Choice of specific treatments for a patient with dementia begins with the establishment of a specific diagnosis and an assessment of the symptoms being experienced by that patient. A multimodal approach is often used, combining, for instance, behavioral and psychopharmacological interventions as available and appropriate. When multiple agents or approaches are being used and problems persist (or new problems develop), it is advisable, if possible, to make one change at a time so that the effect of each change can be assessed. The continuing utility of all interventions must be regularly reevaluated.

The site of treatment for an individual with dementia is determined by the need to provide safe and effective treatment in the least restrictive setting. Approximately two-thirds of patients with dementia live at home and receive care on an outpatient basis. The frequency of office or facility visits is determined by a number of factors, including the patient's clinical status, the likely rate of change, and the need for specific monitoring of treatment effects. Another factor is the reliability and skill of the patient's caregivers, particularly regarding the likelihood of their notifying the clinician if a clinically important change occurs. Most dementias are progressive, and symptoms change over time. Therefore, in order to offer prompt treatment, enhance safety, and provide timely advice to the patient and family, it is generally necessary to see patients, usually together with their caregivers, at regular follow-up visits. Patients who are clinically stable or are taking stable doses of medications should generally be seen at a minimum of every 3–6 months. Patients who require active treatment of psychiatric complications should be seen regularly to adjust doses and monitor for changes in target symptoms and side effects. Similarly, attempts to taper or discontinue psychotropic medications require more frequent assessments than are required for routine care. Weekly or monthly visits are likely to be required for patients with complex, distressing, or potentially dangerous symptoms or during the administration of specific therapies. For example, outpatients with acute exacerbations of depressive, psychotic, or behavioral symptoms may need to be seen as frequently as once or twice a week, sometimes in collaboration with other treating clinicians, or be referred to intensive outpatient treatment or a partial hospitalization program.

Individuals with dementia may need to be admitted to an inpatient facility for the treatment of psychotic, affective, or behavioral symptoms. In addition, they may need to be admitted for treatment of general medical conditions co-occurring with psychiatric conditions. For patients who are very frail or who have significant general medical illnesses, a geriatric psychiatry or medical psychiatric unit may be helpful when available (1). Indications for hospitalization include symptom severity (e.g., significant threats of harm to self or others, violent or uncontrollable behavior, inability to care for self or be cared for by others) and intensity and availability of services needed (e.g., the need for continuous skilled observation, electroconvulsive therapy, or a medication or diagnostic test that cannot be performed on an outpatient basis) (2, 3). The length of stay is similarly determined by the ability of the patient to safely receive the appropriate care in a less restrictive setting.

Decisions regarding the need for temporary or permanent placement in a long-term-care facility often depend on the degree to which the patient's needs can be met in the community, either by relatives or other caregivers, either in an assisted living facility or at home. The decision to remain at home should be reassessed regularly, with consideration of the patient's clinical status and the continued ability of the patient's caregivers to care for the patient, manage the burden of care, and utilize available support services. The appropriate level of care may change over time, and patients often move from one level of care to another during the course of dementia. If available, consultation with a social worker or geriatric case manager may be beneficial to assess the current support system and facilitate referrals to additional services. At the end of life, many patients with dementia are cared for in a hospice program.

Successful management of patients with dementia requires the concurrent implementation of a broad range of tasks, which are grouped under the term "psychiatric management." These tasks help to maximize the patient's level of function and enhance the safety and comfort of patients and their families in the context of living with a difficult disease. In some settings, psychiatrists perform all or most of these tasks themselves. In others, they are part of multidisciplinary or interdisciplinary teams. In either case, they must be aware of the full range of available treatments and take steps to ensure that any necessary treatments are administered. Good communication between the patient's psychiatrist and primary care physician ensures maximum coordination of care, may minimize polypharmacy, and may improve patient outcomes (4).

1. Establish and Maintain an Alliance With the Patient and the Family

As with any psychiatric care, a solid therapeutic alliance is critical to the treatment of a patient with dementia. The care of a patient with dementia requires an alliance with the patient, as well as with the family and other caregivers. Family members and other caregivers are a critical source of information, as the patient is frequently unable to give a reliable history, particularly as the disease progresses. Because family members are often responsible for implementing and monitoring treatment plans, their own attitudes and behaviors can have a profound effect on the patient, and they often need the treating physician's compassion and concern. For these reasons, treatment is directed to the patient-caregiver system. The needs of caregivers will vary based on factors such as their relationship to the patient, their long-standing role in the family, and their current customs. Clinical judgment is needed to determine the circumstances in which it is appropriate or necessary to speak with caregivers without the patient present, as well as how to proceed with clinical care when there are disputes among family members. A clear process for medical decision making should be delineated for each patient, and a capacity assessment of the patient should be performed when necessary.

2. Perform a Diagnostic Evaluation and Refer the Patient for Any Needed General Medical Care

a. General Principles

Patients with dementia should undergo a thorough diagnostic evaluation aimed at identifying the specific etiology of the dementia syndrome, because knowledge of the etiology may guide specific treatment decisions. In addition, the evaluation should determine if any treatable psychiatric or general medical conditions (e.g., major depression, thyroid disease, vitamin B₁₂ deficiency, hydrocephalus, structural brain lesion) might be causing or exacerbating the dementia. The details of this evaluation are beyond the scope of this guideline; the reader is referred to the American Academy of Neurology practice parameter on the diagnosis of dementia (5), the American Academy of Neurology practice parameter on early detection of dementia and mild cognitive impairment (6), and the Agency for Health Care Policy and Research clinical practice guideline Recognition and Initial Assessment of Alzheimer's Disease and Related Dementias (7) for more complete descriptions of the evaluation of patients with dementia. A brief summary follows.

The general principles of a complete psychiatric evaluation are outlined in APA's Practice Guideline for the Psychiatric Evaluation of Adults (8). The evaluation of a patient with dementia frequently involves coordination with a number of medical professionals, including the patient's primary care physician (4). The physician with overall responsibility for the care of the patient oversees the evaluation, which should at a minimum include a clear history of the onset and progression of symptoms; a review of the patient's medical problems and medications (including over-the-counter and herbal medications); assessment of functional abilities; a complete physical examination and a focused neurological examination; and a psychiatric examination, including a cognitive assessment that should include at least a brief assessment of the cognitive domains of attention, memory, language, and visuospatial skills, ideally used with age- and education-adjusted norms (9, 10). An assessment for past or current psychiatric illnesses that might mimic or exacerbate dementia, such as schizophrenia or major depression, is also critical, as are laboratory studies, including a complete blood count (CBC), blood chemistry battery (including glucose, electrolytes, calcium, and kidney and liver function tests), measurement of vitamin B₁₂ level, and thyroid function tests. For some patients, toxicology studies, syphilis serology, erythrocyte sedimentation rate, HIV testing, serum homocysteine, a lumbar puncture, or an electroencephalogram may also be indicated. In general, many elements of the history will need to be obtained from the caregiver or the documented medical record as well as from the patient. Often, it may be necessary to conduct a portion of the interview with the caregiver without the patient present, in order to allow for full disclosure of sensitive information.

b. Neuropsychological Testing

Neuropsychological testing may be helpful in a number of ways. It may help in deciding whether a patient with subtle or atypical symptoms actually has dementia as well as in more thoroughly characterizing an unusual symptom picture. It is particularly useful in the evaluation of individuals who present with mild cognitive impairment (see Section IV.F.2), which requires evidence of memory and/or other cognitive difficulties in the presence of intact functioning, and in the evaluation of individuals with the onset of dementia early in life. Testing may help to characterize the extent of cognitive impairment, to distinguish among the types of dementias, and to establish baseline cognitive function. Neuropsychological testing may also help identify strengths and weaknesses that could guide expectations for the patient, direct interventions to improve overall function, assist with communication, and inform capacity determinations.

c. Neuroimaging

The use of a structural neuroimaging study, such as computerized tomography or magnetic resonance imaging (MRI) scan, is generally recommended as part of an initial evaluation, although clinical practice varies. Imaging is particularly important for those with a subacute onset (less than 1 year), symptom onset before age 65, vascular risk factors suggesting a higher likelihood of cerebrovascular involvement in their dementia, or a history or neurological examination findings suggesting a possible focal lesion. Nonetheless, clinically important lesions may be found on neuroimaging in the absence of these indications (11). The value of imaging in patients with late-stage disease who have not been previously evaluated has not been established. Functional neuroimaging using brain positron emission tomography (PET) scans may contribute to diagnostic specificity in certain instances and has been recently approved by Medicare for the indication of differentiating between Alzheimer's disease and frontotemporal dementia.

The development of additional imaging tools for improved diagnosis, early recognition, and more precise assessment of disease progression is a focus of current study. These additional tools include quantitative MRI, functional MRI, use of investigational PET compounds, and other methods aimed at imaging senile plaques in the brain (12, 13).

d. Biomarkers

A wide variety of biomarkers are also under investigation with the goal of enhancing diagnostic and prognostic knowledge (14). Biomarkers of current interest include proteins such as tau and amyloid beta protein in the cerebrospinal fluid (CSF) and plasma. Except in rare circumstances (notably the use of CSF-14-3-3 protein when Creutzfeldt-Jakob disease is suspected and recent stroke or viral encephalitis can be excluded) (5, 15), these techniques remain investigational, and there is insufficient evidence for their utility in routine clinical practice. However, this area is evolving rapidly, so recommendations may change with new discoveries and the development of new markers and/or therapies.

e. Genetic Testing

Although genes involved in a variety of dementia syndromes have been identified (16), and family members of patients with dementia are often concerned about their risk of developing dementia, genetic testing is generally not part of the evaluation of patients with dementia except in very specific instances (5). In particular, testing for apolipoprotein E4 (APOE4) is not recommended for use in diagnosis. Apolipoprotein E4 is one form of a gene on chromosome 19 that is more common in individuals with Alzheimer's disease than in elderly individuals without dementia and is associated with late-onset Alzheimer's disease occurring with or without a family history (17–19). However, it is also found in many elderly patients who do not have dementia and is not found in many patients who do have Alzheimer's disease. Thus, the presence of an APOE4 allele does not change the need for a thorough workup and does not add substantially to diagnostic confidence (5, 20–22).

First-degree relatives of patients with Alzheimer's disease have a risk of developing the disease that is two to four times that of the general population. Three genes associated with the disease have been identified in families with apparent autosomal dominant inheritance of early-onset Alzheimer's disease. These genes include the amyloid precursor protein (APP) gene on chromosome 21 (23), presenilin 1 (PSEN1) on chromosome 14 (24), and presenilin 2 (PSEN2) on chromosome 1 (25). Genetic testing is commercially available for PSEN1, which is likely to be found in families with apparent autosomal dominant inheritance and dementia developing before age 50 years. Testing for the other two genes is not commercially available but can sometimes be performed in the context of clinical genetics research. However, the role of such testing in clinical practice has not yet been established. Because no preventive treatments are currently available, testing should only be offered in the setting of thorough pre- and posttest counseling (26). In addition, genetic testing is best done in conjunction with experts familiar with Alzheimer's disease genetics, as test results require careful interpretation. A referral to a local Alzheimer's Disease Research Center or the local chapter of the Alzheimer's Association may be helpful in locating someone who can provide the appropriate counseling and testing. If specific Alzheimer's genetics resources are not available locally, a referral to a professional genetic counselor or clinical geneticist may help such families characterize their risk and find appropriate resources (27, 28).

Genetic counseling and sometimes genetic testing may also be appropriate for some patients with other dementias and a family history of similar syndromes. In particular, individuals with a clinical picture suggestive of frontotemporal dementia and a family history suggesting autosomal dominant inheritance can be tested for certain mutations (29, 30). Likewise, individuals with a clinical picture suggestive of Huntington's disease can be tested for the gene defect (31), and those suspected of having CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) can be tested for associated Notch 3 gene polymorphisms (32).

3. Assess and Monitor Psychiatric Status

Ninety percent of patients with dementia develop a neuropsychiatric or behavioral symptom during the course of the disease (33). It is therefore important for the psychiatrist to periodically assess the patient for the presence of noncognitive psychiatric symptoms as well as for the progression of cognitive symptoms.

Both cognitive and noncognitive neuropsychiatric and behavioral symptoms of dementia tend to evolve over time, so regular monitoring allows detection of new symptoms and adaptation of treatment strategies to current needs. For example, among the neuropsychiatric disturbances common in Alzheimer's disease, depression is reported more commonly early in the illness, whereas delusions and hallucinations are more common in the middle and later stages, although any of these symptoms may occur at any stage of the disease (33, 34). It is particularly important to look for the emergence of such symptoms after a medication dose has been lowered or discontinued. Among the cognitive deficits, memory loss is commonly the earliest symptom, whereas language and spatial dysfunction become more overt somewhat later.

Among the neuropsychiatric symptoms that require ongoing assessment are depression (including major depression and other depressive syndromes), suicidal ideation or behavior, hallucinations, delusions, agitation, aggressive behavior, disinhibition, sexually inappropriate behavior, anxiety, apathy, and disturbances of appetite and sleep. Cognitive symptoms that almost always require assessment include impairments in memory, executive function, language, judgment, and spatial abilities. It is often helpful to track cognitive status with a structured simple examination. If the same instrument is used repeatedly, the clinician should watch for practice effects. A detailed assessment of functional status may also aid the clinician in documenting and tracking changes over time as well as providing guidance to the patient and caregivers. Functional status is typically described in terms of the patient's ability to perform instrumental activities of daily living such as shopping, writing checks, basic housework, and activities of daily living such as dressing, bathing, feeding, transferring, and maintaining continence. These regular assessments of recent cognitive and functional status provide a baseline for assessing the effect of any intervention, and they improve the recognition and treatment of acute problems, such as delirium.

Whenever there is an acute worsening of cognition, functioning, behavior, mood, or psychosis, the clinician should bear in mind that elderly persons in general and patients with dementia in particular are at high risk for delirium associated with medications, general medical problems, and surgery. Newly developing or acutely worsening agitation in particular can be a sign of an occult general medical condition (e.g., urinary tract infection, dehydration), untreated or undertreated pain, or physical or emotional discomfort. Elderly patients may not manifest certain typical signs or symptoms such as fever in the face of infection or pain during a myocardial infarction. Thus, a thoughtful assessment of the patient's overall status and a general medical evaluation must precede any intervention with psychotropic medications or physical restraint, except in an emergency. Assessments should also include examination of the patient's sensory function, since sensory deficits can precipitate or worsen psychiatric and cognitive symptoms and increase the risk that patients will make medication errors.

Before undertaking an intervention, the psychiatrist should enlist the help of caregivers in carefully characterizing the target symptoms. Their nature, intensity, frequency, precipitants, and consequences should be reviewed and documented. This process is critical to revealing the cause of the symptoms, as well as monitoring the impact of any intervention. This approach also assists caregivers in beginning to achieve some mastery over the problematic symptom. Before embarking on any intervention, it is also helpful if clinicians explicitly review their own, the patient's, and the caregivers' expectations.

4. Monitor and Enhance the Safety of the Patient and Others

It is important for the psychiatrist treating a patient with dementia to regularly assess cognitive deficits or behavioral difficulties that potentially pose a danger to the patient or others. The psychiatrist should 1) assess suicidality, 2) assess the potential for aggression and agitation, 3) make recommendations regarding adequate supervision, for example of medication administration, 4) make recommendations regarding the prevention of falls and choking, 5) address nutritional and hygiene issues, and 6) be vigilant regarding neglect or abuse. Patients who live alone require careful attention. Events that indicate that the patient can no longer live alone include several falls, repeated hospitalization, dehydration, malnutrition, repeated errors in taking prescribed medications, dilapidated living conditions, or other signs of self-neglect. Other important safety issues in the management of patients with dementia include interventions to decrease the hazards of wandering and recommendations concerning activities such as cooking, driving, hunting, and the operation of hazardous equipment (see Section II.B.5). Caregivers should be referred to available books that provide advice and guidance about maximizing the safety of the environment for patients with dementia (35).

a. Suicidal Ideation

All patients (and their caregivers) should be asked about the presence of wishes for death, suicidal ideation, suicide plans, as well as a history of previous self-injurious behavior. If suicidal ideation occurs in patients with dementia, it tends to be earlier in the disease, when insight is more likely to be preserved. It is a particular concern in patients who are clinically depressed but can also occur in the absence of major depression. Elderly persons in general and elderly men in particular are at increased risk for suicide, although the diagnosis of dementia is not known to confer added risk. Interventions to address suicidal ideation are similar to those for patients without dementia and include psychotherapy; pharmacotherapy; removal of potentially dangerous items such as medications, guns, or vehicles; increased supervision; and hospitalization. Factors affecting the choice of intervention include the nature and intensity of the suicidal ideation or behavior and the capacity and support system of the patient (36).

b. Agitation and Aggression

"Agitation" is an umbrella term that refers to a range of behavioral disturbances, including physical aggression, combativeness, threatening behavior, persistent or intermittent psychomotor hyperactivity, and disinhibition. These behaviors pose a particular problem for patients cared for at home, especially by frail spouses. Agitation is more likely to occur later in the course of dementia and often has multiple causes. New or worsened agitation can result from an occult general medical problem, medication side effects, untreated or undertreated pain, constipation, depression, psychotic symptoms, or delirium. Thus, the first priority is a careful medical evaluation, because the agitation will often resolve with treatment of an underlying condition. The next step is an assessment of other features of the patient's overall situation. Hunger or sleep deprivation can provoke agitation, as can interpersonal or emotional stressors such as undergoing a change in living situation, caregiver, or roommate or experiencing frustration, boredom, loneliness, or overstimulation. Consequently, attending to unmet needs, providing reassurance, redirecting activities, or matching the level of stimulation to the patient's current level of activation may resolve the problem (37).

In designing an intervention to treat a problematic behavior, a structured approach should be taken to facilitate selecting the optimal treatment and monitoring the effect of that treatment (38–40). The first step is to carefully describe the target behavior, including where, when, and how often it occurs. The next step is to assess the specific antecedents and consequences of each problem behavior, which will often suggest specific strategies for intervention. Activities that consistently precede the problem behavior may be acting as precipitants and should be avoided whenever possible. If the activity is a necessary one, for example, bathing, it may be helpful to decrease its frequency or to alter the environment so that the negative consequences are minimized (e.g., switch bath time to allow a home health aid to supervise, or change the location of baths to decrease the impact of aggressive outbursts on family members or other patients). When multistep activities such as dressing and eating precipitate problem behaviors such as aggression, it often helps to simplify the activities (e.g., using clothing with Velcro closures, serving several simple nutritious snacks instead of a large meal). Whatever the intervention, it is critical to match the level of demand on the patient with his or her current capacity, avoiding both infantilization and frustration. Likewise, behavior may also improve by modifying the environment insofar as possible to compensate for the patient's deficits and to capitalize on his or her strengths (41). In assessing the effectiveness of interventions for problematic behaviors, clinicians can recommend that caregivers maintain a log of specific behaviors as well as their intensity, frequency, precipitants, and consequences.

If the agitation is deemed dangerous to the patient or others, it is important to undertake further measures to enhance safety. Such additional measures may include providing one-on-one care, instituting the behavioral measures discussed in Section II.C.4, or initiating pharmacological treatment as discussed in Section II.C.5. If agitation and aggressive behavior cannot be brought under control, hospitalization and/or nursing home placement must be considered.

Within hospital or nursing home settings, physical restraints (e.g., Posey restraints, geri-chairs) are sometimes used to treat agitation or combativeness that puts the patient or others at risk. Nonetheless, principles of humane care as well as federal regulations support minimizing restraint use as much as possible. In addition, some evidence suggests that restraints may increase the risk of falls and contribute to cognitive decline (42, 43) and that reducing restraint use can decrease the rate of serious injuries among nursing home residents (44).

c. Supervision

Decisions regarding supervision of the patient should take into consideration the patient's cognitive deficits, the home environment, and the consequent risk of dangerous activities. For instance, a patient with significant cognitive impairment may not be safe alone at home because he or she might improperly administer medications, be unable to cope with a household emergency, or use the stove, power tools, or other equipment in a dangerous manner. Home occupational therapy functional and safety assessments, as well as other community-based services, may be helpful in determining whether increased supervision is needed.

d. Falls

Psychiatrists caring for patients with dementia should be aware that falls are a common and potentially serious problem for all elderly individuals, especially those with dementia. Falls can lead to hip fracture, head trauma, and a variety of other injuries, including subdural hematomas, which may further worsen cognitive function. A number of interventions to prevent falls in elderly people have been shown to be effective (45). One of the most efficacious is withdrawing medications that are associated with falls, central nervous system sedation, or cardiovascular side effects (especially orthostatic hypotension), when appropriate. If gait disturbances are present, canes, walkers, or other supports may be helpful unless they are otherwise contraindicated (e.g., if their use poses a hazard to others). Patients at high risk for falling may need to be closely supervised while walking.

Environmental modifications can also help reduce the risk of falls. The removal of loose rugs, low tables, and other obstacles can diminish risk. The use of lower beds, night-lights, bedside commodes, and/or frequent toileting may help prevent falls at night. Although bed rails are thought to prevent patients from rolling out of bed, they may actually increase the risk of falls. Therefore, other environmental modifications such as lowering the bed or placing a mattress on the floor are typically recommended. Bed and chair monitors have also been suggested as a way to alert caregivers or nursing staff when patients may be getting out of bed or leaving a chair. In addition, programs for muscle strengthening and balance retraining have been shown to be helpful in reducing falls in elderly people (45). A physical therapy evaluation may be appropriate for certain patients. For patients in acute inpatient or nursing home settings, restraints are occasionally used on a temporary basis to reduce the likelihood of falling. Under such circumstances, documentation should reflect the rationale for the temporary use of restraints and should include a discussion of the other measures that were tried and failed to bring the behavior under control.

e. Abuse and Neglect

The psychiatrist should be alert to the possibility of elder abuse, financial exploitation, and neglect. Individuals with dementia are at particular risk for abuse because of their limited ability to protest, their lack of comprehension, and the significant demands and emotional strain on caregivers. Patients whose caregivers appear angry or frustrated may be at even higher risk. Any concern, especially one raised by the patient, must be thoroughly evaluated. Corroborating evidence (e.g., from physical examination) should be sought in order to distinguish delusions, hallucinations, and misinterpretations from actual abuse. In many states, when neglect or abuse is suspected, the psychiatrist is required to make a report to the appropriate local or state agency responsible for investigating elder abuse.

f. Wandering

Families should be advised that patients with dementia may wander away from home and that wandering may be dangerous to patients. Some patients are unable to find their way back, whereas others lack the judgment to recognize and deal with dangerous situations. Wandering has been associated with more severe dementia and dementia of longer duration. It has also been associated with depression, delusions, hallucinations, sleep disorders, neuroleptic medication use, and male gender (46). Provision of adequate supervision is important to prevent patients from wandering. However, since walking may be beneficial, both as stimulation and exercise, it should not be limited unnecessarily. Providing access to a large, safe area for walking or opportunities for supervised walks is ideal. Environmental changes may also be necessary to prevent unsupervised departures. At home, the addition of a more complex or less accessible door latch may be helpful. Electronic devices to reduce the risk of in-home wandering are under development. If wandering occurs at night when caregivers are asleep, pharmacological intervention may be indicated. In institutional settings, electronic locks or electronic devices that trigger an alarm when the patient tries to leave may be used.

Although a number of interventions of visual and other selective barriers such as mirrors, camouflage, and grids/stripes of tape have been tried, there is no evidence that these subjective barriers prevent wandering in cognitively impaired people (47). If patients are prevented from leaving on their own, adequate supervision must be provided to ensure emergency egress. Pharmacotherapy is rarely effective in the treatment of wandering unless the wandering is due to an associated condition such as mania.

In addition, provision should be made for locating patients should wandering occur. Such measures include sewing or pinning identifying information onto clothes, placing medical-alert bracelets on patients, and filing photographs with local police departments. Referrals to the Safe Return Program of the Alzheimer's Association (1-888-572-8566; http://www.alz.org/safereturn) or similar programs provided by local police departments or other organizations should be considered for patients at risk of wandering.

5. Advise the Patient and Family Concerning Driving (and Other Activities That Put Other People at Risk)

Most of the available evidence suggests that dementia, even when mild, impairs driving performance to some extent and that the risk of accidents increases with increasing severity of dementia (48). For example, compared to age-matched controls, individuals with probable Alzheimer's disease had more difficulties comprehending and operating a driving simulator, drove off the road more often, spent more time driving considerably slower than the posted speed limit, applied less brake pressure in stop zones, spent more time negotiating left turns, and drove more poorly overall (49). Nonetheless, it is well documented that many individuals with dementia, even some with fairly serious impairment, continue to drive, raising significant public health concerns (50–54).

In an office or hospital setting, accurate assessment of functional abilities such as driving is not possible (55). Furthermore, the influence of neuropsychiatric impairments or behavioral symptoms on driving performance is neither clear-cut nor predictive (56, 57). However, risks of driving should be discussed with all patients with dementia and their families, and these discussions should be carefully documented. Discussions should include an exploration of the patient's current driving patterns, transportation needs, and potential alternatives. The psychiatrist should also ask the family about any history of getting lost, traffic accidents, or near accidents. For patients with dementia who continue to drive, the issue should be raised repeatedly and reassessed over time. This is especially true for patients with Alzheimer's disease or other progressive dementias in which driving risk will predictably worsen over time (58).

At this time, there is no clear consensus regarding the threshold level of dementia at which driving should be curtailed or discontinued (48, 58–61). In mild dementia, the driving risk is greater than for age-matched individuals without dementia, although it is less than that for cognitively intact young drivers (e.g., younger than age 25 years) (48). Thus, some clinicians argue that in mild dementia the benefits to the patient of continued independence and access to needed services outweigh the risk of an accident. Other clinicians argue that no patient with a diagnosis of dementia should drive, because the risk of an accident is elevated even in patients with mild dementia, and it is impossible to say at what point this risk becomes unacceptable. In an evidence-based review of driving and Alzheimer's disease from the American Academy of Neurology, it was found that driving was only mildly impaired in drivers with a Clinical Dementia Rating (CDR) of 0.5 (mild cognitive impairment), but those with a CDR of 1 (mild or early stage dementia) were found to pose significant risks from increased vehicular accidents and poorer driving performance (48) (see Section I.V.E for information on the staging of dementia).

Additional increases in risk may also be associated with a diagnosis of dementia with Lewy bodies. Concomitant neurological symptoms such as motor deficits (e.g., due to stroke or a parkinsonian syndrome, impairments in praxis), sensory deficits (e.g., spatial neglect, visual loss, deafness), or deficits in judgment, coordination, processing speed, and reaction time are also thought to increase risk, although this view has not been confirmed by research (56, 62–64). Finally, general medical problems (e.g., symptomatic cardiac arrhythmia, syncope, seizures, poorly controlled diabetes) or the use of sedating medications may also impair driving ability. A history of at-fault traffic incidents may also signal increased risk (65). Thus, in individuals with mild dementia and one or more of these additional factors, driving cessation may be particularly indicated.

Patients with milder impairment may also need to consider giving up driving. For those who are unwilling to do so, it may be helpful to advise them to limit their driving to conditions likely to be less risky (e.g., familiar locations, modest speeds, good visibility, clear roads) (66). The patient's spouse or other individual may act as a navigator or assessor of driving skill, but the utility of this strategy is unproven, and passengers may be injured in the event of an accident (60, 61). Mildly impaired patients who wish to have an independent assessment of their driving skills may be referred to an occupational therapist, rehabilitation center, driving school, or local department of motor vehicles, but the predictive value of these assessments for actual driving performance has not been established.

In individuals with moderate impairment (e.g., those who cannot perform moderately complex tasks, such as preparing simple meals, household chores, yard work, or simple home repairs), there is some evidence and strong clinical consensus that driving poses an unacceptable risk and patients should be instructed not to drive (48, 59–61). risk and patients should be instructed not to drive (48, 59–61). Those with severe impairment are generally unable to drive and certainly should not do so.

Advice about driving cessation should be communicated to family members, as well as to the patient, because the burden of implementing the decision often falls on families. The psychiatrist can also lend moral authority and support to family members who wish to restrict driving but are reluctant to take responsibility for the decision (e.g., writing on a prescription pad, "DO NOT DRIVE"). Eventually, when the point is reached where the danger of continued driving is undeniable, the psychiatrist can provide concrete advice regarding how best to accomplish cessation of driving (e.g., confrontation regarding risks to grandchildren, discussion of the impact on insurance coverage and rates, removing the car from view, hiding the keys, or removing ignition wires). The American Medical Association publication, "Physician's Guide to Counseling and Assessing Older Drivers" (http://www.ama-assn.org/ama/pub/category/10791.html) may be helpful to some clinicians (67). When making recommendations to limit or stop driving, clinicians should be sensitive to the significant psychological meaning of giving up driving. In addition, patients and their families will need to make plans for alternative modes of transportation (60, 61, 68). A social service referral may be helpful for some families to help with transportation arrangements and costs.

Psychiatrists should familiarize themselves with state motor vehicle regulations for reporting individuals with dementia. In some states, disclosure is forbidden. In others, a diagnosis of dementia or Alzheimer's disease must be reported to the state department of motor vehicles, and the patient and family should be so informed. In many states, the physician may breach confidentiality to inform the state motor vehicle department of a patient who is judged to be a dangerous driver. This option is appropriate for patients with significant dementia who refuse to stop driving and whose families are unwilling or unable to stop them.

Although the data and recommendations just described refer to the operation of motor vehicles, similar principles apply to the operation of other equipment that puts the patient and others at risk. Thus, patients whose leisure or work activities involve firearms, use of heavy machinery, aircraft, lawn mowers, or other dangerous equipment or material will need to have these activities limited and discontinued as the disease progresses.

6. Provide Education and Support to Patients and Families

a. Educate the Patient and Family About the Illness and Available Treatments

An important task of the psychiatrist who cares for an individual with dementia is providing or coordinating the education of the patient and family regarding the illness and its natural history. Often the first step is to communicate and explain the diagnosis of dementia, including the specific dementia etiology, if known. Terms should be clarified at the outset to facilitate communication. Patients vary in their ability and desire to understand and discuss their diagnosis. Most mildly and some moderately impaired individuals are able to discuss the matter at some level, but the discussion must be adapted to the specific concerns and abilities of the patient; it may be helpful to seek the family's input regarding the nature and timing of any discussion with the patient (69). The issue of disclosure of the diagnosis to the patient is complex because many patients cannot recognize their deficits. Decisions about how to disclose should take into account factors such as cultural issues that might modify the patient's desire to receive such information (70). In most cases, the psychiatrist will have an explicit discussion with family members regarding the diagnosis, prognosis, and treatment options, adapted to the unique concerns of the patient and family. This discussion will likely span a number of office visits. Certain specific symptoms (e.g., psychosis, extrapyramidal symptoms) are predictive of more rapid decline and thus may be used in tandem with other features to assess prognosis (71).

It is important to educate the patient and family about the range of symptoms that could develop in the current stage of dementia or that may develop in the future. This education allows them to plan for the future and to recognize emergent symptoms that should be brought to medical attention. Family members and other caregivers may be particularly concerned about behavioral and neuropsychiatric symptoms, which they often associate with a loss of dignity, social stigma, and an increased caregiving burden. It may be helpful to reassure patients and their families that these symptoms are part of the illness and are direct consequences of the damage to the brain. Moreover, they may be relieved to know that although cognitive losses are generally not reversible, neuropsychiatric symptoms, especially the more disruptive ones, can often be improved or even eliminated with treatment, resulting in an overall increase in functional status and comfort. By treating these symptoms, educating family caregivers, and providing them with alternative strategies to deal with the patient's disruptive behaviors, the psychiatrist can help to minimize the caregivers' negative reactions to the patient's behavior (72). Section II.B.6.b includes suggestions for reading materials that may be helpful in providing education to families and caregivers.

The family should be educated regarding basic principles of care, including 1) recognizing declines in capacity and adjusting expectations appropriately, 2) bringing sudden declines in function and the emergence of new symptoms to professional attention, 3) keeping requests and demands relatively simple, 4) deferring requests if the patient becomes overly upset or angered, 5) avoiding overly complex tasks that may lead to frustration, 6) not confronting patients about their deficits, 7) remaining calm, firm, and supportive and providing redirection if the patient becomes upset, 8) being consistent and avoiding unnecessary change, and 9) providing frequent reminders, explanations, and orientation cues. For example, when arriving with visitors, families should say, "This is your nephew, your sister's son" rather than repeatedly testing a patient's memory by saying "Do you remember who this is?" It is also important to individualize the approach to the patient's needs, and, in this regard, psychiatrists and other mental health care professionals can offer more specific behavioral interventions that caregivers can use to avoid or deal with difficult behaviors. For additional details on such interventions, see Sections II.B.4.b and II.C.4.

b. Refer the Family to Appropriate Sources of Care and Support

Family members often feel overwhelmed by the combination of hard work and personal loss associated with caring for an individual with dementia. The caring and pragmatic attitude of the psychiatrist may provide critical support. This attitude may be expressed through thoughtful inquiries about current needs and how they are being met, advice about available sources of emotional and practical support, referrals to appropriate community resources, and supportive psychotherapy.

Programs have been developed that reduce the burden and lessen the stress and depression associated with long-term caregiving. These interventions include psychoeducational programs for coping with frustration or depression; psychotherapy focused on alleviating depression and anxiety, and improving coping; exercise interventions for caregivers; and workshops in stress management techniques (73–77). In addition, extensive clinical experience and substantial scientific literature demonstrate that support groups, especially those combining education with support, improve caregiver well-being (78–85). Support groups conforming to this general pattern are available in many localities through local chapters of the Alzheimer's Association and/or hospitals, community organizations, and religious groups. Support groups may vary widely in their approaches as well as composition, and caregivers may elect to try several before finding one that suits them. In addition to providing helpful information about the disease, how to care for someone with the disease, and ways to decrease caregiver burden, these groups may enhance the quality of life of patients and spouses or other caregivers and may delay nursing home placement (79, 86–88). Internet message boards and chat rooms may also be helpful for some caregivers.

In addition to providing families with information on support groups, there are a number of benefits of referral to the local chapter or national office of the Alzheimer's Association (1-800-272-3900; http://www.alz.org), the Alzheimer's Disease Education and Referral Center (ADEAR) (1-800-438-4380; http://www.nia.nih.gov/Alzheimers/), and other support organizations. Services offered by these organizations include providing information about local resources, operating hotlines staffed by well-informed volunteers, offering caregiver support services, and distributing a wide array of educational material written for patients, caregivers, and health professionals.

Many other resources provide logistical support for caregivers who are trying to care for individuals with dementia at home. Respite care allows the caregiver periods of relief from the responsibilities of dementia care. It provides essential physical and emotional support, serving the dual purposes of decreasing the burden of care and allowing caregivers to continue to work, participate in recreational activities, or fulfill other responsibilities. Respite care may last for hours to weeks and may be provided through companions, home health aides, visiting nurses, day care programs, and brief nursing home stays or other temporary overnight care. Depending on the available local resources and individual circumstances, these types of care may be available from local senior services agencies, from the local chapter of the Alzheimer's Association, religious groups, U.S. Department of Veterans Affairs facilities, or other community organizations. Although respite care clearly provides benefit for the caregiver, the evidence is mixed as to whether these programs actually delay institutionalization (89–93). Clinical experience suggests that by decreasing caregiver burden these programs may also improve the quality of life for patients and their families. Other resources that may be helpful include social service agencies, community-based social workers, home health agencies, cleaning services, Meals on Wheels, transportation programs, geriatric law specialists, and financial planners. Useful information for caregivers from the Family Caregiver Alliance is available at http://www.caregiver.org.

Many clinicians also recommend that families read articles or books written specifically for lay readers interested in understanding dementia and its care, such as The Thirty-Six Hour Day: A Family Guide to Caring for Persons With Alzheimer's Disease, Related Dementing Illness, and Memory Loss in Later Life (94); Mayo Clinic: Guide to Alzheimer's Disease: The Essential Resource for Treatment, Coping, and Caregiving (95); Practical Dementia Care (41); or The Complete Guide to Alzheimer's-Proofing Your Home (35) or view informational video media that may be available from the local Alzheimer's Association chapter or public library.

c. Watch for Signs of Caregiver Distress

With or without support, caregivers frequently become frustrated, overwhelmed, or clinically depressed (96). Among the causes of demoralization are the progressive nature of dementia and the patient's lack of awareness of the extent of support being provided. Psychiatrists caring for patients with dementia should be vigilant for these conditions in caregivers, because they increase the risk of substandard care, neglect, or abuse of patients and are a sign that the caregivers themselves are in need of care. Signs of caregiver distress include increased anger, social withdrawal, anxiety, depression, exhaustion, sleeplessness, irritability, poor concentration, increased health problems, and denial. When a caregiver is in significant distress, his or her need for greater psychosocial support should be evaluated. If treatment is indicated, it can be provided (according to the preference of psychiatrist, patient, and caregiver) by the patient's psychiatrist or through a referral to another mental health professional.

d. Support Families During Decisions About Institutionalization

When family members feel that they are no longer able to care for the patient at home, they may need both logistical and emotional support in placing the patient in a long-term-care facility (i.e., continuing care retirement community, group home, assisted living facility, or nursing home). Often, such transitions occur at times of crisis (e.g., medical hospitalizations or caregiver illness). The psychiatrist can be a valuable resource in informing families about the available options and helping them evaluate and anticipate their needs in the context of their values, priorities, and other responsibilities. The question of referral to a long-term-care facility should be raised well before it becomes an immediate necessity so that families who wish to pursue this option have time to select and apply for a suitable facility, plan for financing long-term care, and make needed emotional adjustments. A referral to a social service agency, social worker, or the local chapter of the Alzheimer's Association may assist with this transition. Some social service agencies provide comprehensive home service assessments that may help families recognize and address their needs.

7. Advise the Family to Address Financial and Legal Issues

Patients with dementia usually lose the ability to make medical, legal, and financial decisions as the disorder progresses, and consequently these functions must be taken over by others (97). Clinical evaluation, including cognitive testing when needed, can assist in determining whether a patient with Alzheimer's disease has the capacity to make medical decisions (98–100).

If family members act while the patient is still able to participate, they can seek his or her guidance regarding long-term plans. This approach can help in incorporating the patient's own wishes and values into the decision-making process, as well as in avoiding future conflict. Although the specific laws vary from state to state, advance planning regarding health care and finances can help families avoid the difficulty and expense of petitioning the courts for guardianship or conservatorship should such arrangements become necessary later in the illness. Issues that might be raised related to health care in the later stages of the illness include preferences about medical treatment, the use of feeding tubes, the care desired for infections and other potentially life-threatening medical conditions, and artificial life support. Medical decision making can be transferred in advance to a trusted family member (or friend) in the form of a durable power of attorney for health care or designation of a health care agent. For some patients, a living will or advance directive may also be appropriate, but which document is used and its specific features depend on the prevailing state law.

Patients and family members should be offered the opportunity to discuss preferences about participation in research studies early in the course of the illness, while the patient is still able to make his or her wishes known (101). The Alzheimer's Association has developed recommendations for Institutional Review Boards and investigators for obtaining research consent for cognitively impaired adults (102).

An individual's capacity to understand and give consent to a particular intervention (including taking of medications, particularly those with potentially significant side effects) will vary over time and with the nature and complexity of the intervention (99, 100). As individuals with dementia become more impaired, responsible family members are usually brought into the consent discussion. When a patient's capacity is diminished but still sufficient to give consent, consent or at least agreement is usually obtained from both patient and family member. Once a patient no longer has adequate decisional capacity, consent is obtained from either a health care proxy decision maker designated in an advance directive or a guardian, if either has been named. When such a legally designated decision maker does not exist, the closest relative is typically asked to provide consent. Nevertheless, the psychiatrist is encouraged to be familiar with local jurisdictional requirements, because procedures vary by state and some states require judicial review.

Patients may also transfer authority for legal and financial decision making in the form of a durable power of attorney for financial matters. At a minimum, it is recommended to include a family member as a cosigner on any bank accounts so that payment of expenses can proceed smoothly even when the patient is no longer able to complete the task him- or herself. In some instances, it may be a good idea to warn families about the vulnerability of individuals with dementia to unscrupulous individuals seeking "charitable" contributions, selling inappropriate goods, or promoting sweepstakes. If needed, the family can ask the patient to give up charge cards, ATM cards, and checkbooks to prevent the loss of the patient's resources. Clinicians should remain vigilant for evidence of exploitation of patients.

Patients should be advised to complete or update their wills while they are able to make and express decisions (103). Patients and families should also be advised of the importance of financial planning early in the illness. This advice may include a frank discussion regarding the financing of home health care and/or institutional care. Unfortunately, once the diagnosis of dementia is established, it is often too late to purchase long-term-care insurance, but careful planning in the early stages may help to lessen the burden of nursing home care or home health services later in the disease course. A patient with more complex financial issues should be referred to an attorney or financial planner to establish appropriate trusts, plan for transfer of assets, and make other financial arrangements.

The treatment of dementia varies through the course of the illness, because symptoms evolve over time. Although many symptoms can and do occur throughout the illness, certain symptoms are typical of the broad stages, as outlined in Section IV.E. This outline of stages conforms most to the typical course of Alzheimer's disease, but it does not apply as well to other types of dementias, particularly the frontotemporal dementia spectrum disorders.

The following sections provide general recommendations for treating patients in three stages of illness (mild, moderate, and severe) and specific recommendations for the implementation of select psychotherapeutic and pharmacological treatments. The evidence supporting the efficacy of these treatments is reviewed in Section V of this guideline. At each stage of the illness, the psychiatrist should be vigilant for cognitive and noncognitive symptoms likely to be present and should help the patient and family anticipate future symptoms. The family may also benefit from reminders to plan for the care likely to be necessary at later stages.

1. Mildly Impaired Patients

At the early stages of a dementing illness, patients and their families are often dealing with acceptance of the illness and recognition of associated limitations. They may benefit from pragmatic suggestions for how to cope with these limitations (e.g., making lists, using a calendar, avoiding overwhelming situations such as certain child-care responsibilities). Patients may benefit from referral to health promotion activities and recreation clubs (104). It may be helpful to identify specific impairments and highlight remaining abilities. Patients often experience a sense of loss and perceived stigma associated with the illness. Consequently, psychotherapeutic interventions may be helpful for patients who are struggling with the diagnosis and its implications. Features of treatment plan development for mildly impaired patients that have already been outlined in detail include addressing the issue of driving cessation (see Section II.B.5), assigning a durable power of attorney and addressing other legal and financial matters (see Section II.B.7), and addressing caregiver well-being (see Section II.B.6.b). Support groups for patients and families with mild Alzheimer's disease exist in many communities.

Patients with early Alzheimer's disease should be offered a trial of one of the three available cholinesterase inhibitors approved and commonly used for the treatment of cognitive impairment (i.e., donepezil, rivastigmine, galantamine), after a thorough discussion of their potential risks and benefits. Given the possible risks of long-term high-dose vitamin E and selegiline and the minimal evidence for their benefit, they are no longer recommended. Specific recommendations for implementing these treatments are provided in Section II.C.5.a. Mildly impaired patients may also be interested in referrals to local research centers for participation in clinical trials of experimental agents for the treatment of early Alzheimer's disease. Additional information regarding such trials may be obtained from a local or the national chapter of the Alzheimer's Association, from the National Institute on Aging, or at http://www.clinicaltrials.gov.

Mildly impaired patients should be evaluated for neuropsychiatric symptoms, especially depressed mood or major depression, which may require pharmacological or psychotherapeutic intervention, as described in Section II.C.5.c. Patients with moderate to severe major depression who do not respond to or cannot tolerate antidepressant medications should be considered for ECT. Mildly impaired patients should also be carefully assessed for suicidality, even if they are not obviously depressed.

2. Moderately Impaired Patients

As patients become more impaired, they are likely to require more supervision to remain safe, and safety issues should be addressed as part of every evaluation (see Section II.B.4). Families should be advised about the possibility of accidents due to forgetfulness (e.g., fires while cooking), of difficulties coping with household emergencies, and of the possibility of wandering. Family members should also be advised to determine whether the patient is handling finances appropriately and to consider taking over the paying of bills and other responsibilities. At this stage of the disease, nearly all patients should not drive. Families should be counseled to undertake measures to prevent patients from driving, as many patients lack insight into the risk that their continued driving poses to themselves or others (as described in Section II.B.5).

As a patient's dependency increases, caregivers may begin to feel more burdened. A referral for some form of respite care (e.g., home health aid, day care, brief assisted living, or nursing home stay) may be helpful. At this stage, families should begin to consider and plan for additional support at home as well as discuss the patient's possible transfer to a long-term-care facility. Family members may differ in their opinion of the patient's level of functioning and may have different psychological responses to the patient's impairments, generating family conflict. It may be beneficial to meet with family members to openly discuss these issues.

Treatment for cognitive symptoms should also be considered. For patients with Alzheimer's disease, currently available data suggest that the combination of a cholinesterase inhibitor plus memantine is more likely to delay symptom progression than a cholinesterase inhibitor alone during this stage of the illness. Specific implementation of these treatments is described in Section II.C.5.a.

Delusions and hallucinations are prevalent in moderately impaired patients, as are agitation and combativeness. The patient and family may be troubled and fearful about these symptoms, and it may be helpful to reassure them that the symptoms are part of the illness and are often treatable. Therapeutic approaches to these symptoms are described in Section II.C.5.b. For patients in whom wandering is the only symptom, pharmacotherapy will rarely be indicated. Depression often remains part of the picture at this stage and should be treated vigorously (105). The pharmacotherapy of behavioral and neuropsychiatric symptoms is described in Sections II.C.5.b, II.C.5.c, and II.C.5.d.

3. Severely and Profoundly Impaired Patients

At this stage of the illness, patients are severely incapacitated and are almost completely dependent on others for help with basic functions, such as dressing, bathing, and feeding. Families are often struggling with a combined sense of burden and loss and may benefit from a frank exploration of these feelings and any associated resentment or feelings of guilt. They may also need encouragement to get additional help at home or to consider transient respite or relocation of the patient to a nursing home.

Of the cholinesterase inhibitors, only donepezil has thus far been approved for use in late-stage disease, and some studies show that other members of this class may also be beneficial (106, 107). Memantine, which has been approved for use in severe dementia, may provide modest benefits and has few adverse effects (108). If the benefit of a medication is unclear, a brief medication-free trial may be used to assess whether continued treatment is worthwhile.

Depression may be less prevalent and more difficult to diagnose at this stage but, if present, should be treated vigorously. Psychotic symptoms and agitation are often present and should be treated pharmacologically if they cause distress to the patient or significant danger or disruption to caregivers or to other residents of long-term-care facilities.

At this stage, it is important to ensure adequate nursing care, including measures to prevent bedsores and contractures. The treatment team should help the family prepare for the patient's death. Ideally, discussions about feeding tube placement, treatment of infection, cardiopulmonary resuscitation, and intubation will have taken place when the patient could participate, but if they have not, it is important to raise these issues with the family before a decision about one of these options is urgently required.

Hospice care is an underused resource for patients with end-stage dementia (109, 110). Hospice provides physical support for the patient (with an emphasis on attentive nursing care and relief of discomfort rather than medical intervention) and emotional support for the family during the last months of life. A physician must certify that the patient meets hospice criteria for admission for hospice benefits to be available (111).

4. Implementation of Psychosocial Treatments

The psychiatric care of patients with dementia involves a broad range of general psychosocial interventions for the patient and his or her family, as introduced in Section II.B. In addition, some patients may benefit from more specific psychosocial interventions. These more specific psychosocial treatments for dementia can be divided into four broad groups: behavior oriented, emotion oriented, cognition oriented, and stimulation oriented. Although these treatment approaches differ in philosophy, focus, and methods, they share the broadly overlapping goals of improving quality of life and maximizing function in the context of existing deficits (see references 112 and 113 for a comprehensive review). Many of these therapies have the improvement of cognitive skills, mood, or behavior as an additional goal. All of these approaches reflect a person-centered philosophy of care in which an understanding of the individual is emphasized (114). For many individuals, several modalities will be selected at the same time. Because these treatments generally do not provide lasting effects, those that can be offered regularly may be the most practical and beneficial. These treatments are generally delivered daily or weekly. Beyond these considerations, the choice of therapy is generally based on the patient's characteristics and preference, availability of the therapy, and cost. For instance, some approaches are available only in institutional settings, such as nursing homes or day care centers, whereas others can be used at home.

Behavioral techniques and interventions are in wide clinical use with patients who have difficult-to-manage behavioral problems. There is some evidence for modest benefits of such therapies, particularly while the intervention is ongoing (112, 115, 116), but additional well-designed clinical trials are needed. There also is some evidence that behavioral interventions can reduce patients' depressive symptoms (117, 118).

Stimulation-oriented treatments (e.g., recreational activities or therapies, art therapies, exercise) are often included in the care of patients with dementia as well. They provide the kind of environmental stimulation that is recognized as part of humane care, and modest efficacy data exist that support their use for improving mood and reducing behavioral disturbances (117, 119–121).

Emotion-oriented treatments (e.g., reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration, simulated presence therapy) are often used in the treatment of patients with dementia to address issues of loss and to improve mood and behavior. Although there is modest research support for the effectiveness of reminiscence therapy for improvement of mood and behavior (122–124), none of these modalities has been subjected to rigorous scientific testing. Cognition-oriented treatments (e.g., reality orientation, cognitive retraining, skills training) may provide mild short-term improvements in selected domains of cognition, but such improvements, when achieved, are not lasting (125, 126).

Short-term adverse emotional consequences have sometimes been reported with psychosocial treatments. This is especially true of the cognitively oriented treatments, during which frustration, catastrophic reactions, agitation, and depression have been reported (86, 127). Thus, treatment regimens must be tailored to the cognitive abilities and frustration tolerance of each patient.

5. Implementation of Pharmacological Treatments

The following summarizes principles that underlie the pharmacological treatment of elderly patients and those with dementia (128). First, elderly individuals have decreased renal clearance and slowed hepatic metabolism, which alter the pharmacokinetics of many medications. Moreover, because elderly individuals may have multiple coexisting medical conditions and therefore may take multiple medications, it is important to consider how these general medical conditions and associated medications may interact to further alter the absorption, serum protein binding, metabolism, and excretion of the medication (129). Therefore, low starting doses, small dose increases, and long intervals between dose increases are necessary. This is true even in the inpatient setting, where utilization review pressures may encourage physicians to employ rapid titration schedules. However, some patients may ultimately need doses as high as would be appropriate for younger patients.

Pharmacodynamics may also be altered in elderly patients and those with dementia. As a result, certain medication side effects pose particular problems for elderly patients and those with dementia; medications with these side effects must therefore be used judiciously. Anticholinergic side effects may be more burdensome for elderly patients owing to coexisting cardiovascular disease, prostate or bladder disease, or other general medical conditions. These medications may also lead to worsening cognitive impairment, confusion, or even delirium (130). Orthostasis is common in elderly patients because of decreased vascular tone and medication side effects. As a result, elderly patients, especially those with dementia, are more prone to falls and associated injuries. Medications associated with central nervous system sedation may worsen cognition, increase the risk of falls, and put patients with sleep apnea at risk for additional respiratory depression. Finally, elderly patients, especially those with Alzheimer's disease, Parkinson's disease, or dementia with Lewy bodies, are especially susceptible to extrapyramidal side effects.

For all these reasons, medications should be used with considerable care, and polypharmacy should be avoided whenever possible. In nonemergency situations or when neuropsychiatric symptoms are not severe, nonpharmacological approaches should be attempted first to avoid the very significant morbidities associated with psychotropic medication use in elderly patients. Nonetheless, many elderly individuals with dementia manifest neuropsychiatric symptoms that do not respond to psychosocial or environmental interventions but may respond to psychotropic medications individually or in combination.

The sections that follow describe somatic therapies used to treat the cognitive symptoms and functional losses associated with dementia, as well as the prevalent neuropsychiatric symptoms of psychosis, anxiety, agitation, depression, apathy, and sleep disturbances. Although the sections are organized by these specific target symptoms, many medications have broader impact in actual practice.

a. Treatments for Cognitive and Functional Losses

Because there is no cure for most cases of dementia, the primary goal of medication treatment for cognitive symptoms in dementia is to delay the progression of symptoms, with the hope that this delay will translate into a preservation of functional ability, maintaining the patient for as long as possible at a particular level of symptom severity. However, no medication treatment has been shown to delay the progression of neurodegeneration.

A number of psychoactive medications are used to achieve these goals. The only FDA-approved medications for dementia or cognitive impairment are the cholinesterase inhibitors (tacrine, donepezil, rivastigmine, and galantamine), memantine, and the combination of ergoloid mesylates (approved for nonspecific cognitive decline). In addition, other drugs, including vitamin E, ginkgo biloba, and selegiline (approved by the FDA for treatment of Parkinson's disease and in patch form for the treatment of depression), are occasionally used for this purpose in selected patients, although they are not generally recommended, because their efficacy and safety are uncertain.

Several other medications that had been proposed for the treatment or prevention of cognitive decline, including NSAIDs, statin medications, and estrogen supplementation (with conjugated equine estrogens), have shown a lack of efficacy and safety in placebo-controlled trials in patients with Alzheimer's disease and therefore are not recommended. Many additional agents are currently being tested. Participation in clinical trials is another option available to patients with dementia.

Certain interventions for specific medical conditions such as the use of antihypertensive medications to control blood pressure, use of aspirin to prevent further strokes, and prescription of levodopa as a general treatment of Parkinson's disease may also lead to positive effects on cognition but are beyond the purview of this practice guideline.

In 1993 tacrine became the first agent approved specifically for the treatment of cognitive symptoms in Alzheimer's disease. Tacrine is a reversible cholinesterase inhibitor with evidence for efficacy from multiple double-blind placebo-controlled trials (131–135) that is thought to work by increasing the availability of intrasynaptic acetylcholine in the brains of patients with Alzheimer's disease. The FDA approved other cholinesterase inhibitors—donepezil, rivastigmine, and galantamine—in 1997, 2000, and 2001, respectively, for treatment of cognitive decline in mild to moderate Alzheimer's disease. These agents are now preferred over tacrine because of tacrine's reversible hepatic toxicity and the requirement that it be given 4 times per day. Evidence for the efficacy of these medications in mild to moderate Alzheimer's disease also comes from a substantial number of randomized, double-blind, placebo-controlled trials of donepezil (136–146), rivastigmine (147–152), and galantamine (153–159). Results of a smaller number of clinical trials (106, 107) suggested that cholinesterase inhibitors might have some limited benefits in severe Alzheimer's disease. In 2006, donepezil was approved by the FDA for this indication.

Given the evidence from randomized controlled trials for modest improvement in some patients treated with cholinesterase inhibitors and the lack of established alternatives, it is appropriate to offer a trial of one of these agents for patients with mild or moderate Alzheimer's disease for whom the medication is not contraindicated. Many clinicians in fact prescribe cholinesterase inhibitors for patients with the entire range of Mini-Mental State Examination (MMSE) scores, with moderate medical or psychiatric comorbidity, or with possible Alzheimer's disease, even though these patients would not have been eligible for most clinical trials completed to date. Whenever cholinesterase inhibitors are prescribed, patients and their families should be apprised of the limited potential benefits as well as the potential costs.

Results of the numerous large placebo-controlled trials of individual cholinesterase inhibitors have suggested similar degrees of efficacy, although tolerability may differ among the medications. Nonetheless, currently available data do not allow a fair, unbiased direct comparison among the cholinesterase inhibitors. Four clinical trials have compared cholinesterase inhibitors (two compared donepezil and galantamine, and two compared donepezil and rivastigmine) (160–163), but a number of these studies have significant methodological problems and none resolves the question of superiority (164). There are also no data on whether or how to switch from one cholinesterase inhibitor to another.

As would be expected with cholinesterase inhibitors, common side effects in clinical trials are associated with cholinergic excess, particularly nausea and vomiting, but these symptoms tend to be mild to moderate in severity for all agents. In the randomized clinical trials noted earlier, these side effects were observed in approximately 10%–20% of patients (136–159). Additional cholinergic side effects include muscle cramps; bradycardia, which can be dangerous in individuals with cardiac conduction problems; decreased appetite and weight; and increased gastrointestinal acid, a particular concern in those with a history of ulcers. These side effects occur infrequently with these agents, but bradycardia should be considered a relative contraindication to their use. In general, cholinergic side effects tend to wane within 2–4 days, so if patients can tolerate unpleasant effects in the early days of treatment, they may be more comfortable later on. Finally, cholinesterase inhibitors may induce or exacerbate urinary obstruction, worsen asthma and chronic obstructive pulmonary disease, cause seizures, induce or worsen sleep disturbance, and exaggerate the effects of some muscle relaxants during anesthesia.

Reversible, direct medication-induced hepatotoxicity with hepatocellular injury is a unique property of tacrine, occurring in approximately 30% of those taking it 6–8 weeks after initiating the medication (165). Because of this hepatotoxicity, tacrine is very uncommonly used. Hepatotoxicity has not been associated with donepezil, rivastigmine, or galantamine.

The main contraindication to use of cholinesterase inhibitors is hypersensitivity to the individual drugs. Some considerations in limiting treatment include the existence of gastrointestinal disorders such as gastritis, ulcerative disease, or undiagnosed nausea and vomiting, because cholinesterase inhibitors will increase gastric acid secretions. Cholinesterase inhibitors should also be used with care in patients with sick sinus syndrome or conduction defects, cerebrovascular disease, or seizures, as well as in patients with asthma or chronic obstructive pulmonary disease.

With respect to dosing and dosage, donepezil is given once per day, usually starting at 5 mg/day. This dosage can be increased to 10 mg/day, if tolerated. Some clinicians start treatment with 2.5 mg/day for patients who are frail or very sensitive to medication side effects and increase the dose by 2.5-mg increments. Galantamine is started at 8 mg/day in divided doses and increased gradually to a target range of 16–24 mg/day in divided doses, although certain patients may benefit from dosages up to 32 mg/day. A once-daily formulation of galantamine has recently been released. Rivastigmine is started at 3 mg/day in divided doses and increased gradually to a target range of 6–12 mg/day in divided doses. Doses may be titrated upward every 4 weeks. Slower titration can be helpful in managing side effects, if these occur. Higher dosages may be effective in some patients when lower dosages are not; therefore, patients who have not shown clear benefit while taking a lower dosage should receive an increased dose, if tolerated, before the conclusion is made that the medication is ineffective. Minimal effective dosages are 5 mg/day for donepezil, 16 mg/day for galantamine, and 6 mg/day for rivastigmine.

It is uncertain how long patients should be treated with cholinesterase inhibitors. Data from placebo-controlled clinical trials have demonstrated benefits over placebo for 6 months to 2 years with donepezil (136, 137, 139), for up to 1 year with rivastigmine (150), and for up to 6 months with galantamine (156). A number of open-label extension clinical trials have been conducted examining the efficacy of these agents beyond the time in which placebo controls were actually used. Subjects who continued to take the study drug were compared to a "historical" control group, namely a projection of the decline of a placebo control group. The authors of these studies claimed to demonstrate ongoing efficacy beyond the conclusion of the actual placebo-controlled trials, but comparisons using projected outcomes of a placebo group are methodologically problematic and do not establish efficacy.

In practice, the decision whether to continue treatment with cholinesterase inhibitors is a highly individualized one. Reasons that patients choose to stop taking these medications include side effects, adverse events, lack of motivation, lack of perceived efficacy, and cost. Individual patients may be observed to have some stabilization of symptoms or slowing of their decline. Under these circumstances, a physician might consider continuing the medication. Conversely, a patient who is declining rapidly despite taking cholinesterase inhibitors may be considered a medication nonresponder, and the medication can be discontinued. Discontinuation of cholinesterase inhibitor medication during placebo-controlled trials after 12–24 weeks has been associated with a regression of cognitive improvement to the level of the associated placebo group. Whether resumption of the cholinesterase inhibitor reverses this symptomatic worsening is unclear. Some patients have shown pronounced deterioration within several weeks of discontinuing cholinesterase inhibitors and improvement when the medication has been restarted. In contrast, the results of one study suggested that donepezil-treated patients who had treatment interrupted for 6 weeks and then restarted treatment never regained cognition back to the level achieved before medication discontinuation (166).

Trials of cholinesterase inhibitors in patients with vascular dementia and mixed dementia have produced inconclusive results. In addition, serious concerns about safety and potential increases in mortality have arisen with the use of these medications in this patient population (167). As a result of these factors, as well as the lack of FDA approval for this indication (see Sections III.B.4 and V.B.1.a.2), no specific recommendation can be made in favor of the routine use of cholinesterase inhibitors in patients with vascular dementia at this time, although individual patients may benefit from their use.

Cholinesterase inhibitors could be considered for patients with dementia with Lewy bodies. Dosing and titration are similar to those for patients with Alzheimer's disease (168, 169).

Cholinesterase inhibitors should be considered for patients with mild to moderate dementia associated with Parkinson's disease. Only rivastigmine has been studied in a randomized, double-blind, placebo-controlled trial (170) with an open-label extension (171) and approved by the FDA for this indication. Nevertheless, there is no reason to believe the benefit is specific to this cholinesterase inhibitor. Dosing and titration are similar to those for patients with Alzheimer's disease.

The term "mild cognitive impairment" describes a heterogeneous group of individuals, with some patients in the earliest stages of Alzheimer's disease and others suffering from other conditions. There are no FDA-approved medications for the treatment of mild cognitive impairment at this time. Clinical trials of cholinesterase inhibitors for mild cognitive impairment have enrolled a narrower and better defined population of patients with mild cognitive impairment than most clinicians actually treat in practice, but even with these well-defined patients the evidence from clinical trials supporting use of cholinesterase inhibitors is weak (172, 173). Given the inconclusive data, the potential safety concerns that exist with this class of medications in this patient population, and the lack of FDA approval for this indication (reviewed in Sections V.B.1.a.4 and II.C.5.a.1.a), no specific recommendation can be made in favor of routine use of cholinesterase inhibitors in patients with mild cognitive impairment at this time. Nonetheless, individual patients may benefit from their use.

Memantine is a noncompetitive NMDA receptor antagonist approved by the FDA for the treatment of moderate to severe Alzheimer's disease.

Given the evidence for its efficacy in randomized controlled trials (174, 175), memantine should be considered for treatment of patients with moderate to severe Alzheimer's disease. Memantine can be prescribed for people either currently taking or not taking a cholinesterase inhibitor. There is modest evidence that the combination of memantine and donepezil is better than donepezil alone (175), but there is no evidence that this combination is better than memantine alone. There are not yet data to argue for or against the use of memantine beyond 6 months (108, 176).

In patients with mild Alzheimer's disease, the evidence is suggestive of a small clinical benefit of memantine over placebo (108, 177), although this result is not conclusive and additional trials should be performed. Given that there are few safety concerns with the use of memantine in mild Alzheimer's disease, clinicians may consider using it for individual patients.

For vascular dementia, the evidence does not support the use of memantine (178, 179), although further trials are necessary.

Reported adverse events with memantine are infrequent, appear to be mild, and include confusion, dizziness, headache, sedation, agitation, falls, and constipation (174, 175, 177). Dropout rates during clinical trials have generally been the same for memantine as for placebo.

Memantine treatment begins at 5 mg once daily, and this dosage is increased by 5 mg/day every week until a target dosage of 10 mg b.i.d. is reached. A therapeutic dosage range for memantine has not been conclusively established. One study demonstrated efficacy at a dosage of 10 mg/day (180), and the effects of dosages above 20 mg/day have not been studied. Because memantine is cleared primarily by the kidneys, lower dosages (e.g., 10 mg/day) should be considered in patients with compromised renal function.

Vitamin E is no longer recommended for the treatment of cognitive symptoms of dementia. Previous recommendations for its use had balanced the weakness of the evidence for its efficacy with the perceived lack of risk with use of vitamin E. However, new safety concerns, namely the unexpected findings of increased dose-dependent mortality in a meta-analysis of vitamin E clinical trials (181) and an increased rate of heart failure with vitamin E treatment in a large randomized trial of cancer and heart disease prevention in individuals with diabetes mellitus and/or vascular disease (182), make the case for its use much less compelling. The evidence from the one placebo-controlled, double-blind, multicenter trial of vitamin E for the treatment of moderate Alzheimer's disease is limited (183). Furthermore, vitamin E failed to show efficacy in one study of individuals with mild cognitive impairment (173). In this trial nearly one-half of the subjects later received a diagnosis of Alzheimer's disease during the 3 years of observation and hence had early Alzheimer's disease at the beginning of the trial. Nevertheless, after considering the potential risks and benefits of vitamin E, some physicians and their patients may elect to use it, particularly at doses at or below 400 IU daily. Because vitamin E has been associated with worsening of coagulation defects in patients with vitamin K deficiency (184), it should be avoided in this population.

A number of medications marketed for other indications have been proposed for the treatment of dementia on the basis of epidemiological data or pilot studies (185–189), but they are not recommended for routine use at this time because of lack of efficacy in subsequent studies (190–200) and potential for adverse effects. These other agents include aspirin and other NSAIDs, hormone replacement therapy, the hormone melatonin, the botanical agent ginkgo biloba, the chelating agent desferrioxamine, the irreversible monoamine oxidase B (MAO-B) selective inhibitor selegiline, and a mixture of ergoloid mesylates currently marketed under the trade name Hydergine. Because some of these agents are popular, psychiatrists should routinely inquire about their use and should advise patients and their families that some of these agents are marketed with limited quality control and have not been subjected to adequate efficacy evaluations.

b. Treatments for Psychosis and Agitation

As discussed in Section II.B.3, psychosis and agitation occur commonly in patients with dementia and are important targets of psychiatric intervention. In DSM-IV-TR Alzheimer's disease and other dementias with delusions and hallucinations and Alzheimer's disease with behavioral disturbances are classified separately, and provisional criteria for psychosis of Alzheimer's disease have been published (201). In clinical practice, however, these symptoms frequently co-occur.

Treatments that decrease psychotic symptoms (delusions and hallucinations) and associated or independent behavioral disturbances such as aggression, combativeness, and agitation are often essential to increasing the comfort and safety of patients and easing the burden of provision of care by families and other caregivers.

Clinicians facing the challenge of treating patients with significant psychosis or behavioral disturbances must weigh the risk of not treating these complications of dementia against the risks of active treatment described below in Sections II.C.5.b.1, II.C.5.b.2, II.C.5.b.3, and II.C.5.b.4. This weighing of risks also includes consideration of the evidence supporting the efficacy of the agent in question, the patient's overall medical condition, and the evidence of risk and benefit of any potential treatment alternatives, followed by documentation of the reasons for using the medication and the fact that a discussion has taken place with the patient or caregiver.

As outlined in Section II.C.4, there are a number of nonpharmacological interventions that can be used before a trial of an antipsychotic or other medication is begun. Consideration and use of behavioral, psychosocial, and psychotherapeutic treatments is particularly critical, given the large number and potential severity of side effects associated with pharmacotherapy. Interventions for psychosis should be guided by the patient's level of distress and the risk to the patient, caregivers, or other patients. If psychotic symptoms cause minimal distress to the patient and are unaccompanied by agitation or combativeness, they are best treated with environmental measures, including reassurance and redirection. If the symptoms do cause significant distress or are associated with behavior that may place the patient or others at risk, treatment with low doses of antipsychotic medication is indicated in addition to nonpharmacological interventions. Treatment with an antipsychotic medication is also indicated if a patient is agitated or combative in the absence of psychosis, as this indication for antipsychotic use has significant support in the literature. The use of these agents should be reevaluated and their benefit documented on an ongoing basis. When antipsychotics are ineffective, carbamazepine, valproate, or an SSRI may be used in a careful therapeutic trial. If behavioral symptoms are limited to specific times or settings (e.g., a diagnostic study), or if other approaches fail, a low-dose benzodiazepine may prove useful, although side effects in elderly patients can be problematic (see Section II.C.5.b.2). Although mood stabilizers and SSRIs are commonly used in clinical practice to treat agitation, delusions, and aggression, they have not been consistently shown to be effective in treating these symptoms, nor is there substantial evidence for their safety. Thus, in making decisions about treatment, these agents should not be seen as having improved safety or comparable efficacy, compared to antipsychotic medications.

As a dementing illness evolves, psychosis and agitation may wax and wane or may change in character. As a result, the continued use of any intervention for behavioral disturbances or psychosis must be evaluated and justified on an ongoing basis. In the nursing home setting, this clinical recommendation is also a requirement under regulations of the Federal Nursing Home Reform Act of the Omnibus Budget Reconciliation Act of 1987 (see Section III.C.3). In addition, periodic reevaluation and revision of the treatment plan, including a change in dose, a change in medication, or medication discontinuation, may be indicated. Patients whose symptom severity was relatively low at the time of medication initiation may be more easily withdrawn from psychotropic medications than those with more severe symptoms at the time of treatment initiation (202).

Antipsychotics are the primary pharmacological treatment available for psychotic symptoms in dementia. They are also the most commonly used and best-studied pharmacological treatment for agitation. There is considerable evidence from randomized, double-blind, placebo-controlled trials and meta-analyses for the efficacy of both first-generation (203–217) and second-generation agents (201, 212, 218–227), although this benefit is often modest. Findings from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE-AD) study, funded by the National Institute of Mental Health (NIMH), failed to demonstrate conclusive benefits of second-generation antipsychotics over placebo in patients with Alzheimer's disease and psychosis or aggression, although there were advantages to the medications on certain outcome variables and the discontinuation rate due to lack of efficacy was lower with olanzapine and risperidone than it was for placebo or quetiapine (228).

Given the side effects and potential toxicity of antipsychotic agents (225, 228), the risks and benefits of these medications must be reassessed on an ongoing basis. The lowest effective dose should be sought, and emergent side effects should first be treated by dose reduction. Because of the risks involved with the use of antipsychotics, indications for their use should be generally limited to psychosis or behavioral disturbances, and they should not be used primarily for sleep disorders or anxiety. In addition, periodic attempts (e.g., every several months) to reduce or withdraw antipsychotic medications should be considered for all patients, while weighing the probability of a relapse and the dangerousness of the target behavior(s) (229). In general, agents with significant anticholinergic properties should be avoided in patients with dementia, although they may be considered under specific circumstances.

Mild to moderate adverse effects of antipsychotics include akathisia, parkinsonism, sedation, peripheral and central anticholinergic effects, delirium, postural hypotension, cardiac conduction defects, urinary tract infections, urinary incontinence, and falls. Antipsychotic agents are also associated with a risk of more serious complications that must be considered in weighing the risks and benefits of antipsychotic treatment (see Section V.B.2.a.2 for additional details). Serious complications include tardive dyskinesia (the incidence of which increases with dose and duration of treatment and which occurs more commonly in women, in individuals with dementia or brain injury, and in elderly patients in general), neuroleptic malignant syndrome (a rare but potentially lethal adverse effect of antipsychotic medications that occurs less frequently with second-generation antipsychotic agents), agranulocytosis (with clozapine), hyperlipidemia, weight gain, diabetes mellitus, cerebrovascular accidents, and death. An increased risk of cerebrovascular accidents has recently been found with the second-generation antipsychotics aripiprazole, olanzapine, and risperidone, although not with quetiapine. Meta-analyses of clinical trials of the second-generation antipsychotics aripiprazole, olanzapine, quetiapine, and risperidone (225), as well as of first-generation antipsychotics (230), have found an increased mortality when used in elderly patients with dementia. These concerns have led to "black box" warnings on the second-generation antipsychotics (231).

Accepted clinical practice is to prescribe antipsychotic agents at standing doses rather than as needed, although as-needed doses may be appropriate for symptoms that occur infrequently. Oral administration is generally preferred, although an intramuscular injection may sometimes be used in an emergency or when a patient is unable to take medications by mouth (e.g., for a surgical procedure). Low starting dosages are recommended, e.g., 0.25–0.5 mg/day of haloperidol, 0.25–1.0 mg/day of risperidone, 12.5 mg/day of clozapine, 1.25–5.0 mg/day of olanzapine, 12.5–50 mg/day of quetiapine. The best starting dosages for aripiprazole and ziprasidone are not known, although the available evidence suggests that 5 mg/day of aripiprazole may be safe for most patients. The dose can be increased on the basis of the response of the target symptom(s). The usual maximum dosages of these agents for patients with dementia are 2 mg/day of haloperidol, 1.5–2 mg/day of risperidone, 75–100 mg/day of clozapine, 200–300 mg/day of quetiapine, 10 mg/day of olanzapine, and 15 mg/day of aripiprazole. In addition, risperidone causes fewer extrapyramidal symptoms when used at dosages of 1 mg/day than when used at higher doses (218). Clinicians should keep in mind that these medications take time to work and that increasing doses too rapidly may lead to the development of side effects rather than more rapid efficacy. Although most patients with dementia do best with dosages below these maxima, younger and less frail individuals may tolerate and respond to somewhat higher doses, and very severely agitated patients may also need higher dosages. In contrast, antipsychotic agents must be used with extreme caution in patients with dementia with Lewy bodies or Parkinson's disease, who can be exquisitely sensitive to the extrapyramidal effects of these agents (232).

There are few relative efficacy data to guide the choice among second-generation antipsychotic agents. The CATIE-AD trial did not find significant differences in efficacy or tolerability among olanzapine, quetiapine, and risperidone, although the time to discontinuation due to lack of efficacy was longer for olanzapine and risperidone than for quetiapine (228). Instead, the choice is based most often on the side effect profile. As the overall side-effect burden appears to be lower with second-generation agents, drugs in this class are usually selected first. Widespread clinical practice is to select the agent whose most common side effects are least likely to cause problems for a given patient. For instance, clozapine might be avoided if the patient is likely to be sensitive to anticholinergic effects, or an agent lacking significant motor side effects such as aripiprazole, clozapine, or quetiapine might be chosen if the patient has Parkinson's disease, dementia with Lewy bodies, or other sensitivity to extrapyramidal side effects. Aripiprazole and quetiapine may be better first choices because their overall side effect profile is more benign than that of clozapine (233–237).

The side effects of some medications might actually be beneficial for certain patients. For example, a more sedating medication could be given at bedtime for a patient who has difficulty falling asleep in addition to agitation or psychosis. Antipsychotics are most commonly administered in the evening, so that maximum blood levels occur when they will help foster sleep and treat behavioral problems that peak in the evening hours (sometimes called "sundowning"). Most of these medications have long half-lives, and once-a-day dosing is generally sufficient. The one exception may be quetiapine, which is usually administered twice daily. However, morning doses or twice-a-day doses of the other agents may be helpful for patients with different symptom patterns.

The availability of a specific formulation of an antipsychotic may also contribute to the choice of a particular agent. Some antipsychotics are available in liquid form (e.g., aripiprazole, risperidone, ziprasidone, fluphenazine, haloperidol), and some (e.g., clozapine, olanzapine, risperidone, aripiprazole) are available as rapidly dissolving wafers. Olanzapine, ziprasidone, aripiprazole, fluphenazine, and haloperidol are available in a rapid-onset injectable form, whereas risperidone, haloperidol, and fluphenazine are available in long-acting injectable forms. With the exception of olanzapine (223), these formulations have not been studied in patients with dementia.

Benzodiazepines may have a higher likelihood of side effects and a lower likelihood of benefit than antipsychotics (223, 238–243); nonetheless, they are occasionally useful in treating agitation in certain patients with dementia, particularly those in whom anxiety is prominent. Their long-term use is generally to be avoided, but they may be particularly useful on an occasional as-needed basis for patients who have only rare episodes of agitation or those who need to be sedated for a particular procedure, such as a tooth extraction or a diagnostic study. Given the risk of disinhibition and consequent worsening of target behaviors, oversedation, falls, and delirium, their use should be kept to a minimum, with a maximum of 1–3 mg of lorazepam (or equivalent doses of other benzodiazepines) in 24 hours.

Among the benzodiazepines, many clinicians favor agents such as oxazepam and lorazepam that do not require oxidative metabolism in the liver and have no active metabolites. Temazepam shares these characteristics but is more problematic because of its long half-life. Oral lorazepam (or intramuscular in the event of an emergency) may be given on an as-needed basis in doses from 0.5 to 1.0 mg every 4–6 hours. Standing oral doses of 0.5–1.0 mg may be given from 1 to 4 times per day. Oxazepam is absorbed more slowly, so it is less useful on an as-needed basis. Standing doses of 7.5–15.0 mg may be given 1 to 4 times per day. Some clinicians prefer long-acting agents, such as clonazepam (starting at 0.5 mg/day with increases up to 2 mg/day) (244). However, such agents must be used with caution as described in the next paragraph.

The most commonly reported side effects with benzodiazepines are sedation, ataxia, amnesia, confusion (even delirium), and possibly paradoxical anxiety. These can lead to worsening cognition and behavior and increase the risk of falls (245). Benzodiazepines also carry a risk of respiratory suppression in patients with sleep-related breathing disorders. Because all of these effects are dose related, the minimum effective dose should be used. Agents with long half-lives (e.g., clonazepam) and long-lived metabolites (e.g., diazepam, chlordiazepoxide, clorazepate, flurazepam) can take weeks to reach steady-state levels, especially in elderly patients, so they generally are not used in this patient population. Under unusual circumstances when they have to be used, it must be with particular caution, with very low starting doses and very gradual dosage increases. Elderly patients taking long-acting benzodiazepines are more likely to fall, and to suffer hip fractures, than those taking short-acting agents (246), although it is possible that the total dose, not the duration of action, is responsible for the increased fall risk (247). Clinical experience suggests that like alcohol, benzodiazepines may lead to disinhibition, although there are few data to support this association. The risk of benzodiazepine dependence is also a concern. If benzodiazepines are prescribed for an extended period (e.g., 1 month), they should be tapered rather than stopped abruptly because of the risk of withdrawal.

There is some evidence to suggest that carbamazepine may have modest benefit for agitation when used in low doses in patients with dementia (248–252). However, given the relatively small body of clinical trials evidence, the high risk of drug-drug interactions, and the known tolerability problems expected with long-term use, carbamazepine is not recommended for the routine treatment of agitation in patients with dementia.

Routine use of valproate to treat behavioral symptoms in dementia is not recommended based on the current evidence. Most (253–255), but not all (256), randomized placebo-controlled trials showed no benefit of valproate, compared with placebo. In addition, a 2004 Cochrane review (257) concluded that the various formulations of valproate had not yet been shown to be effective.

Nonetheless, a therapeutic trial of carbamazepine or valproate may be considered in individual cases (258), for example, in patients who are sensitive or unresponsive to antipsychotics, who have significant vascular risk factors, or who do not have psychosis but are mildly agitated. Given the potential toxicity of both of these anticonvulsant agents, it is important to identify and monitor target symptoms and to discontinue the medication if no improvement is observed.

If used, carbamazepine may be given in two to four doses per day, started at a total dosage of 50–100 mg/day, and increased gradually as warranted by behavioral response and side effects or until blood levels reach 8–12 ng/ml. Divalproex sodium may be given in two or three doses per day and should be started at 125–250 mg/day, with gradual increases based on behavioral response and side effects or until blood levels reach 50–60 ng/ml (or, rarely, 100 ng/ml).

The principal side effects of carbamazepine include ataxia, falls, sedation, and confusion, all of which are of particular concern for elderly patients and those with dementia. Carbamazepine can cause drug interactions through its effect on the cytochrome P450 system. In rare instances, carbamazepine can lead to bone marrow suppression or hyponatremia through the syndrome of inappropriate antidiuretic hormone secretion. Valproate's principal side effects are sedation, gastrointestinal disturbances, confusion, ataxia, and falls. Bone marrow suppression, hepatic toxicity, thrombocytopenia, and hyperammonemia can occur. Many clinicians monitor the CBC and electrolyte levels in patients taking carbamazepine and monitor the CBC and liver function values in patients taking valproate, owing to the possibility of bone marrow suppression, hyponatremia, and liver toxicity. However, these practices are not followed by all clinicians. A particularly cautious approach is warranted when treating elderly patients and those with dementia, who may be more vulnerable to adverse effects, particularly central nervous system effects, and yet less likely to be able to report warning symptoms.

For additional details concerning the assessment and monitoring necessary during use of these agents, along with their side effects and potential toxicities, the reader is referred to APA's Practice Guideline for the Treatment of Patients With Bipolar Disorder, 2nd edition (259).

Support for the use of trazodone or buspirone is limited to data from case series and small clinical trials (214, 260–269). Therefore, neither agent can be recommended for the routine treatment of agitation and psychosis in patients with dementia. Although the evidence suggesting efficacy of SSRIs for agitation is somewhat stronger (262, 270, 271), further study is needed before they can be recommended for routine use. Nonetheless, a therapeutic trial of trazodone, buspirone, or an SSRI may be appropriate for some nonpsychotic but agitated patients, especially those with relatively mild symptoms or those who are intolerant of or unresponsive to antipsychotics.

When patients are taking SSRIs, clinicians need to keep in mind the serotonin syndrome, caused by excessive serotonergic activity, usually as a result of serotonergic medications being combined (including buspirone and SSRIs). Symptoms include delirium, autonomic instability, and increased neuromuscular activity, such as myoclonus.

When trazodone is used, the principal side effects are postural hypotension, sedation, and dry mouth. Priapism can occur but is uncommon. Trazodone is generally given before bedtime but can be given in two or three divided doses per day. It can be started at 25–50 mg/day and gradually increased to a maximum dosage of 150–250 mg/day.

When male patients display inappropriate sexual behavior, a particular problem in patients with frontal lobe dementias, medroxyprogesterone and related hormonal agents are sometimes recommended (272–274), a recommendation supported only by case series at present. Because SSRIs may reduce libido and are probably safer, they may be tried before hormonal agents (275).

Lithium carbonate has also been suggested as a treatment for agitation because of its occasional utility for agitated patients with mental retardation, but support for it is quite limited, and side effects and toxicity are common, including delirium (210). Therefore, routine use of lithium to treat agitation in patients with dementia is not recommended.

Beta-blockers, notably propranolol, metoprolol, and pindolol, have also been reported to be helpful for some agitated patients with dementia (276). However, most of the patients included in the case reports had somewhat atypical clinical features, raising questions about the generalizability of these reports. In addition, large dosages (e.g., 200–300 mg/day of propranolol) were used, and such dosages create a considerable risk of bradycardia, hypotension, and delirium for elderly patients. One small randomized, double-blind, placebo-controlled trial of propranolol in patients with Alzheimer's disease and behavioral disturbance did show benefit over placebo for certain symptoms although it was noted that beta-blocker use was contraindicated for many subjects who would otherwise have been eligible for the study (277). Therefore, routine use of beta-blockers to treat agitation in patients with dementia is not recommended.

c. Treatments for Depression and Related Symptoms

Recognition and treatment of depression is crucial in individuals with dementia, because the presence of depression has been associated with higher rates of disability, impaired quality of life, and greater mortality (278). The best approach to diagnosing depression in the context of dementia is not yet clear. Provisional criteria for depression of Alzheimer's disease have been proposed but not yet validated (279). The Depression and Bipolar Support Alliance Consensus Statement Panel reported that the diagnostic criteria for depression in individuals with dementing disorders must be revised (105). They recommended that the criteria take into account the instability and fluctuation of symptoms over time, the reduction in positive affect or pleasure, and the inclusion of irritability, social withdrawal, and isolation as indicators of depression. Until criteria for depression in dementia are established, patients should be carefully evaluated for any of the symptoms of depression outlined in DSM-IV-TR. Even those patients with depressive symptoms who do not meet the diagnostic criteria for major depression should be considered as candidates for depression treatment. The presence of neurovegetative symptoms, suicidal ideation, and mood-congruent delusions or hallucinations may indicate a need for more vigorous and aggressive therapies (such as higher medication dosages, multiple medication trials, or ECT).

Depression may worsen cognitive impairment associated with dementia. Therefore, one goal of treating depression in dementia is to maximize cognitive functioning. Sometimes cognitive deficits partially or even fully resolve with successful treatment of the depression. Nonetheless, because as many as one-half of such persons do develop dementia within 5 years (280, 281), caution is urged in ruling out an underlying early dementia in patients with both affective and cognitive symptoms, particularly when the first episode of depression is in old age. Treatment of depression may also reduce other neuropsychiatric symptoms associated with depression such as aggression, anxiety, apathy, and psychosis (282, 283).

When treatment for depression is being considered, patients should be evaluated for conditions that may be causing or contributing to the depression. Among these conditions are other psychiatric disorders (e.g., alcohol or sedative-hypnotic dependence), other neurological problems (e.g., stroke, Parkinson's disease), general medical problems (e.g., thyroid disease, cardiac disease, or cancer), and the use of certain medications (e.g., corticosteroids, benzodiazepines).

As described in APA's Practice Guideline for the Treatment of Patients With Major Depressive Disorder , 2nd edition (284), many well-designed clinical trials support the efficacy of antidepressants in depressed elderly patients without dementia (285–288). However, these data may not extrapolate to patients with co-occurring dementia. Placebo-controlled trials of antidepressants in patients with dementia have shown mixed results (289–296). Despite this mixed evidence, clinical consensus supports a trial of an antidepressant to treat clinically significant, persistent depressed mood in patients with dementia. SSRIs may be preferred because they appear to be better tolerated than other antidepressants (297–299). Some patients with dementia and depression do not tolerate the dosages needed to achieve full remission. When a rapid response is not critical, a very gradual dosage increase may increase the likelihood that a therapeutic dosage will be reached and tolerated. After prolonged use, medications should be withdrawn gradually whenever possible, in order to avoid withdrawal symptoms.

The reader is referred to APA's Practice Guideline for the Treatment of Patients With Major Depressive Disorder , 2nd edition (284) for a detailed discussion of the side effects of antidepressant agents. Side effects, divided by medication class, are briefly summarized here.

Compared to cyclic antidepressants and monoamine oxidase inhibitors (MAOIs), SSRIs tend to have a more favorable side-effect profile and generally have fewer anticholinergic and cardiovascular side effects. However, SSRIs can produce nausea and vomiting, agitation and akathisia, parkinsonian side effects, sexual dysfunction, weight loss, and hyponatremia. Some of these effects are more common with specific SSRIs than with the entire class. As with most psychotropic medications, SSRI use is associated with an increased risk of falls in elderly patients (300). Physicians prescribing SSRIs should also be aware of the many possible medication interactions associated with the metabolism of these agents through the cytochrome P450 system.

Alternative agents to SSRIs include but are not limited to venlafaxine, mirtazapine, and bupropion. The serotonin-norepinephrine reuptake inhibitor venlafaxine is metabolized through the cytochrome P450 system, but because it does not induce or inhibit these enzymes, it is less likely to interact with other drugs metabolized through the same system. One side effect more commonly seen with venlafaxine than other antidepressants is an elevation in blood pressure, which may be less likely with the sustained release formulation. Duloxetine, another inhibitor of serotonin and norepinephrine reuptake, is commonly used to treat major depression, but clinical experience with its use in geriatric patients with dementia is limited, and there are no published clinical trials to support its use. Mirtazapine, a noradrenergic/specific serotonergic antidepressant, can produce sedation and weight gain, especially at low doses. Rare but potentially serious side effects of mirtazapine are liver toxicity and neutropenia. Bupropion, a norepinephrine-dopamine reuptake inhibitor, has been associated with a risk of seizures, especially at high doses, in patients with anorexia or with structural neurological problems. Trazodone, a serotonin-2 antagonist/reuptake inhibitor, has sedative side effects and can be used when insomnia or severe agitation are prominent. At higher doses, significant side effects include postural hypotension and priapism.

Cyclic antidepressants or MAOIs can be used to treat depression in patients with dementia if other classes of agents have failed or are contraindicated. However, the prominent cardiovascular and anticholinergic side effects associated with these agents make them undesirable first- or second-line agents. The most problematic side effects are cardiovascular effects, including orthostatic hypotension and cardiac conduction delay, and anticholinergic effects, including blurred vision, tachycardia, dry mouth, urinary retention, constipation, sedation, impaired cognition, and delirium. If a cyclic antidepressant is used, agents with significant anticholinergic properties such as imipramine and amitriptyline should be avoided. In terms of MAOI treatment, only the reversible MAOI moclobemide has been studied for treating depression in patients with dementia. Although moclobemide is less toxic than the irreversible MAOIs, it is not currently available in the United States. If nonselective irreversible MAOIs are prescribed, the required dietary restrictions necessitate close monitoring of food intake, because a patient with dementia cannot be relied on to adhere to these restrictions.

As with most other medications, low starting doses, small dose increases, and long intervals between dose increases are generally necessary when implementing antidepressants for elderly patients. Citalopram is started at 5–10 mg/day and increased at several-week intervals to a maximum of 40 mg/day. Sertraline may be started at 12.5–25.0 mg/day and increased at 1–2-week intervals up to a maximum dosage of 150–200 mg/day.

If these agents are ineffective and other agents are chosen, the starting doses are as follows. Venlafaxine can be started at a dosage as low as 25 mg/day (extended release, 37.5 mg/day) and increased at approximately weekly intervals up to a maximum dosage of 375 mg/day in divided doses (extended release, 225 mg/day). If venlafaxine is prescribed, careful monitoring of blood pressure is indicated. Mirtazapine can be started at a dosage as low as 7.5 mg at bedtime and increased by 7.5-mg or 15-mg increments to 45–60 mg at bedtime. Lower dosages have been associated with sedation and appetite increase, both of which may be beneficial for depressed patients with insomnia or anorexia. Less sedation is found in dosages over 15 mg/day. Caution should be used in prescribing this agent for patients with liver dysfunction or renal impairment and for patients who develop signs of infection. Bupropion can be started at 37.5 mg once or twice per day (sustained release, 100 mg/day) and increased slowly to a maximum dosage of 300 mg/day in divided doses (sustained release, 300 mg/day). No more than 150 mg of immediate release bupropion should be given within any 4-hour period because of the risk of seizures. Duloxetine can be started at 20–40 mg/day and increased slowly to a maximum of 60–80 mg/day, typically in divided doses.

There is a small amount of evidence (301, 302) that dopaminergic agents such as psychostimulants (d-amphetamine, methylphenidate), amantadine, bromocriptine, and bupropion may be helpful in the treatment of severe apathy in patients with dementia. Psychostimulants have also received some support for the treatment of depression in elderly individuals with severe general medical disorders (303–305). In general, these agents may be associated with tachyarrhythmias, hypertension, restlessness, agitation, sleep disturbances, psychosis, confusion, dyskinesias, and appetite suppression, particularly at high doses, and amantadine may also be associated with significant anticholinergic effects. Starting dosages of dextroamphetamine and methylphenidate are 2.5–5.0 mg in the morning. The starting dose can be increased by 2.5 mg every 2 or 3 days to a maximum of 30–40 mg/day.

Although the data supporting the efficacy and safety of ECT in the treatment of depression in dementia are limited to one small retrospective chart review study, there are significant data supporting its use in geriatric depression in patients without dementia (306–308). Therefore, in the presence of dementia, ECT should only be considered for treating depression that is severe, life-threatening, or does not respond to other treatments. The most common significant side effect is transient confusion, which in turn increases the risk of falls, dehydration, and other complications. Twice weekly rather than thrice weekly and high-dose unilateral (309) or bifrontal rather than bitemporal ECT may decrease the risk of cognitive side effects after ECT. Clinicians should refer to The Practice of Electroconvulsive Therapy. Recommendations for Treatment, Training, and Privileging: A Task Force Report of the American Psychiatric Association (310) for a full discussion of the use of ECT and other potential side effects of ECT treatment.

d. Treatments for Sleep Disturbance

Sleep problems have been reported in 25%–50% of patients with dementia (311, 312), and provisional criteria for sleep disturbances associated with Alzheimer's disease have been proposed (313). Major causes of sleep disturbances in this population include physiological changes associated with aging (fragmented nocturnal sleep, multiple and prolonged awakenings, relative decrease in slow-wave sleep percentage, and increased daytime napping), pathological involvement of the suprachiasmatic nucleus, the effects of co-occurring medical or psychiatric disorders or medications, untreated pain, and poor sleep hygiene (314, 315). Cholinesterase inhibitors can also cause insomnia (141). Some over-the-counter sleep medications (e.g., diphenhydramine) can contribute to delirium and paradoxically worsen sleep. Thus, it is important to ask if the patient is using over-the-counter diphenhydramine or other over-the-counter or herbal preparations to treat sleep disturbance.

Treatment of sleep disturbance in dementia is aimed at decreasing the frequency and severity of insomnia, interrupted sleep, and nocturnal confusion in patients with dementia. In addition to addressing the sleep complaints of people with dementia, treatment goals are to increase patient comfort, decrease disruption to families and caregivers, and decrease nocturnal wandering and nighttime accidents.

Available data do not support the recommendation of a specific course of action for treating sleep disturbances in patients with dementia. Although the data are sparse, clinical practice favors beginning with nonpharmacological approaches when the sleep disorder is an isolated problem. There are few studies of behavioral, environmental, or pharmacological interventions to improve sleep in this population, although there is some evidence that training caregivers in how to implement proper sleep hygiene can result in improved sleep for patients with dementia (316, 317). A number of trials of bright light therapy have been conducted but have failed to demonstrate significant clinical benefit (315, 318–322). Nevertheless, the psychiatrist treating a patient for a sleep disorder can follow a number of general clinical guidelines in developing a treatment plan. In meeting the needs of both the patient and his or her caregivers, clinicians should consider behavioral and environmental interventions, combine nonpharmacological and pharmacological therapies, and seek to avoid use of multiple psychotropic medications (314). Other initial steps may include establishing regular sleep and waking times, limiting daytime sleeping, avoiding fluid intake in the evening, establishing calming bedtime rituals, and providing adequate daytime physical and mental activities (323–325). Underlying medical and psychiatric conditions that could disturb sleep should be evaluated and treated. Medications that could interfere with sleep should be adjusted if possible. If the patient lives in a setting that can provide adequate supervision without causing undue disruption to others, allowing the patient to sleep in the daytime and be awake at night is an alternative to pharmacological intervention. Pharmacological treatment should be instituted only after other measures have been unsuccessful and the potential benefits outweigh the risk of side effects. It is particularly important to identify sleep apnea (326), which may affect 33%–70% of patients with dementia (324). This condition is a relative contraindication to the use of benzodiazepines or other agents that suppress respiratory drive.

If another behavioral or neuropsychiatric condition is present, and medications used to treat that condition have sedative properties, clinical practice favors prescribing that agent at bedtime, if appropriate, to assist with treatment of insomnia. For example, an antidepressant with sedative properties (e.g., mirtazapine or trazodone) can be given at bedtime if both sleep disorder and depression are present. If the patient has psychotic symptoms and sleep disturbance, second-generation antipsychotics may be the initial treatment of choice. If there are clear deficits in the patient's sleep hygiene, then education and behavioral management might be the preferred treatment course.

Pharmacological interventions include a number of agents. Some clinicians prefer 25–100 mg of trazodone at bedtime for sleep disturbances, whereas others prefer the nonbenzodiazepine hypnotics such as zolpidem (5–10 mg at bedtime) or zaleplon (5–10 mg at bedtime). Benzodiazepines (e.g., 0.5–1.0 mg of lorazepam, 7.5–15.0 mg of oxazepam) may be used but are generally recommended only for short-term sleep problems because of the possibility of tolerance, daytime sleepiness, rebound insomnia, worsening cognition, falls, disinhibition, and delirium. Rebound insomnia and daytime sleepiness can occur with any of these agents (327). Triazolam is not recommended for individuals with dementia because of its association with amnesia. Diphenhydramine, which is found in most over-the-counter sleep preparations, is used by some clinicians, but it is not recommended for the treatment of patients with dementia because of its anticholinergic properties.