consulting fees from Lundbeck and Eli Lilly, grant support from Lundbeck, lecture fees from Lundbeck, Lilly, Shire, and Pfizer, payment for development of educational presentations from Lundbeck, and reimbursement for travel expenses from Pfizer and being a board member of Lundbeck; Dr. Ballard, receiving consulting and lecture fees from Lundbeck, Eisai, Bristol-Myers Squibb, Janssen, Acadia, and Novartis and grant support from Lundbeck and Acadia; Dr. Brown, receiving lecture fees from UCB Pharma, GlaxoSmithKline, Solvay, and Lundbeck; Dr. Banerjee, receiving grant support from Pfizer, lecture fees from Lundbeck, and reimbursement for travel expenses from Pfizer and Eisai; and Dr. Bentham, receiving consulting fees from TauRx Therapeutics.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

No other potential conflict of interest relevant to this article was reported.

We thank the trial steering committee: Cornelius Katona (chair), Ken Wilson (independent psychiatrist for the elderly), Robert Hills (independent statistician), and Victoria Morgan and Angela Clayton-Turner (patient and caregiver representatives from the Alzheimer’s Society); the independent data monitoring and ethics committee: Brian Lawlor (chair), Tony Bayer (independent physician), and Deborah Ashby (independent statistician); local collaborators: Paul Koranteng (Northamptonshire) and Stephen Pearson (Plymouth); Elaine Bygrave, Hannah Mason, and Jacky Pullen (Joint Clinical Trials Office, King’s College London); Debbie Johnson and Sue Tebbs (Medical Research Council Clinical Trials Unit); Graham Cadwallader (Medical Research Council); the Dementia and Neurodegenerative Diseases Research Network; the participating patients and their caregivers; and our National Health Service colleagues who supported recruitment for the trial.
Source Information

From the Institute of Psychiatry (R. Howard, M.K., R. Brown, S.B., J.A.) and the Wolfson Centre for Age Related Disease (C.B.), King’s College London, the Centre for Mental Health, Imperial College London (C.R.), the Department of Mental Health Sciences, University College London (C.K.), and the Medical Research Council (MRC) Clinical Trials Unit (T.J., P. Phillips) — all in London; the Fulbrook Centre, Churchill Hospital (R.M.), and the Department of Psychiatry (R. Jacoby), the Centre for Statistics in Medicine (E.J.), and the Clinical Trial Service Unit (R.G.), University of Oxford — all in Oxford; Health Sciences, University of Leicester, Leicester (J.L.); Knowlsey Resource & Recovery Centre, Whiston Hospital, Prescot (A. Baldwin); Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne (R. Barber, I.M., J.O.); the School of Psychiatry and Behavioural Sciences, Wythenshawe Hospital, Manchester (A. Burns); Older People’s Mental Health Service, Fulbourn Hospital (T.D.), and the MRC Biostatistics Unit, Cambridge University (T.J.) — both in Cambridge; Royal Dundee Liff Hospital, Dundee Community Health Partnership, Dundee (D.F.); Memory Assessment and Research Centre, University of Southampton, Southampton (C.H.); the Department of Geriatric Psychiatry, Inverclyde Royal Hospital, Inverclyde (A.H.); Section of Old Age Psychiatry (Rob Jones) and Faculty of Medicine & Health Sciences (C.O.), University of Nottingham, Nottingham; the Research Institute for the Care of Older People, Bath (Roy Jones); Mental Health Directorate, Crichton Royal Hospital, Dumfries (A.M.); Centre for Public Health, Queens University Belfast, Belfast (P. Passmore); Health Sciences Research Institute, University of Warwick, Coventry (B.S.); the Department of Haematology, University of Wales, Cardiff (R. Hills); South West Dementias and Neurodegenerative Diseases Research Network, Avon and Wiltshire Mental Health Partnership, Chippenham (M.G.); and Queen Elizabeth Psychiatric Hospital, Birmingham (P.B.) — all in the United Kingdom.

Address reprint requests to Dr. Howard at King’s College London, Institute of Psychiatry, Department of Old Age Psychiatry, Box PO70, 16 DeCrespigny Park, London SE5 8AF, United Kingdom, or at robert.j.howard@kcl.ac.uk.

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