Diagnosis, Management, and Treatment of Alzheimer Disease a Guide for the Internist

REVIEW ARTICLE Diagnosis, Management, and Treatment of Alzheimer Disease A Guide for the Internist

Stephanie S. Richards, MD; Hugh C. Hendrie, MB, ChB

lzheimer disease (AD) is a diagnosis of inclusion based on patient history, physical examination, neuropsychological testing, and laboratory studies; however, there is no definitive diagnostic test for AD. Early recognition of AD allows time to plan for the future and to treat patients before marked deterioration occurs. Effective treatment requires moni- Atoring of symptoms, functional impairment, and safety, and the use of multiple treatment modalities including pharmacotherapy, behavioral management, psychotherapies, psychosocial treatments, and support and education for families. Pharmacotherapeutic agents available for AD only provide symptomatic relief. The cholinesterase inhibitors, tacrine and donepezil, are effective in improving cognition, delaying nursing home placement, and improving behavioral complications in some patients. Other cholinesterase inhibitors are in development, as are other cholinomimetic agents such as muscarinic and nicotinic receptor agonists. Symptomatic treatments are available for the psychiatric manifestations of AD. Anti-inflammatories, antioxidants, neurotrophic factors, and other agents are promising new treatments for the future. Arch Intern Med. 1999;159:789-798

Alzheimer disease (AD) is one of a group the past decade, yet the definitive cause of neurodegenerative disorders that fre- remains unclear and a cure has been elu- quently cause dementia. Dementia is char- sive. Nevertheless, we now have avail- acterized by a progressive cognitive de- able effective pharmacological and psy- cline leading to social or occupational chosocial interventions to alleviate the disability occurring in a state of clear symptoms and suffering of patients with consciousness. AD and their families. The purpose of this Specifically, AD is characterized clini- article is to discuss the epidemiology, pre- cally not only by an impairment in cogni- sentation, diagnosis, and pharmacologi- tion but also by a decline in global func- cal management of the disorder. tion, a deterioration in the ability to perform activities of daily living, and the appear- EPIDEMIOLOGY ance of behavioral disturbances. When AD was originally described by Alois Alzhei- The prevalence of dementia in the United mer in 1907,1 it was considered to be a rela- States in individuals aged 65 years or older tively uncommon disorder. However, sub- is about 8%, with these rates doubling if sequent clinical and neuropathological those with milder forms of dementia or studies identified the characteristic AD pa- cognitive impairment are included. Rates thology of senile plaques and neurofibril- of dementia are very much age depen- lary tangles as the most common cause of dent, doubling every 5 years from 1% to dementia in the elderly. With the aging of 2% at ages 65 to 70 years, to 30% and our population, the management and treat- higher after the age of 85 years. Alzhei- ment of AD is likely to become one of the mer disease is by far the most common of major public health problems facing our the dementing disorders in the United society in the next century. Our knowledge of the pathophysiology and natural history of the disease has increased greatly over This article is also available on our Web site: www.ama-assn.org/internal. From the Department of Psychiatry, Indiana University School of Medicine, Indianapolis.

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 States, accounting for 65% to 75% of cases.2-5 Criteria for Clinical Diagnosis of Probable Alzheimer Disease*

COST Criteria include Dementia established by clinical examination and cognitive test (Mini-Mental State Examination or Blessed Dementia Scale) and confirmed by neuropsychological tests The calculated economic cost of the Deficits in Ն2 areas of cognition management and treatment of AD is Progressive worsening of memory and other cognitive function staggering. The combined direct No disturbance of consciousness costs, including medical and long- Onset between ages 40 and 90 years term care and lost productivity, and Absence of systemic disorder or brain disease that could account for progressive cognitive deficits indirect costs, including resource The diagnosis is supported by loss and family care, approach $100 Progressive deterioration of specific cognitive functions such as language (aphasia), billion per year.6 In addition, there motor skills (apraxia), and perception (agnosia) is also the immeasurable emotional Impaired activities of daily living cost to families who suffer tremen- Altered behavior dously watching their affected loved Family history of similar disorders Normal lumbar puncture, normal electroencephalogram or nonspecific changes, ones slowly lose their identity. progressive cerebral atrophy on computed tomography Features consistent with the diagnosis RISK FACTORS Plateaus in the course of progression Associated symptoms including depression, insomnia, incontinence, delusions, illusions, Our knowledge of putative genetic hallucinations, catastrophic outbursts, sexual disorders, or weight loss Neurologic signs including increased muscle tone, myoclonus, or gait disorder risk factors for AD has increased Seizures (in advanced stage) dramatically over the past decade. Computed tomography normal for age There is now evidence that certain Features that make the diagnosis uncertain or unlikely types of early-onset, autosomal Sudden, apoplectic onset dominant AD are associated with Focal neurologic findings such as hemiparesis, sensory loss, visual field deficits, gene mutations on chromosome and incoordination (early in the course) 21, chromosome 14, and chromo- Seizures or gait disturbance (at the onset or early in the course) 7-9 some 1. These findings are im- *From the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s portant for determining pathologic Disease and Related Disorders Association Work Group.15 mechanisms but account for only a small proportion (about 2%) of all cases of AD.10 AD, may increase the specificity of municative Disorders and Stroke– The presence of the APOE⑀4 al- the diagnosis.14 Alzheimer’s Disease and Related Dis- lele on chromosome 19 has been as- Research on other risk factors orders Association (Table).15 Using sociated with a considerably greater for AD is relatively new. To date, these criteria, the clinical diagnosis risk for developing the more com- only age, family history of demen- of AD has been confirmed at au- mon, late-onset form of AD.8,11,12 The tia, and Down syndrome consis- topsy in close to 90% of cases. It has effect appears to be dose depen- tently have been shown to be asso- been stated that AD is a diagnosis of dent. The presence of a single ⑀4 al- ciated with AD. However, high exclusion. This is only partially cor- lele increases the risk of AD by 2- to education and ingestion of estro- rect. While it is essential for the phy- 4-fold, whereas possessing the gen, nonsteroidal anti-inflamma- sician to evaluate other possible double ⑀4 allele increases the risk tory drugs, and vitamin E may be causes of memory loss, a positive di- from 4- to 8-fold. It must be remem- protective. It is likely in the future agnosis of probable AD can be made bered that possessing the ⑀4 allele is that risk factor models involving ge- based on a characteristic history neither necessary nor sufficient for netic and environmental interac- from a spouse or a knowledgeable the development of AD. Therefore, tions will emerge. informant together with a physical APOE genotyping is not recom- and neurologic examination. The mended as a predictive test for AD DIAGNOSTIC PROCESSES AND differential diagnosis for AD in- in asymptomatic individuals.13 How- DIFFERENTIAL DIAGNOSIS cludes a broad range of other causes ever, experts disagree on the utility of dementia and nondementing of APOE genotyping as a diagnos- As AD is both a clinical and a neu- metabolic or psychiatric illnesses. tic test. It may be useful for confir- ropathological entity, the defini- Among the more important mation in some patients with de- tive diagnosis of AD can be made nondementing causes of dementia mentia when a diagnosis of AD is only with a brain biopsy or an au- are delirium and depression. De- unclear, although the presence of 1 topsy. One of the major clinical ad- lirium is common in elderly sub- or 2 copies of the APOE ⑀4 allele still vances in the diagnosis of AD has jects, particularly in inpatient set- does not make the diagnosis cer- been the promulgation of diagnos- tings and in nursing homes. Unlike tain and absence of the ⑀4 allele does tic criteria for possible and prob- delirium in children, which is an not preclude a diagnosis of AD. able AD by a select group spon- acute disorder, delirium in the el- APOE genotyping, when used in sored by the National Institute of derly can be subacute at onset, stretch- patients with a clinical diagnosis of Neurological and Related and Com- ing over weeks or even months, char-

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 acterized by apathy rather than the illness. Memory and construc- what they ate for the previous meal, agitation, and vague paranoid symp- tional praxis are relatively spared or if they have trouble keeping ap- toms rather than vivid hallucina- early on. Frontal and temporal lobe pointments. Be aware that patients tions. Thus, delirium in the elderly atrophy is usually evident on com- and families often make excuses for can often be misdiagnosed. Com- puted tomography. Dementia with memory problems. For the lan- mon causes of delirium include in- Lewy bodies is a progressive demen- guage domain, one could ask if the fection (particularly urinary tract in- tia characterized by detailed recur- patients have trouble finding the fections), hypoglycemia, electrolyte rent visual hallucinations, parkin- right word for things or call some- abnormalities (such as those accom- sonism, and fluctuations of alertness thing by the wrong name, mispro- panying dehydration), hepatic dys- and attention.18 Other common fea- nounce words, or if they feel that function, renal insufficiency, endo- tures include frequent falls, syn- they have more trouble expressing crine dysfunction (particularly cope, systematized delusions, and themselves verbally. For praxis, it thyroid abnormalities), and medi- neuroleptic sensitivity. Autopsy se- would be appropriate to ask if they cations (especially anticholinergic ries findings demonstrate cortical have trouble figuring out how to use agents, benzodiazepines, hista- Lewy bodies in 20% to 30% of de- machines that they knew how to use mine2 antagonists, and narcotics), all mentia cases and there may be over- before (microwave, washing ma- of which are eminently treatable. De- lap with AD.18 A long history of chine, or lawn mower) or if they lirium and dementia can coexist. In heavy use of alcohol can also cause have trouble with any skills (crafts fact, dementia predisposes to the de- dementia. or hobbies) in which they previ- velopment of delirium with even Creutzfeld-Jakob disease is an ously engaged. For agnosia, deter- modest metabolic insults. example of an infectious cause of de- mine if they have trouble recogniz- Severe depression in the el- mentia caused by prions. Creutzfeld- ing common objects such as a derly is often accompanied by com- Jakob disease is characterized by telephone, toaster, or broom. Diffi- plaints of memory loss and the pres- relatively sudden onset and rapid culty with executive functioning ence of mild cognitive deficits on progression with myoclonic jerks, manifests as trouble with complex neuropsychological testing. In de- pyramidal frontal motor signs, vi- tasks such as preparing a meal or pression, the subjective complaints sual agnosia, and death within managing finances. In addition to in- of cognitive impairment often ex- months. quiring about cognitive function, it ceed the neuropsychological defi- Other neurologic disorders less is critical to inquire about the use of cits, and the primary problem seems commonly associated with demen- prescription and over-the-counter to be one of motivation or lack of ef- tia include normal pressure hydro- medications, alcohol, and illicit fort. Depression and dementia can cephalus, subdural hematoma, brain drugs and their temporal relation- coexist, however. tumor, posttraumatic brain injury, ship to any cognitive changes. Among the dementing disor- and posthypoxic damage. The instrument used most ders, vascular dementia follows AD commonly for assessing cognitive as the second most common form.16 DIAGNOSTIC EVALUATION function is the MMSE. This instru- The vascular dementias usually, but ment is a nonspecific screen for cog- not always (eg, Binswanger dis- A diagnostic evaluation for demen- nitive function and has some limi- ease), have a relatively acute onset tia involves a complete history, neu- tations. The MMSE is not sensitive temporally related to a vascular event ropsychological examination (eg, the for detecting cognitive impairment such as transient ischemic attack or Mini-Mental State Examination in individuals with higher levels of stroke and have a more fluctuating [MMSE]),19 physical examination, education or high levels of premor- course than AD. Focal neurologic and selected laboratory studies and bid functioning. Conversely, those signs or symptoms usually accom- neuroimaging.20 The history should with low levels of education or mi- pany them. Cerebrovascular changes be obtained from a reliable in- nority cultural backgrounds may can also coexist with AD path- formant. In this regard, attention score low on the test without hav- ology, and this combination can should be paid to change in cogni- ing impairment. However, the adversely affect the dementing tion and functioning relative to pre- MMSE is especially useful when re- process.17 vious performance, mode of onset of peated regularly to follow illness pro- Other neurodegenerative dis- impairment (insidious onset is char- gression. orders that can cause dementia in- acteristic of AD), progression of A complete physical and neu- clude Parkinson disease, Hunting- illness (slow gradual decline is typi- rologic examination is indicated. Fo- ton disease, Pick disease, and cal of AD), and duration of impair- cal neurologic signs may suggest dementia with Lewy bodies. Parkin- ment (it is important to repeatedly vascular dementia or some other son disease and Huntington dis- ask if there were any earlier signs that neurologic disorder, and parkinson- ease are characterized by extrapy- may have indicated a change). One ism suggests Parkinson disease or ramidal signs, which usually predate should ask about all cognitive do- dementia with Lewy bodies disease the cognitive decline. Pick disease is mains and give examples of early depending on the time course of one of the frontal lobe dementias and signs. For example, when asking symptoms relative to the cognitive usually presents with behavioral dis- about memory impairment, one impairment. Results of the neuro- inhibition, poor insight, and lan- could ask if the patients have diffi- logic examination are usually essen- guage deficits early in the course of culty remembering what day it is, tially normal in early AD.

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 Laboratory evaluation should higher price, and while it is a better families often underreport symp- include tests for complete blood cell tool for research purposes, it has lim- toms, families attribute symptoms to counts, electrolytes, blood chemis- ited clinical application. Single pro- normal aging and compensate for tries, liver functions, thyrotropin lev- ton emission computed tomogra- functional impairment, and social els, vitamin B12 levels, and a sero- phy is simpler to perform, less skills are maintained, masking any logic test for syphilis. Other tests expensive, and has greater poten- impairment during a short, fo- should be obtained as indicated tial in the clinical setting than posi- cused office visit. Even when cog- by the history such as erythrocyte tron emission tomography.22 nitive testing is performed, individu- sedimentation rate (autoimmune Detailed neuropsychological als with dementia may score in the disease), heavy metal screen (indus- testing is also helpful in character- “normal” range on the MMSE. Re- trial exposure), human immunode- izing the pattern of cognitive im- sults of laboratory tests are normal ficiency virus (with human immu- pairment. It is also more sensitive in AD so a diagnostic workup will nodeficiency virus risk factors), and than a screening instrument such as not reveal any abnormalities. toxicology screen (suspected use of the MMSE in detecting early impair- There is a need to improve early illicit drugs). An electroencephalo- ment in highly educated individu- recognition of AD in the primary gram reveals nonspecific changes als. It also provides a quantitative care setting and to avoid delays in and is rarely indicated except to di- measure, which affords the ability to diagnosis. Practitioners should agnose Creutzfeld-Jakob disease, a follow disease progression over time. screen for functional and cognitive disease associated with a character- If the diagnosis remains un- decline and any concerns should istic periodicity on the electroen- clear after a complete evaluation, prompt a full dementia workup. cephalogram, or hepatic encepha- there are several options. Repeat- lopathy with characteristic triphasic ing the cognitive testing in 6 months TREATMENT OF AD IN THE waves. will determine if there is progres- PRIMARY CARE SETTING A neuroimaging study may be sive cognitive decline during the in- obtained in a complete workup to tervening period. More complete The successful treatment of AD in- rule out neurologic disease, which neuropsychological testing may also volves multiple treatment modali- may contribute to cognitive decline, be helpful. Consultation with a spe- ties targeting various aspects of the but is not required for diagnosis un- cialist, either a neurologist or geri- illness and its consequences for the less warranted by unusual findings. atric psychiatrist, is warranted. patient and the family. Again, it is A computed tomographic scan of the important to stress the necessity for head without contrast is usually suf- IMPORTANCE OF EARLY accurate diagnosis of AD and early ficient to rule out cerebrovascular dis- DIAGNOSIS recognition to provide the best pos- ease, subdural hematoma, normal sible treatment. While there is no pressure hydrocephalus, or brain tu- Early diagnosis of AD is important cure for AD, there are approaches to mor. Magnetic resonance imaging is for many reasons. Patients may improving cognition and possibly more expensive but is better for vi- present with nonspecific physical delaying the progression of the ill- sualizing small subcortical lacunae complaints that may prompt exten- ness, and there are efficacious treat- and mesial temporal lobe atrophy sive and costly diagnostic workups ments for the psychiatric and be- (in coronal slices). However, there is and unnecessary treatments. Early havioral manifestations. Another a tendency to overread vascular recognition allows the possibility of important aspect of treatment is changes (periventricular and subcor- treating with agents that can slow the helping the patient and the family tical white matter hyperintensities) cognitive decline at a point where with the legal aspects, supporting on magnetic resonance imaging. there is still minimal impairment. the family through caregiving, and Single proton emission computed to- Early diagnosis also allows the assisting with decisions about long- mography may be helpful in atypi- patient and the family time to plan term care placement. Providing reg- cal, difficult, or early cases. In AD, for the future such as developing ular appointments for maintenance there is a characteristic hypoperfu- advanced directives and appoint- and surveillance is necessary to sion in the temporal and parietal ing durable power of attorney while meet the goals of minimizing ex- lobes. In vascular dementia, there are competence is not yet an issue. The cess disability and ensuring safety more patchy changes. Pick disease practitioner can educate the pa- and security. is marked by frontal and temporal tient and the family regarding dis- lobe perfusion defects. Single pro- ease progression and prognosis, PHARMACOLOGICAL ton emission computed tomogra- provide support, and monitor judg- TREATMENT OF AD phy may be most useful in distin- ment and safety issues so that the guishing AD from vascular dementia patient can continue independent There are several conceptual ap- and frontotemporal dementia, but or community dwelling as long as proaches to the treatment of AD. The should be used selectively and only possible. first approach is to treat symptom- as an adjunct to clinical evaluation Unfortunately, AD is frequently atically. This includes treating the and computed tomography.21 Posi- not diagnosed at this early stage de- cognitive impairment, decline in glo- tron emission tomography has the spite visits to the primary care phy- bal function, deterioration in the advantage of greater sensitivity and sician. There are many reasons for ability to perform activities of daily spatial resolution but at a much this delay in diagnosis. Patients and living, and behavioral distur-

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 bances. This approach reflects the clude the open-label, nonrandom- tensive titration. Dosing is initiated current state of treatment. Another ized, and nonblinded design. at 5 mg/d and may be increased to approach is to slow disease progres- Studies of acetylcholinesterase 10 mg/d in 1 month. It is well tol- sion or delay onset of disease. Even- inhibitors have generally shown an erated and the most common ad- tually, it may be possible to be able initial improvement in cognitive verse effect is gastrointestinal tract to prevent the development of AD scores beginning early in the treat- distress (nausea, vomiting, and di- or even repair neuronal damage af- ment course with a subsequent de- arrhea). ter onset of disease. These latter ap- cline at a rate similar to untreated Other cholinesterase inhibi- proaches are currently being inves- patients with AD.32 When the medi- tors are in development and are tigated at a basic science level. The cation is stopped, cognitive function- expected to reach the market soon. only currently available therapeu- ing declines to nontreatment levels. Metrifonate is a prodrug for the tic agents are targeted at specific This is consistent with the hypoth- long-acting cholinesterase inhibi- symptoms of AD. esis that cholinesterase inhibitors pro- tor, 2,2-dichlorovinyl dimethyl vide symptomatic relief without al- phosphate. Its pharmacokinetic Cognitive Impairment tering the disease course. The long- profile permits once-daily dosing. term effects or continued benefit of Early studies demonstrate improve- Cholinesterase Inhibitors.—Alzhei- cholinesterase inhibitors will be- ment in cognitive scores and global mer disease is in part a disorder of come clearer in clinical practice. One function compared with placebo, with cholinergic functioning. Degenera- neuroimaging study33 demonstrated few adverse effects.34-36 Rivastig- tion of basal forebrain cholinergic sys- increased regional cerebral blood mine is a central nervous system– tems is a hallmark feature of AD and flow in the parietal lobe, which per- selective, pseudo-irreversible, car- appears to be associated with cogni- sisted up to 14 months with contin- bonate-selective cholinesterase tive deficits, functional impairment, ued treatment. inhibitor.37 Dosing is 2 or 3 times and behavioral disturbances. One Treatment with tacrine re- daily and extensive titration is re- strategy for ameliorating the symp- quires a lengthy dose titration begin- quired. It is well tolerated at the lower toms of AD is to enhance choliner- ning with 10 mg orally 4 times daily doses with predominantly adverse ef- gic neurotransmission. Acetylcho- and increasing by 10 mg 4 times daily fects on the gastrointestinal tract. linesterase inhibitors are the best every 6 weeks as tolerated to a maxi- Heptylphysostigmine is a derivative studied and the only currently avail- mum of 160 mg/d. Only doses of 120 of physostigmine with a long dura- able agents for the symptomatic treat- to 160 mg/d are significantly more ef- tion of inhibition.38 Several other ment of AD. Acetylcholinesterase in- ficacious than placebo. However, dose agents are also in development. hibitors delay the degradation of titration is frequently limited by ad- acetylcholine at the synaptic cleft, verse effects to the gastrointestinal Other Cholinergic Agents.— An- thus potentiating cholinergic neuro- tract or hepatic transaminase eleva- other strategy targeting the cholin- transmission. tions. Transaminase activity (ala- ergic system is specific cholinergic The only 2 agents currently nine and aspartate aminotransfer- receptor agonists. Muscarinic ace- available for the treatment of AD are ase) must be monitored weekly until tylcholine postsynaptic m1 recep- the cholinesterase inhibitors ta- a steady dose has been achieved for tors are relatively intact in AD, while crine and donepezil. Both agents in- 6 weeks, after which monitoring ev- the m2 presynaptic receptors are de- hibit acetylcholinesterase in a dose- ery 3 months is sufficient. If trans- creased. Agents that target the post- dependent manner. Both are effective aminase activity levels rise to more synaptic m1 receptors are being de- in improving performance on a test than 5 times the upper limit of nor- veloped. There is some evidence of cognitive function and global per- mal, treatment with tacrine should be suggesting that these agents may also formance in patients with mild to discontinued. Transaminase eleva- slow disease progression, but most moderate AD.23-29 Cognitive im- tions are usually asymptomatic and have not been well tolerated at thera- provements are, on average, mod- reversible and patients may be rechal- peutic doses. Xanomeline is a selec- est and may not be clinically rel- lenged after transaminase normaliza- tive m1 and m4 agonist that has evant in many patients. However, tion (see package insert for details). demonstrated moderate efficacy in some patients demonstrate a dra- Donepezil has replaced ta- improving cognitive performance, matic improvement in cognitive crine as the first choice “cognitive but even greater efficacy in decreas- scores that is readily observable in enhancer” owing to ease of admin- ing psychotic symptoms and agita- daily functioning. Some cholinester- istration, less titration, greater tol- tion.39 However, adverse events to ase inhibitors are also associated with erability, relative lack of hepa- xanomeline were associated with improvement in behavioral symp- totoxic side effects, and absence of high discontinuation rates prima- toms, including depression, psycho- monitoring requirements. Donepe- rily because of adverse effects on the sis, and agitation, even in the ab- zil is selective for acetylcholinester- gastrointestinal tract and syncope. sence of profound cognitive change.30 ase and is longer acting than ta- Other cholinergic agonists in de- However, this is based on an open- crine. It is metabolized via the velopment include milameline, label study. Cholinesterase inhibi- hepatic cytochrome P450 system SB202026, AF 102B, and ENS-163. tors are also associated with a delay and is highly plasma protein bound. Stimulation of presynaptic nico- in nursing home placement.31 Meth- Donepezil is administered in once- tinic receptors increases the release odological limitations of this study in- daily dosing and requires less ex- of acetylcholine and may be associ-

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 ated with cognitive improvement in phorylation of tau proteins, prevent- dering, is associated with greater selected domains. Therefore, nico- ing amyloid deposition, blocking cognitive impairment, is the symp- tinic acetylcholine receptor ago- amyloid toxicity, and lowering APOE tom most likely to emerge during the nists also appear promising. ⑀4 levels. Ganglioside GM1 and course of treatment, and is the most phosphatidylserine have mem- persistent.47 It is the symptom that Disease-Altering brane effects that may interfere with is the most troubling to families and Treatment Strategies the disease process. Other poten- caregivers and is the most common tial treatment under investigation in- reason for institutionalization in One target for disease-altering treat- clude ergot alkaloids (ergoloid me- long-term care facilities and for re- ments is apoptosis or programmed sylates and nicergoline45), nootropics ferral to specialists. Psychosis is the cell death. Mechanisms that are im- (piracetam, oxiracetam, prami- next most common psychiatric plicated in neuronal degeneration are racetam, and aniracetam), and vinca manifestation and includes delu- the inflammatory response and oxi- alkaloids. These agents have mul- sions, most commonly paranoid and dative stress. The inflammatory re- tiple putative mechanisms of ac- misidentification delusions, and hal- sponse contributes to cell death in part tion including cholinergic and do- lucinations, with visual more com- by triggering release of free radicals. paminergic properties, as well as mon than auditory hallucinations. An accumulation of free radicals in effects on protein processing and cel- Delusions are associated with greater turn damages cell membranes and lular metabolism. However, stud- cognitive and functional impair- triggers the neurodegenerative cas- ies to date involving these agents ment and show moderate persis- cade. In addition, components of the have shown them to be generally tence over time.47 Psychosis may also inflammatory response are found in ineffective. be associated with more rapid cog- association with senile plaque forma- nitive decline. Depressive symp- tion. Anti-inflammatory agents may FUNCTIONAL IMPAIRMENT toms are present in up to 86% of pa- be protective against AD; in epide- tients with AD, with about 10% to miological studies, the use of anti- Alzheimer disease is associated with 20% having a diagnosable depres- inflammatory drugs is associated with a gradual decline in global function- sive disorder.48 Depressive symp- a decreased risk of AD. Prednisone is ing. Instrumental activities of daily toms are less likely to emerge dur- currently under investigation for living are the first to deteriorate. ing the course of AD than psychosis the treatment of AD.40 Antioxidants These include managing finances, and behavioral disturbance, and are may also be protective against cell shopping, cooking, cleaning, and the least persistent.47 Comorbid de- death. In one clinical trial,41 alpha- maintaining an independent life- pression is associated with greater tocopherol (vitamin E) and selege- style. Basic activities of daily living cognitive impairment, greater level line hydrochloride (L-deprenyl), a se- include bathing, toileting, dress- of disability, and higher rates of in- lective monoamine oxidase–type B ing, and feeding oneself. Eventu- stitutionalization, mortality, and inhibitor that acts as an antioxidant, ally, patients with AD become un- functional impairment.49 demonstrated efficacy in delaying ad- able to perform even these basic Effective treatment of the psy- verse events. Methodological limita- tasks. Functional impairment of- chiatric manifestations of AD can im- tions of this study include poor ran- ten prompts changes in levels of care prove quality of life for patients and domization whereby baseline scores from independent living to more ac- their families, decrease caregiver bur- on the MMSE were higher in the tive involvement of family to living den, decrease health care utiliza- placebo group, requiring adjust- with a family member or assisted liv- tion, and delay institutionalization. ment for this in the analysis. Chelat- ing, and often eventually to skilled Treatment can also significantly de- ing agents may also work via an an- care or a nursing home. crease the risk of harm to the pa- tioxidant mechanism. Other Effective treatment for func- tients and their caretakers. monoamine oxidases are currently tional decline is the same as for cog- Nonpharmacological treat- under investigation. nitive impairment. The cholinester- ment approaches should be at- Neurotropic factors may have ase inhibitors have been shown to tempted first before pharmacologi- a modulating effect on neuronal delay outcomes of functional de- cal treatments. Environmental structural integrity and neurotrans- cline and are the only currently avail- manipulation or simple behavioral mitter function. Estrogen acts as a able treatment. techniques may be helpful. In this neurotropic factor and may be pro- regard, creating a safe and consis- tective in decreasing the incidence PSYCHIATRIC tent environment with moderate or delaying the onset of AD and en- MANIFESTATIONS OF AD stimulation, contrasting colors, and hancing response to cholinesterase pictures for directions and signs may inhibitors.42,43 It is currently being Psychiatric manifestations are com- be useful. A structured routine and investigated as a treatment for AD. mon in AD and occur in almost all consistent environment as free from Other neurotrophic factors under in- patients at some point in their ill- change as possible also can help vestigation include nerve growth fac- ness. Behavioral disturbance is the eliminate confusion. Additionally, it tor and other agents that enhance its most common symptom and oc- may be desirable to provide familiar effect.44 curs in up to 90% of patients with personal objects such as pictures and Other treatment strategies in- dementia.46 Behavioral distur- momentos, as well as cues for orien- volve blocking the abnormal phos- bance, especially agitation and wan- tation like calendars and clocks. Com-

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 munication should be clear and be lower than in adults or may be the receptor antagonist and may be ef- simple. Behavioral interventions such same as in younger patients. fective in treating refractory pa- as validation and not correcting mis- Selective serotonin reuptake tients. However, it is sedating and statements can ease anxiety. Pa- inhibitors (SSRIs) are first-line causes weight gain in some patients should be encouraged to be ac- agents because they are the best tients.57 Nefazodone is a serotonin tive participants in their care and tolerated, do not have cognitive reuptake inhibitor and 5HT2A recep- in decision making. Emotion- adverse effects, and may even tor antagonist. It is administered in oriented psychotherapy, supportive improve cognitive function inde- twice-daily dosing and the most psychotherapy, interpersonal psycho- pendent of antidepressant effects.53 common adverse effects are leth- therapy, and reminiscence therapy The choice of an SSRI is dependent argy, dizziness, and dry mouth.58 may be beneficial in individual cases. on pharmacokinetics and adverse- Tricyclic antidepressants Stimulation-oriented therapy such as effect profiles.54 Sertraline has few should be used only if better toler- music, art, and pet therapy and exer- interactions with the cytochrome ated agents are ineffective or in de- cise may be helpful for others. P450 system and little anticholin- pression severe enough to warrant Because the psychopathology ergic activity, so it is a good first inpatient psychiatric hospitaliza- changes over the natural course of choice SSRI for the patient with tion. Tertiary tricyclic antidepres- the illness, treatments must be moni- AD. Fluoxetine, with its long half- sants (imipramine and amitripty- tored and periodically reevaluated life and active metabolite, make it line) should never be used in for continued appropriateness. Since less desirable in the elderly unless patients with AD because of the an- depressive symptoms are not per- noncompliance is a problem; the ticholinergic effects. Nortriptyline is sistent over time, short-term anti- long half-life allows for adequate the tricyclic antidepressant of choice depressant treatment is probably in- levels to be maintained even when because of fewer anticholinergic ef- dicated. Psychotic symptoms are doses are missed. Paroxetine is the fects. Serum levels and electrocar- moderately persistent and long- most anticholinergic of the diogram should be monitored at term antipsychotic use is associ- SSRIs and, theoretically, may have steady state before each dose in- ated with significant morbidity and more adverse effects on cognition. crease with target levels of 50 to150 adverse effects, so antipsychotics Fluvoxamine has a relatively short ng/mL. Adverse effects include or- should be tapered if possible. Be- half-life and the twice-daily dosing thostatic hypotension, which places cause behavior disturbance is more may impair compliance. The start- patients at risk for falls and hip frac- persistent, long-term treatment is ing dose of SSRI therapy should be tures, cardiac conduction delays, and likely necessary. half that normally used in adults anticholinergic effects such as uri- (ie, 25 mg of sertraline or 10 mg of nary retention, constipation, cogni- TREATMENT OF DEPRESSION fluoxetine). The most common tive impairment, and delirium. IN AD adverse effects with the SSRIs are Specific target symptoms transient headache, nausea and should be identified and moni- Recognition of depression in AD vomiting, diarrhea, anxiety, rest- tored through the course of treat- may be complicated by an overlap lessness, psychomotor agitation, ment to determine treatment re- of symptoms between the 2 disor- insomnia, and lethargy. sponse and to guide dose titration. ders and failure to meet strict crite- Several atypical antidepres- Cognition should also be moni- ria for a depressive disorder. Any sants are available. Venlafaxine in- tored with a simple instrument such patient with dementia with signifi- hibits both serotonin and norepi- as the MMSE. Treatment should be cant depressive symptoms such as nephrine reuptake without having reevaluated periodically as depres- sleep, appetite, or energy distur- anticholinergic adverse effects. Most sive symptoms may decrease with bance, depressed mood or irritabil- common adverse effects are nau- natural disease progression. If symp- ity, anhedonia, social withdrawal, sea, anxiety, insomnia, dizziness, toms are adequately controlled and excessive guilt, a passive death constipation, and sweating.55 Bupro- there is no history of recurrent ma- wish or suicidal ideation, or agita- pion has an atypical and not well- jor depression, consider tapering the tion should be considered for treat- understood mechanism of action.56 antidepressant in 6 months. Be pre- ment of depression even if failing It is a weak norepinephrine uptake pared to reinstitute treatment if any to meet criteria for a depressive inhibitor but is a stronger inhibitor depressive symptoms reemerge. disorder.50 of dopamine uptake. The dopamin- There are limited data on the ergic effect may be beneficial in some TREATMENT OF PSYCHOSIS treatment of depression in AD,51,52 patients and may be stimulating and IN AD so treatment strategies are extrapo- particularly effective for apathy. Bu- lated from the treatment of depres- propion is generally well tolerated Choice of antipsychotic is deter- sion in elderly patients without de- with most common adverse effects mined by the adverse-effect profile. mentia. In general, starting doses are being insomnia, anxiety, headache, The low-potency agents, such as half those normally used in adults tremor, nausea, dry mouth, and con- chlorpromazine, have significant an- and titration is at smaller incre- stipation as well as a dose-related in- ticholinergic adverse effects while the ments and slower, to allow for the crease in risk of seizures. Mirtazap- high-potency agents, such as halo- decreased rate of metabolism. Effec- ine is an ␣2-antagonist and serotonin peridol, have significant extrapyra- tive doses in patients with AD may type 2 and type 3 (5HT2 and 5HT3) midal adverse effects causing parkin-

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 sonism; both can predispose to falls. TREATMENT OF AGITATION awakened at night and may have to The newer atypical agents (risperi- IN AD be vigilant to prevent wandering done, olanzapine, quetiapine, and away from home or self-injury of the clozapine) or midpotency agents such The diagnostic evaluation of agi- patient. Insomnia often occurs con- as perphenazine are preferred because tated behavior should begin with a currently with other symptoms. of fewer adverse effects. thorough medical evaluation to search Treatment of insomnia and sleep- Haloperidol has demonstrated for a treatable cause such as urinary wake cycle disturbance is not well efficacy for psychosis and behav- tract infection, fracture, decubitus, studied in AD. Effective strategies in- ioral disturbance in dementia and was constipation, or reaction to a medi- clude trazodone and zolpidem ad- considered the criterion standard cation or drug interaction. The un- ministered at bedtime. Chloral hy- agent. However, its use is limited by derlying medical problem should be drate and benzodiazepines should extrapyramidal adverse effects even at treated or the offending medication only be used for short-term treat- relatively low doses, and it also causes discontinued. Once a physical ill- ment. The benzodiazepine tria- cognitive deterioration.59 ness has been ruled out, the under- zolam should be avoided due to am- Risperidone has demon- lying psychopathology should be nesia. Diphenhydramine should be strated efficacy in psychosis and agi- determined and treated appropri- avoided because of anticholinergic tation in AD.60 Even relatively low ately.62 Agitation may be associated effects. doses can produce the disabling ex- with underlying depression, anxi- trapyramidal syndrome in older pa- ety, psychosis, or delirium. If there is CAREGIVER DISTRESS tients. Other potential adverse ef- no underlying problem and the agi- fects include postural hypotension tation is an isolated disturbance, an- Treatment of a patient with AD in- and sedation. Olanzapine and queti- tipsychotics are the most effective variably also involves treatment of apine, the newest atypical antipsy- treatments. In a meta-analysis of an- the family, especially the primary chotic agents, have not yet been well tipsychotic trials,63 antipsychotics caregiver. The emotional, physical, studied in this population. Clozap- were significantly more effective than and often financial stresses associ- ine has demonstrated efficacy in el- placebo in reducing agitation, but ated with caring for a relative with derly patients with psychosis but, there was a modest effect size, with AD are enormous. Thus, it should owing to the risk of agranulocyto- only 18% of patients benefiting from come as no surprise that up to 50% sis and need for weekly blood moni- antipsychotics over placebo. No an- of caregivers suffer from “caregiver toring, it is not a first-line agent tipsychotic was better than any other. burnout.” This may take the form of in AD. It should be reserved for Other treatment strategies for which depression, anxiety, isolation, sub- patients who develop significant there is limited evidence of efficacy in- stance abuse, or physical illness. In- extrapyramidal syndrome or who clude buspirone, carbamazepine, val- dividual and family counseling and remain refractory to other antipsy- proate, trazodone, propranolol, and support as well as involvement in chotics. Clozapine is a low-potency lithium. Benzodiazepines are gener- support groups can avoid or delay agent and is associated with ortho- ally not useful for agitation and may nursing home placement by almost static hypotension and sedation. produce paradoxical reactions (in- 1 year.64 These family intervention There are no data on the long- creased agitation and disinhibition) strategies are most effective in the term benefits of antipsychotics al- and cause sedation, falls, ataxia, early to middle stages of the illness, thoughthelong-termrisksarewellun- amnesia, and delirium. Cholinergic again reinforcing the need for early derstood. Antipsychotic use should be agents such as the cholinesterase in- illness recognition. Respite ser- reevaluated periodically (every 3-6 hibitors and cholinergic agonists may vices can also provide a source of re- months) to determine continued ne- also be effective for the behavioral dis- lief to family members so that they cessity. Dose tapering should be at- turbances. Theoretically, the behav- can have some time for taking care tempted if symptoms are under ad- ioral complications may be due in part of themselves and renewing social equate control. If symptoms reemerge to altered cholinergic function, ex- relationships with others. The Alz- during drug taper, an effective dose plaining why cholinomimetics can heimer’s Association is an excel- should be reinstituted. The most se- improve behavior. There is evidence lent source of information on local rious long-term risk is tardive dyski- that the cholinesterase inhibitors such services such as support groups and nesia, which occurs at a much higher as donepezil, tacrine, and metrifo- respite care. Families should be re- rate in elderly patients. Estimates of nate and the muscarinic agonist ferred to their local chapter for ad- the risk of tardive dyskinesia in the el- xanomeline can improve psychosis ditional support. derly begin at 29% in the first year and and behavioral disturbance in AD.30,39 increase to 40% after 10 years of an- CONCLUSIONS tipsychotic exposure.61 The Omnibus TREATMENT OF INSOMNIA Reconciliation Act regulations for IN AD Alzheimer disease is the most com- nursing home care require frequent mon cause of dementia and will af- reevaluation of continued use of an- Insomnia or sleep-wake cycle dis- fect a growing number of people as tipsychotics and other psychotropic turbance is common in AD and oc- the US population ages. It is now medications. Dose reductions should curs in up to 20% to 40% of pa- clear that AD is both diagnosable and be attempted at least twice per year to tients. This can cause significant treatable. Because most patients with determine continued necessity. distress to family caregivers who are AD are treated in the primary care

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 setting, it is important for primary ily. This includes providing educa- a general population: the Framingham Study. Neu- care practitioners to be able to action and support, referral to the Alz- rology. 1993;43:515-519. 6. Ernst RL, Hay JW. The US economic and social curately diagnose and effectively heimer’s Association and other costs of Alzheimer’s disease revisited. Am J Pub- treat AD. The primary care practi- support networks, evaluating care- lic Health. 1994;84:1261-1264. tioner has multiple roles in the treat- giver burnout, helping assess and 7. Hardy J. Amyloid, the presenilins and Alzheimer ment of AD. The primary care prac- maintain safety in the community, disease. Trends Neurosci. 1997;20:154-159. and helping families deal with the le- 8. Schellenberg GD. Progress in Alzheimer’s dis- titioner must accurately diagnose AD ease genetics. Curr Opin Neurol. 1995;8:262- and distinguish it from depression, gal issues and with long-term care 267. delirium, and other causes of de- when and if appropriate. 9. Plassman BL, Breitner JCS. Recent advances in mentia. This practitioner must also Primary care physicians are not the genetics of Alzheimer’s disease and vascular be prepared to treat the cognitive im- alone in treating patients and their dementia with an emphasis on gene-environ- families with dementia and AD. Spe- ment interactions. J Am Geriatr Soc. 1996;44: pairment, treat the behavioral dis- 1242-1250. turbances, refer to a specialist when cialists should be consulted in atypi- 10. Roses AD. Apolipoprotein E alleles as risk fac- 50 there is uncertain diagnosis or dif- cal or complex cases. Neurologic tors in Alzheimer’s disease. Ann Rev Med. 1996; ficult-to-manage psychiatric mani- consultation is important for pa- 47:387-400. festations, provide education and tients with parkinsonism, focal neu- 11. Farlow MR. Alzheimer’s disease: clinical implica- rologic signs and atypical presenta- tions of the Apolipoprotein E genotype. Neurol- support to the patient and their fam- ogy. 1997;48(suppl 6):S30-S34. ily, help maintain safety in the com- tions, or course of illness. Geriatric 12. Strittmatter WJ, Roses AD. Apolipoprotein E and munity, and address long-term care psychiatrists should be consulted for Alzheimer’s disease. Ann Rev Neurosci. 1996;19: issues. difficult-to-treat behavioral or psy- 53-77. Early recognition is important chiatric manifestations. Psycholo- 13. Statement on the use of Apolipoprotein E testing gists can provide behavior manage- for Alzheimer’s disease. American College of Medi- to begin pharmacological therapy at cal Genetics/American Society of Human Genet- the point in the illness when it can ment, family counseling, and ics Working Group on ApoE and Alzheimer Dis- be most effective and to provide edu- functional evaluations. Neuropsy- ease. JAMA. 1995;274:1627-1629. cation about progression of the ill- chologists can help clarify uncer- 14. Mayeux R, Saunders AM, Shea S, et al. Utility of ness, help families and patients an- tainties in diagnosis and ascertain the apolipoprotein E genotype in the diagnosis of Alzheimer’s disease. Alzheimer’s Disease Cen- ticipate the course of the illness, and cognitive and functional impair- ters Consortium in Apolipoprotein E and Alzhei- discuss planning for the future. Alz- ment. Other supports include so- mer’s Disease. N Engl J Med. 1998;338:506- heimer disease is a diagnosis of in- cial workers, attorneys, commu- 511. clusion based on history and clini- nity support agencies, area councils 15. McKhann G, Drachman D, Folstein M, et al. Clini- cal presentation. A full laboratory on aging, and the Alzheimer’s As- cal diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the aus- and neuroimaging workup is not sociation. pices of the Department of Health and Human Ser- necessary in every case to rule out vices Task Force on Alzheimer’s Disease. Neurol- other causes of dementia. Accepted for publication July 15, 1998. ogy. 1984;34:939-944. Cognitive impairment may im- This study was supported by a 16. Morris JC. Classification of dementia and Alzhei- prove in the short-term with the cho- mer’s disease. Acta Neurol Scand Suppl. 1996; grant from Bayer Pharmaceuticals, 165:41-50. linesterase inhibitors tacrine and West Haven, Conn. 17. Snowdon DA, Greiner LH, Mortimer JA, et al. Brain donepezil. New cholinesterase in- We thank Francine Bray for her infarction and the clinical expression of Alzheim- hibitors such as metrifonate and cho- help in the preparation of the manu- er’s disease: The Nun Study. JAMA. 1997;227: linergic agents such as specific mus- script. 813-817. carinic and nicotinic agonists will be 18. McKeith IG, Galasko K, Kosaka K, et al. Consen- Reprints: Hugh C. Hendrie, MB, sus guidelines for the clinical and pathologic di- available soon. Vitamin E and selege- ChB, Department of Psychiatry, In- agnosis of dementia with lewy bodies (DLB): re- line may slow disease progression. diana University School of Medicine, port of the consortium on DLB international Other disease-altering strategies are Room 298, 541 Clinical Dr, India- workshop. Neurology. 1996;47:1113-1124. currently being investigated includ- napolis, IN 46202-5111. 19. Folstein MR, Folstein SE, McHugh PR. “Mini- Mental State”: a practical method for grading the ing estrogen, nonsteroidal anti- cognitive state of patients for the clinician. J Psy- inflammatory drugs, and neuro- REFERENCES chiatr Res. 1975;12:189-198. trophic factors. 20. Geldmacher DS, Whitehouse PJ. Evaluation of de- Behavioral disturbances includ- mentia. N Engl J Med. 1996;335:330-336. ing depression, psychosis, and agi- 1. Alzheimer A. Uber eine eigenartige Erkrankung der 21. Talbot PR, Lloyd JJ, Snowden JS, et al. A clinical Hirnrinde. Allemeine Zeitschr Psychiatr Psy- role for 99mTc-HMPAO SPECT in the investiga- tation are common in AD and are chisch Gericht Med. 1907;64:146-148. tion of dementia? J Neurol Neurosurg Psychia- treatable with antidepressants, an- 2. Jorm AF, Korten AE, Henderson AS. The preva- try. 1998;64:306-313. tipsychotics, and other psycho- lence of dementia: a quantitative integration of the 22. Waldemar G. Functional brain imaging with SPECT tropic medications, as well as with literature. Acta Psychiatr Scand. 1987;76:465- in normal aging and dementia: methodological, acetylcholinesterase inhibitors. The 469. pathophysiological, and diagnostic aspects. Ce- 3. Ritchie K, Kildea D, Robine JM. The relationship rebrovasc Brain Metabol Rev. 1995;7:89-130. natural course of behavior distur- between age and the prevalence of senile demen- 23. Summers WK, Majowski LV, Marsh GM, et al. Oral bance changes with progression of tia: a meta-analysis of recent data. Int J Epide- tetrahydroaminoacridine in long-term treatment the illness, so patients require re- miol. 1992;21:763-769. of senile dementia, Alzheimer type. N Engl J Med. peated regular reassessment of treat- 4. Skoog I, Nilsson L, Palmez B, et al. A population- 1986;315:1241-1245. based study of dementia in 85-year-olds. N Engl 24. Davis KL, Thal LJ, Gamzu ER, et al. A double blind, ment and alteration as appropriate. J Med. 1993;328:153-158. placebo-controlled, multi-center study of tacrine Treatment of a patient with AD 5. Bachman DL, Wolf PA, Linn RT, et al. Incidence and Alzheimer’s disease. N Engl J Med. 1992;327: also involves treatment of the fam- of dementia and probable Alzheimer’s disease in 1253-1259.

ARCH INTERN MED/ VOL 159, APR 26, 1999 797

Downloaded From: https://jamanetwork.com/ on 09/29/2021 25. Farlow M, Gracon SI, Hershey LA, et al. A 12- 38. Asthana S, Greig NH, Hegedus L, et al. Clinical mer’s Association, and the American Geriatrics So- week, double-blind, placebo controlled, parallel- pharmacokinetics of physostigmine in patients with ciety. JAMA. 1997;278:1363-1371. group study of tacrine in patients with probable Al- Alzheimer’s disease. Clin Pharmacol Ther. 1995; 51. Reifler BV, Teri L, Raskind M, et al. Double-blind zheimer’s disease. JAMA. 1992;268:2523-2529. 58:299-309. trial of imipramine in Alzheimer’s disease pa- 26. Knapp MJ, Knopman DS, Solomon PR, et al. Con- 39. Bodick NC, Offen WW, Levey AL, et al. Effects of tients with and without depression. Am J Psy- trolled trials of high-dose tacrine in patients with xanomeline, a selective muscarinic receptor ago- chiatry. 1989;146:45-49. Alzheimer’s disease. JAMA. 1994;271:985-991. nist, on cognitive function and behavioral symp- 52. Nyth AL, Gottfries CG. The clinical efficacy of cita- 27. Rogers SL, Friedhoff LT. E2020 improves cogni- toms in Alzheimer disease. Arch Neurol. 1997; lopram in treatment of emotional disturbances in tion and quality of life in patients with mild-to- 54:465-473. dementia disorders: a Nordic multicentre study. moderate Alzheimer’s disease: results of a phase-II 40. Aisen PS, Altstiel L, Marin D, Davis K. Treatment Br J Psychiatry. 1990;157:894-901. trial [abstract]. Neurology. 1994;44(suppl 2): of Alzheimer’s disease with prednisone: results of 53. Oxman TE. Antidepressants and cognitive impair- A165. pilot studies and design of multicenter trial [ab- ment in the elderly. J Clin Psychiatry. 1996;57 28. Rogers SL, Doody R, Mohs R. E2020 produces stract]. J Am Geriatr Soc. 1995;43:SA27. (suppl 5):38-44. both clinical global and cognitive test improve- 41. Sano M, Ernesto C, Thomas RG, et al. A con- 54. Preskorn SH. Clinically relevant pharmacology of ment in patients with mild to moderately severe trolled trial of selegeline, alpha-tocopherol, or both, selective serotonin reuptake inhibitors: an over- Alzheimer’s disease: results of a 30-week phase- as treatment for Alzheimer’s disease: the Alzhei- view with emphasis on pharmacokinetics and ef- III trial [abstract]. Neurology. 1996;46:A217. mer’s Disease Cooperative Study. N Engl J Med. fects on oxidative drug metabolism. Clin Phar- 29. Robert SL, Friedhoff LT. The efficacy and safety 1997;336:1216-1222. macokinet. 1997;32(suppl 1):1-21. of donepezil in patients with Alzheimer’s dis- 42. Simpkins JW, Singh M, Bishop J. The potential 55. Rudolph RL, Derivan AT. The safety and tolerabil- ease: results of a US multicentre, randomized, role for estrogen replacement therapy in ity of venlafaxine hydrochloride: analysis of the double-blind, placebo-controlled trial. Dementia. the treatment of the cognitive decline and neu- clinical trial database. J Clin Psychopharmacol. 1996;7:293-303. rodegeneration associated with Alzheimer’s dis- 1996;16(suppl 2):S54-S59. 30. Kauffer DI, Cummings JL, Christine D. Effect of ease. Neurobiol Aging. 1994;15(suppl 2):S195- 56. Ascher JA, Cole JO, Colin J-N, et al. Bupropion: a tacrine on behavioral symptoms in Alzheimer’s dis- S197. review of its mechanism of antidepressant activ- ease: an open label study. J Geriatr Psychiatry Neu- 43. Schneider LS, Farlow MR, Henderson WW, et al. ity. J Clin Psychiatry. 1995;56:395-401. rol. 1996;9:1-6. Effects of estrogen replacement therapy on re- 57. Montgomery SA. Safety of Mirtazapine: a review. 31. Knopman D, Schneider L, Davis K, et al. Long- sponse to tacrine in patients with Alzheimer’s dis- Int Clin Psychopharm. 1995;10(suppl 4):37-45. term tacrine (Cognex) treatment: effects on nurs- ease. Neurology. 1996;46:1580-1584. 58. Goldberg RJ. Antidepressant use in the elderly: ing home placement and mortality. Neurology. 44. Aisen PS, Davis KL. The search for disease modi- current status of Nefazodone, venlafaxine and mo- 1996;47:166-177. fying treatment for Alzheimer’s disease. Neurol- clobemide. Drugs Aging. 1997;11:119-131. 32. Tune LE, Sunderland T. New Cholinergic thera- ogy. 1997;48(suppl 6):S35-S41. 59. Devanand DP, Sackheim HA, Brown RP. A pilot pies: treatment tools for the psychiatrist. J Clin 45. Saletu B, Paulus E, Linzmayer L, et al. Nicergo- study of haloperidol treatment of psychosis and Psychiatr. 1998;59:31-35. line in senile dementia of Alzheimer type and multi- behavioral disturbance in Alzheimer’s disease. Arch 33. Minthon L, Nillson K, Edvinsson L, et al. Long- infarct dementia: a double-blind, placebo- Neurol. 1989;46:854-857. term effects of tacrine on regional cerebral blood controlled, clinical and EEG/ERP mapping study. 60. Goldberg RJ, Goldberg J. Risperidone for demen- flow changes in Alzheimer’s disease. Dementia. Psychopharmacology. 1995;117:385-395. tia-related disturbed behavior in nursing home resi- 1995;6:245-251. 46. Tariot PN, Blazina L. The psychopathology of de- dents: a clinical experience. Int Psychogeriatr. 34. Becker RE, Colliver J, Elbie R, et al. Effects of met- mentia. In: Handbook of Dementing Illnesses. New 1997;9:65-68. rifonate, a long-acting cholinesterase inhibitor, in York, NY: Marcel Dekker Inc; 1993:461-475. 61. Sweet RA, Mulsant BH, Gupta B, et al. Duration Alzheimer’s disease: report of an open trial. Drug 47. Devanand DP. Behavioral complications and their of neuroleptic treatment and prevalence of tar- Develop Res. 1990;19:425-434. treatment in Alzheimer’s disease. Geriatrics. 1997; dive dyskinesia in late life. Arch Gen Psychiatry. 35. Becker RE, Colliver JA, Markwell SJ, et al. Double- 52(suppl 2):537-539. 1995;52:478-486. blind, placebo-controlled study of metrifonate, an 48. Wragg RE, Jeste DV. Overview of depression and 62. Rosen J, Mulsant BH, Wright BA. Agitation in se- acetylcholinesteraseinhibitor,forAlzheimerdisease. psychosis in Alzheimer’s disease. Am J Psychia- verely demented patients. Ann Clin Psychiatry. Alzheimer Dis Assoc Disord. 1996;10:124-131. try. 1989;146:577-587. 1992;4:207-215. 36. Cummings JL, Cyrus PA, Bieber F, et al. Metrifo- 49. Rovner BW, Broadhead J, Spencer M, et al. De- 63. Schneider LS, Pollock VE, Lyness SA. A metaan- nate treatment of the cognitive deficits of Alzhei- pression and Alzheimer’s disease. Am J Psychia- alysis of controlled trials of neuroleptic treatment mer’s disease. Neurology. 1998;50:1203-1205. try. 1989;146:350-353. in dementia. J Am Geriatr Soc. 1990;38:553-563. 37. Sramek JJ, Anand R, Wardle TS, Irwin P, Hart- 50. Small GW, Rabins PV, Barry PP, et al. Diagnosis 64. Mittelman MS, Ferris SH, Shulman E, et al. A fam- man RD, Cutler NR. Safety and tolerability of ENA and treatment of Alzheimer’s disease and related ily intervention to delay nursing home placement 713 in patients with probable Alzheimer’s dis- disorders: consensus statement of the American of patients with Alzheimer disease: a randomized ease. Life Sci. 1996;58:1201-1207. Association for Geriatric Psychiatry, the Alzhei- controlled trial. JAMA. 1996;276:1725-1731.

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