Management of Neuropsychiatric Symptoms of Dementia

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Management of neuropsychiatric symptoms of dementia

Authors: Daniel Press, MD, Michael Alexander, MD
Section Editors: Kristine Yaffe, MD, Kenneth E Schmader, MD
Deputy Editor: Janet L Wilterdink, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2019. | This topic last updated: Nov 09, 2018.
INTRODUCTION
Neuropsychiatric symptoms in Alzheimer disease (AD) and other types of dementia are extremely common and often much more
troubling than cognitive symptoms. This topic will review the causes and treatment of behavioral disturbance and other neuropsychiatric
symptoms related to dementia. These symptoms include agitation, aggression, delusions, hallucinations, paranoia, wandering,
depression, apathy, disinhibition, and sleep disturbances (table 1). One or more of these symptoms are observed in 60 to 90 percent of
patients with dementia; the prevalence increases with disease severity [1-5]. The presence of neuropsychiatric symptoms leads to
greater functional impairment in patients with dementia and cognitive impairment [5,6]. These behaviors often accelerate or lead to
nursing home placement [6-10].
Treatment of the cognitive features of dementia, the approach to safety and societal issues related to dementia, and the palliative care
of patients with advanced dementia are discussed separately. (See "Treatment of dementia" and "Frontotemporal dementia: Treatment"
and "Prognosis and treatment of dementia with Lewy bodies" and "Treatment and prevention of vascular dementia" and "Safety and
societal issues related to dementia" and "Care of patients with advanced dementia".)
SYMPTOM ASSESSMENT
Neuropsychiatric symptoms are common in dementia, but may be under-reported by patients and families [11,12]. Screening for
agitation and other neuropsychiatric symptoms in patients with dementia should be done at regular follow-up visits [12]. We ask both
caregivers and patients explicit questions regarding such symptoms, for example, "Does the patient have any behaviors that worry
you?" and "Do you/the patient have hallucinations, see things, or hear voices that aren't there?" and "How do you/the patient sleep at
night?" Clinicians should regularly inquire about aggression, delusions, hallucinations, paranoia, wandering, depression, apathy, and
disinhibition. The presence of either delusions or hallucinations is associated with increased risk for cognitive and functional decline;
hallucinations predict institutionalization and death [9].
Behavioral disturbances commonly peak in the late afternoon or evening, a phenomenon often referred to as "sundowning."
Sundowning affects up to two-thirds of patients with dementia and is closely related to disturbed circadian rhythms [10,13-16]. Risk
factors include poor light exposure and disturbed sleep [17]. Sleep disorders are common in dementia but may also be a manifestation
of or contributor to neuropsychiatric symptoms. A sleep history should be regularly assessed. (See "Sleep-wake disturbances and sleep
disorders in patients with dementia", section on 'Clinical assessment'.)
Delusions are common in patients with Alzheimer disease (AD), with a reported prevalence of 30 percent in patients with severe AD [1].
A long-term follow-up study suggests that these may be more pervasive; among 456 patients with mild to moderate AD followed for a
mean of 4.5 years, 34 percent had delusions at baseline, but 70 percent had them during at least one evaluation [9]. Paranoid delusions
in particular can be very distressing to the patient or caregivers. Common paranoid delusions include beliefs that the house has been
invaded, that personal objects have been misplaced or stolen, that family members have been replaced by impostors (Capgras
syndrome), or that spouses have been unfaithful. By contrast, some delusions or hallucinations may be fleeting or unobtrusive, which
impacts how aggressively that are treated.
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Hallucinations are less frequent than delusions, present in 7 percent at baseline and in 33 percent at some point over the course of
follow-up in patients with severe AD [1,9]. The presence of visual hallucinations early in the course of a dementing illness suggests
dementia with Lewy bodies (DLB) disease, a disorder with very specific management issues. (See "Clinical features and diagnosis of
dementia with Lewy bodies" and "Prognosis and treatment of dementia with Lewy bodies".)
AGITATION OR AGGRESSION
Evaluation for underlying cause — Agitation and other behavioral abnormalities can arise from a variety of underlying causes in
patients with dementia, and identifying the genesis of the abnormal behavior is critical to effective management. In many patients,
behavioral changes herald a new infection or medication toxicity. In others, agitation is driven by pain, fear, confusion, or poor sleep. As
with physical symptoms such as shortness of breath, no single approach or medication can be expected to treat the symptom of
agitation without regard to the underlying cause. New or worsening symptoms should prompt assessment of safety and evaluation for
an underlying cause (algorithm 1).
Medication side effects — Medication toxicity is a common precipitant of neurobehavioral disturbances in patients with dementia.
Individuals with dementia have an increased risk of adverse cognitive and behavioral effects from a range of medications, both
prescribed and over the counter.
In particular, clinicians should consider anticholinergic side effects of drugs used to treat sleep disturbance, bladder incontinence, or
other illnesses. Benzodiazepines and other hypnotics/sedatives are other drugs that should generally be avoided in patients with
dementia due to risk of adverse cognitive effects, among others. (See 'Drugs to avoid' below.)
Pain assessment — Pain may also precipitate neuropsychiatric symptoms. Older adults with mild to moderate dementia can report
pain reliably [18]. Both interview and observation should be used to determine whether pain reporting represents pain-related suffering,
pain perseveration, or a signal of some other type of distress. (See "Treatment of persistent pain in older adults", section on
'Considerations for patients with dementia'.)
In patients with advanced dementia who are unable to verbally communicate about their pain, clinicians must rely on caregiver reports
and observational scales. Behavioral domains that should be observed and assessed include [19]:
● Facial expressions
● Verbalizations/vocalizations
● Body movements
● Changes in interpersonal interactions
● Changes in activity patterns/routines
● Mental status changes
A variety of tools are available to assess pain in older adults with advanced dementia; one commonly used scale that incorporates
scoring on five areas is the Pain Assessment in Advanced Dementia (PAINAD) (table 2) [20].
Delirium — Delirium is an acute confusional state characterized by impairments in attention and behavior developing over a short
period of time and often fluctuating over the course of the day. The most common causes of delirium are medical illnesses, substance
intoxication, and medication side effects.
A concomitant medical illness (particularly urinary tract infection or pneumonia) and other causes of delirium must be considered
whenever new behavioral disturbances arise in patients with dementia, particularly in the setting of an acute worsening in cognition
(table 3) [21,22]. Most behavioral symptoms have precipitants.
These possibilities should be ruled out prior to initiation of any treatment. (See "Diagnosis of delirium and confusional states" and
"Delirium and acute confusional states: Prevention, treatment, and prognosis".)
Depression — Agitation or aggression may be the primary manifestation of depression in a patient too impaired to express distress
in any other manner. A therapeutic trial with antidepressant medication may be the only reasonable diagnostic strategy in difficult cases.
(See 'Clinical features and diagnosis' below.)
Sleep disorders — Sleep-wake disturbances are common in patients with dementia and can be caused by a variety of factors.
When sleep disturbances are prominent, daytime agitation is unlikely to improve until sleep has been optimized. Sleep disturbances can
be caused by a variety of factors, and evaluation is essential to appropriate treatment. This topic is discussed in detail separately. (See
"Sleep-wake disturbances and sleep disorders in patients with dementia".)
Misperception or misunderstanding — There is a hierarchy of causes of misunderstanding.
This can be as simple as poor vision or poor hearing; hearing loss is very common in older adults and may be a factor in paranoia
through misunderstanding. There is evidence that hearing loss accelerates cognitive decline, and the two together may increase risk of
agitation [23]. Poor hearing may allow auditory hallucinations to emerge. Tinnitus may be misinterpreted or transformed into
hallucinations, even musical ones. Poor vision can also be a source of visual hallucinations. (See "Geriatric health maintenance",
section on 'Vision screening' and "Geriatric health maintenance", section on 'Hearing loss' and "Approach to the patient with visual
hallucinations", section on 'Etiologies'.)
Misunderstanding may also be due to cognitive, language, or memory deficits; behavioral management is usually sufficient after
analysis of the antecedent behaviors, but awareness of family and caretakers about the nature of these deficits is essential to recognize
the precipitating perceptual, language, or memory error. (See 'Nonpharmacologic therapies' below.)
Delusions emerge in dementia for many reasons. They often have a suspicious nature. The misunderstanding of others' behaviors may
precipitate fleeting or unthreatening notions but also more permanent and fixed ones. One example is imposter (Capgras) syndrome, in
which the patient believes that someone they know or recognize has been replaced by an imposter. If delusions appear to trigger
aggression, pharmacologic treatment may be helpful or necessary, but they can be very resistant to medications. (See 'Severe or
refractory symptoms' below.)
Initial management strategies — A number of treatment options exist for the management of agitation in dementia (algorithm 1). A
proactive approach, with early recognition and treatment of mild symptoms along with education and collaboration among health care
providers, patients, caregivers, and community agencies on person-centered nonpharmacologic approaches, may provide maximal
benefits and help to curb excessive use of antipsychotic drugs [24-28].
As discussed above, agitation and other behavioral abnormalities can arise from a variety of underlying causes in patients with
dementia, and identifying the genesis of the abnormal behavior is critical to effective management. (See 'Evaluation for underlying
cause' above.)
Assess risk of harm and ensure safety — Patients with agitation may pose safety risks to themselves or others. When severe,
agitation may require an elevated level of care, either temporarily or indefinitely. Safety strategies may include a higher level of practical
support for family and other caregivers, increased one-on-one supervision, inpatient hospitalization, and, if risk or distress is severe,
short-term pharmacotherapy. (See 'Severe or refractory symptoms' below.)
Assessing the associated caregiver distress is also important in determining the urgency of intervention. In some cases, aggression
may manifest as abusive behavior toward the caregiver. Distressed or overburdened caregivers may benefit from increased supportive
services, education, and community resources. (See 'Support for caregivers' below.)
Nonpharmacologic therapies — Caregivers should be counseled in strategies involving distraction and redirection, structured
routines, and providing calm, reassuring responses when patients seem anxious (table 4) [12]. Increasing evidence suggests that these
approaches as well as a variety of other nonpharmacologic measures can be effective in reducing agitation and anxiety in patients with
dementia [12,29-31].
Behavioral interventions employ different strategies and techniques. These include identifying any preceding events that generate
agitation, determining whether unmet needs can be anticipated and alleviated, and avoiding environmental triggers such as a sudden
change in surroundings (table 4) [29,31]. Behavioral approaches to agitation may also address sleep-wake disturbances, including
insomnia, by focusing on establishing and maintaining consistent sleep and wake times as well as incorporating more exposure to
natural, bright light during the early part of the day. (See "Sleep-wake disturbances and sleep disorders in patients with dementia",
section on 'Insomnia and other sleep-wake disturbances'.)
A 2014 systematic review of nonpharmacologic interventions for agitation in dementia included 33 randomized trials with at least 45
participants; effective interventions in one or more trials were the implementation of activities, music therapy, sensory interventions such
as massage, and person-centered communication skills training for caregivers [32]. For the most part, positive trials demonstrated
evidence of short-term but not long-term benefit, or did not include long-term follow-up results.
As one example, a randomized, controlled trial studied 73 residents of skilled nursing homes who had aggression or agitation with
assisted bathing [33]. Treatment groups were a usual care control group (showering); "person-centered showering," an intervention
focused on resident comfort and preferences; and "towel-bath," an in-bed bag bath method that kept the resident covered at all times
and cleansed by using gentle massage. Both treatment groups showed significant declines in all measures of agitation, aggression, and
discomfort compared with controls. The postulated mechanism underlying the effectiveness of the improved personal care involved a
reduction in the insistent, task-focused, impersonal, and intrusive "usual care" methods that can provoke agitation and aggression [33].
Other nonpharmacologic therapies have demonstrated some benefit for neuropsychiatric symptoms of dementia in small studies:
● Aromatherapy has been studied in several small randomized trials in patients with dementia and agitation, with mixed results [34].
Aromatherapy is safe and well tolerated. Lemon balm or lavender oil are most frequently used and can be delivered by either
inhalation or skin application. The mechanism by which these agents may be effective is unclear.
● Exercise training in combination with caregiver education may improve outcomes in patients with Alzheimer disease (AD). A
randomized trial in 153 community-dwelling patients with AD found that compared with routine medical care, patients who were
assigned to exercise (goal minimum of 30 minutes per day) and whose caregivers received training in managing behavioral
problems had improved physical functioning and less depression [35]. We have found that regular physical activity can be very
useful in managing behaviors in some patients with dementia.
● Music therapy and pet therapy also have some evidence of efficacy [36-39].
● In preliminary studies, massage and touch therapy appear to be potentially beneficial in the immediate management of agitated
behavior and in encouragement to eat [40].
Pain management — Pain is an important source of behavioral disturbances in patients with dementia. As discussed above, the
assessment of pain in patients with advanced dementia who are unable to verbally report pain can be challenging and relies heavily on
caregiver report and observation. (See 'Pain assessment' above.)
Regardless of the stage of dementia, pain management and drug prescribing should be approached pragmatically (see "Treatment of
persistent pain in older adults", section on 'Considerations for patients with dementia'):
● Prescribe a trial of scheduled analgesics.
● Use a stepped-care approach to analgesic prescribing.
● Start low, go slowly, but use enough.
● Monitor the patient carefully to balance risks and benefits of pain treatment versus persistent pain. Adequate pain control may be
observed as improvements in behavior and function [41].
One randomized study evaluated a systematic approach to pain evaluation and pharmacologic management in 352 patients with
behavioral disturbances and dementia [42,43]. The intervention was a stepwise protocol that followed recommendations of the
American Geriatrics Society, consisting of acetaminophen, low-dose morphine, buprenorphine patch, and pregabalin [44]. After eight
weeks, those in the intervention group had reduced neuropsychiatric symptoms and lower agitation scores, although cognition and daily
function were not affected, and agitation scores were similar at 12 weeks.
Antidementia drugs — While the evidence for efficacy in the treatment of neurobehavioral symptoms is not robust, cholinesterase
inhibitors are well tolerated and may have additional benefit for cognition and function. Therefore, we suggest starting a cholinesterase
inhibitor for patients with neuropsychiatric symptoms and mild to moderate dementia. (See "Cholinesterase inhibitors in the treatment of
dementia".)
A 2015 systematic review and meta-analysis that included 15 randomized placebo-controlled trials of cholinesterase inhibitors for
neuropsychiatric symptoms of dementia generally found small but statistically significant efficacy, similar to results of previous analyses
[45,46]. The small benefits seen were of questionable clinical significance, and most studies included patients with relatively mild
neuropsychiatric symptoms.
Patients with dementia with Lewy bodies (DLB) may have a more beneficial response to cholinesterase inhibitors than patients with AD.
This is discussed in detail separately. (See "Prognosis and treatment of dementia with Lewy bodies".)
The potential efficacy of memantine to ameliorate the behavioral effects in AD requires further study. Post hoc analyses of clinical trial
results suggest that patients assigned to memantine treatment may have diminished agitation/aggression, irritability, and other
behavioral disturbances [47,48]. However, systematic reviews have concluded that studies have not demonstrated a clinically significant
effect of memantine for neuropsychiatric symptoms of dementia [45,49,50].
Antidepressant medication — Despite mixed results in clinical trials, we have found selective serotonin reuptake inhibitors (SSRIs)
(table 5), in particular citalopram (10 to 20 mg daily), useful in the management of agitation and paranoia in patients with AD, as the
symptoms are often driven by a mood disorder that is poorly verbalized. As an alternative, trazodone (starting dose 25 mg at bedtime) is
well tolerated and is often used for sleep onset in patients with dementia. The use of SSRIs and other antidepressants for management
of depression in patients with dementia is discussed below. (See 'Depression' below.)
The US Food and Drug Administration (FDA) recommends a maximum daily dose of 20 mg of citalopram for patients older than 60
years of age [51]. Citalopram should be avoided in patients at increased risk for arrhythmias (eg, congenital long QT syndrome,
hypokalemia, hypomagnesemia, active heart disease) and discontinued in patients with persistent corrected QT measurements >500
milliseconds. We sometimes overlap with an antipsychotic (eg, quetiapine) in the first few weeks, as the efficacy of the SSRI may
require that time frame to emerge.
As with other drugs, when antidepressant agents are administered to patients with dementia, there should be an ongoing assessment of
benefits versus harms, and consideration for withdrawing the medications should be made periodically. However, in one randomized
study of 128 patients with dementia who were treated with SSRIs for an indication other than depression, withdrawal of medication was
associated with significantly worse depressive symptoms and a nonsignificant worsening of neuropsychiatric symptoms [52].
The evidence of efficacy for SSRIs is limited. Authors of systematic reviews of randomized controlled trials have concluded that
antidepressant agents are well tolerated but have limited evidence for efficacy in the treatment of neuropsychiatric symptoms of
dementia other than depression [49,53]. Of six studies that compared SSRIs (citalopram, sertraline, fluoxetine, fluvoxamine) with
placebo, only two trials found a benefit for citalopram in the reduction of neuropsychiatric symptoms such as reduced agitation and
caregiver distress [54-59]. There was no difference in the rates of trial withdrawals due to adverse events for SSRIs compared with
placebo. However, in one study that used a higher than currently recommended dose of citalopram, QT prolongation and worse
cognitive scores were noted in the citalopram-treated patients [59]. In randomized trials that have compared SSRIs (citalopram,
sertraline, fluoxetine) with antipsychotic agents (haloperidol, risperidone, perphenazine) there was no difference between treatment
groups in regard to benefit on neuropsychiatric symptoms nor on adverse events, although other studies have suggested risks with
antipsychotic agents in this population [54,57,60,61]. (See 'Excess mortality' below.)
Trazodone was compared with placebo in one trial that found no benefit on neuropsychiatric symptoms [62]. Two trials that compared
trazodone with haloperidol found no significant relative benefit or harm between these two treatments [62,63]. We sometimes trial
trazodone in this setting, particularly in patients with sleep impairment, starting at 25 mg at bedtime and gradually increasing to effect or
side effect, rarely in doses as high as 100 to 150 mg.
Some evidence suggests that deficits in the serotoninergic system have a major role in the production of behavioral symptoms in
frontotemporal dementia (FTD). There is limited evidence of benefit, largely from uncontrolled observational studies, for serotonergic
antidepressant agents in these patients. (See "Frontotemporal dementia: Treatment", section on 'Serotonergic medications'.)
Drugs with uncertain benefit — A number of antiseizure drugs have been investigated for the treatment of neuropsychiatric
symptoms in dementia because of their mood-stabilizing properties:
● Carbamazepine was effective in a placebo-controlled study of agitation in nursing home patients with advanced dementia [64].
Relatively low doses were used, with a modal dose of 300 mg/day achieving a mean serum level of 5.3 mcg/mL. However, a
subsequent trial found no benefit [65], and a systematic review concluded that there is currently not enough evidence of benefit for
carbamazepine to recommend its use for neuropsychiatric symptoms [49].
● Valproate improved aggressive behavior in several earlier reports [66,67]. However, a systematic review that analyzed three
randomized controlled trials and two studies of valproate concluded that neither the short- nor long-acting preparations were
effective for treatment of neuropsychiatric symptoms of dementia [49].
● Gabapentin is often used because of its relatively mild side effect profile, but its efficacy is unproven, with one open-label
prospective study showing little benefit [68]. For patients receiving this for postherpetic or neuropathic pain, we have found a
modest benefit for agitation as collateral benefit.
● Lamotrigine has been advocated based on case reports, but no randomized, placebo-controlled studies have been published to
date.
Other therapies with possible benefit include:
● Melatonin – The observation that circadian rhythm disturbances appear to be associated with depressed mood, impaired cognition,
and behavioral and sleep disturbances has suggested a potential benefit for melatonin and/or light therapy in patients with
dementia. Studies have had somewhat mixed results, but in the aggregate do not suggest convincing benefit for agitation [69-75].
Melatonin dose varied widely in published studies, ranging from 1.5 to 10 mg. Timing of administration was also variable.
● Light therapy – Increasing bright-light exposure in the mornings may have benefits independent of melatonin and can lead to
improvement in sleep disturbances as well. (See "Sleep-wake disturbances and sleep disorders in patients with dementia", section
on 'Multicomponent behavioral therapy'.)
Drugs to avoid — Benzodiazepines are not recommended for the management of neuropsychiatric symptoms of dementia. One
randomized controlled trial of a benzodiazepine for neuropsychiatric symptoms of dementia found benefit for either intramuscular
lorazepam or intramuscular olanzapine compared with placebo assessed two hours after treatment; the benefit of lorazepam was not
sustained at 24 hours on one outcome scale [76].
Benzodiazepine side effects include worsening gait, potential paradoxic agitation, and possible physical dependence. Benzodiazepine
use should be limited to brief stressful episodes, such as a change in residence or an anxiety-provoking medical event [77]. When used
in this fashion, those with shorter half-lives should be preferred.
Antihistamines and other sedatives are discouraged because of high rates of side effects, particularly for drugs with anticholinergic
effects, such as diphenhydramine. (See 'Sleep disorders' below.)
Severe or refractory symptoms — As with mild symptoms, management of severe symptoms requires ongoing collaboration among
health care providers, patients, and caregivers and regular re-evaluation of the balance of risks and benefits.
When nonpharmacologic interventions and the above pharmacologic approaches fail to manage neuropsychiatric symptoms effectively
and they result in severe distress or safety issues, acute pharmacologic therapy with an antipsychotic drug may become necessary.
Efficacy is seldom complete, however, and often comes with a cost of side effects, including increased mortality. Clinicians should use
one drug at a time, start with a low dose, and titrate slowly, as treatment may help some problems but cause or exacerbate others.
There should also be an ongoing assessment of benefits versus harms, and withdrawal of medications should be considered
periodically.
As discussed above, no single approach or medication can be expected to treat the symptom of agitation without regard to the
underlying cause. Identifying the genesis of the abnormal behavior is critical to effective management. A concomitant medical illness,
uncontrolled pain, medication toxicity, and other causes of delirium should be considered and ruled out whenever new behavioral
disturbances arise. (See 'Evaluation for underlying cause' above.)
Antipsychotic drugs — Atypical neuroleptics have been the agents of choice for treating psychotic symptoms and agitation in
patients with dementia. However, these drugs may increase mortality and are not approved for the treatment of behavioral disorders in
patients with dementia by the FDA. They should not be used routinely to treat neuropsychiatric symptoms of dementia [78,79].
Nonetheless, their benefits often still outweigh their risks in patients with dementia when treatment of psychotic symptoms including
hallucinations, paranoia, and delusions is critical to patient and caregiver safety, wellbeing, and quality of life. In the absence of other
effective agents, we continue to advocate cautious use for severe aggression or psychosis when nonpharmacologic strategies have
failed and quality of life is not being adequately addressed by other means, after informing the patients and families of the potential
risks, including increased mortality. (See 'Excess mortality' below.)
Clinical use — Given the risk of increased mortality associated with the use of atypical neuroleptics in older adults with dementia
(see 'Excess mortality' below), we reserve their use for patients who have neuropsychiatric symptoms, particularly psychosis, that are
severe, debilitating, or posing safety risks [79]. There is often no good alternative. Somnolence is also of concern with all of these
agents, and may be dose limiting.
In the absence of clear differences in efficacy among various drugs, selection of a specific drug is primarily based on consideration of
side effects and individual patient characteristics. (See 'Efficacy' below and 'Side effects' below.)
In general, we prefer one of the following:
● Olanzapine can be started at a dose of 2.5 mg daily and titrated up to a maximum of 5 mg twice a day. This drug appears to be at
least modestly effective for treating the neuropsychiatric symptoms of dementia in patients with AD or vascular dementia as
discussed below. The incidence of extrapyramidal symptoms is low at doses of 5 mg per day or less, but metabolic side effects (eg,
weight gain, diabetes, and hypercholesterolemia) can be more severe than with some other agents.
● Risperidone at no more than 1 mg daily also appears to be at least modestly effective, but higher doses are associated with
increased side effects, particularly drug-induced parkinsonism as discussed below.
● Quetiapine is an alternative, starting at a dose of 25 mg at bedtime and titrating up to a maximum of 75 mg twice a day. There are
few data regarding the effectiveness of quetiapine in this setting.
Treatment should be maintained only if benefits are apparent, and discontinuation should be attempted at regular intervals, weighing the
risk of relapse versus the risk of adverse effects from continued treatment [80,81]. The American Psychiatric Association recommends
that an attempt to taper and withdraw antipsychotic therapy be made within four months of initiation in patients who have responded to
therapy and who have no prior history of relapse with medication taper [79].
For some patients, discontinuation of antipsychotic agents may not be possible. One randomized study examined relapse risk in 180
patients with AD and psychosis or agitation who had initially responded to treatment with risperidone [82]. Discontinuation of risperidone
was associated with an increased risk of relapse over 16 weeks of follow-up: 60 versus 33 percent in those assigned to early
discontinuation and 48 versus 15 percent in those assigned to delayed discontinuation. In another trial in which eight nursing homes
were cluster randomized to antipsychotic review, a social intervention, and/or an exercise program, antipsychotic review reduced
antipsychotic use by 50 percent but resulted in worsened neuropsychiatric symptoms among residents with dementia, an effect that was
partially mitigated by concurrent social intervention [83]. Patients with severe baseline irritability/lability and severe auditory
hallucinations may be at increased risk for relapse [84].
Efficacy — Despite the fact that these medications are widely used and believed to be efficacious, they have not been extensively
studied in randomized controlled clinical trials. The trials that exist are often short, 6 to 12 weeks, despite the fact that patients are often
maintained on these agents for much longer. Trials also often suffer from methodologic limitations [49].
● Typical antipsychotics – A systemic review of typical antipsychotics included two meta-analyses of 12 trials plus two additional
studies of haloperidol, thioridazine, thiothixene, chlorpromazine, trifluoperazine, and acetophenazine, and concluded that, in the
aggregate, there was no clear evidence of benefit for these agents in patients with dementia [49]. A Cochrane review concluded
that haloperidol may help control aggression but not other neuropsychiatric manifestations of dementia [85]. No trials compared
agents with one another.
● Atypical antipsychotics – These agents include clozapine, olanzapine, risperidone, and quetiapine and have been somewhat more
extensively studied. Two independently conducted systematic reviews have concluded that these agents have, at most, modest
efficacy [49,86]. Of seven trials studied, four found a statistically significant benefit for the primary endpoint with olanzapine or
risperidone; there were no studies of clozapine or quetiapine for this indication at the time of this analysis. A subsequent meta-
analysis that included three randomized trials of quetiapine found no evidence that it confers benefit [87].
A subsequent small randomized clinical trial that compared the cholinesterase inhibitor rivastigmine and the atypical antipsychotic agent
quetiapine for agitation in nursing home patients with AD found no benefit for either treatment compared with placebo [88].
A multicenter, double-blind trial randomly assigned 421 patients with AD and either psychosis, aggression, or agitation to treatment with
either olanzapine, quetiapine, risperidone, or placebo [89]. Median time to discontinuation of drug for any reason was similar in all four
groups (5.3 to 8.1 weeks). However, more patients taking placebo discontinued medication for lack of efficacy compared with those on
olanzapine or risperidone (70 versus 39 and 44 percent, respectively). For patients still taking the assigned treatment at 12 weeks, there
were no differences among groups in the percentages of patients who improved on the Clinical Global Impression of Change (CGIC)
scale (range 21 to 32 percent). One limitation of the study was the inclusion of patients with a broad array of behavioral symptoms. It
seems likely that a subset of patients, perhaps those with hallucinations, would have shown more clear improvement. However, the
general use of antipsychotic drugs for the treatment of agitation in patients with AD should be avoided, as the benefit is likely to be small
and offset by adverse effects. (See 'Side effects' below.)
Side effects — The choice of specific antipsychotic drug used to treat hallucinations is driven by drug side effects such as
sedation or extrapyramidal disturbances (table 6). The older low-potency typical (conventional) neuroleptics (eg, chlorpromazine and
thioridazine) are highly sedating, and their anticholinergic activity can worsen memory and cognition. High-potency neuroleptics (eg,
haloperidol and fluphenazine) are associated with an often unacceptably high incidence of extrapyramidal side effects. In a trial of
haloperidol, for example, there was a high rate of extrapyramidal side effects and decline in cognitive function even at relatively low
doses of 1 to 5 mg [49,90].
Intravenous haloperidol has been associated with clinically significant QT prolongation and requires additional precautions regarding its
use, including monitoring of QT interval and serum potassium. (See "First-generation antipsychotic medications: Pharmacology,
administration, and comparative side effects", section on 'QT interval prolongation and sudden death'.)
While the atypical neuroleptics are perceived to have a lower incidence of adverse effects, this may be true only with low doses.
Systematic reviews and clinical trials find that adverse events with these agents in patients with dementia are common and dose related
[49,86,88,89]. These include extrapyramidal symptoms, confusion, somnolence, falls, and fractures (table 6). In 2017, the FDA issued a
formal warning about the risk of falls and fractures and recommended that a fall risk assessment be completed when initiating
antipsychotic treatment and recurrently for patients continuing on long-term antipsychotics. (See "Second-generation antipsychotic
medications: Pharmacology, administration, and side effects", section on 'Adverse effects'.)
Patients who have DLB may be especially sensitive to antipsychotic medication and may experience idiosyncratic, life-threatening
adverse reactions. When pharmacotherapy is necessary for treatment of behavioral symptoms related to DLB, very low doses of
atypical neuroleptics (eg, quetiapine, clozapine) should be used. Clozapine use requires regular blood monitoring due to risk of
agranulocytosis [91]. Risperidone and the typical antipsychotic agents should not be used in patients who have DLB. (See "Guidelines
for prescribing clozapine in schizophrenia", section on 'Monitoring' and "Prognosis and treatment of dementia with Lewy bodies".)
Excess mortality — Accumulating data from both observational studies and pooled analyses of randomized trials indicate that
antipsychotic medications are associated with an increased risk of stroke, myocardial infarction, and death when used to treat
behavioral symptoms in older adults with dementia, in particular those with vascular disease. The mechanism for this effect has not
been firmly established. The medications may lead to weight gain, hyperinsulinemia, and diabetes and thereby increase cardiovascular
risk. Alternatively, there may be a component of "reverse causality," ie, vascular disease that disrupts frontal lobe white matter pathways
may predispose both to behavioral symptoms requiring neuroleptic use and to cardiovascular events.
In 2005, the FDA issued a boxed warning that second-generation antipsychotics (eg, aripiprazole, olanzapine, quetiapine, and
risperidone) were associated with increased mortality when used for the treatment of behavioral symptoms in older adult patients with
dementia [92,93]. Their findings were confirmed in an independently conducted meta-analysis, as well as a subsequent randomized,
placebo-controlled study [94,95]. The reported odds ratio for increased mortality in these analyses ranged from 1.54 to 1.7, with an
absolute increased risk of death that ranged from 1 to 2 percent (3.5 to 4.5 versus 2.2 to 2.6 percent). Additional studies found that
haloperidol and other first-generation antipsychotics were also associated with increased mortality [96,97], leading the FDA to extend
the boxed warning to all antipsychotics in 2008.
The excess mortality risk appears to be higher for first-generation than second-generation drugs and varies among different second-
generation drugs, being highest for olanzapine and risperidone and lowest for quetiapine [96-103]. Both short-term and long-term
treatment is problematic [104], and higher doses are associated with increased risk [99,102]. Concurrent use of nonsteroidal
antiinflammatory drugs may also increase risk [105].
The magnitude of the absolute mortality risk associated with antipsychotic drugs in this population may be higher than previously
estimated, based on results of a large retrospective case-control study that included >90,000 older adults with dementia [102].
Compared with no treatment, the absolute increase in mortality risk in the first 180 days of antipsychotic treatment was 3.8 percent for
haloperidol (number needed to harm [NNH]: 26), 3.7 percent for risperidone (NNH: 27), 2.5 percent for olanzapine (NNH: 40), and 2.0
percent for quetiapine (NNH: 50). As a group, the second-generation antipsychotics showed a dose-response effect, with 3.5 percent
greater absolute risk of mortality in the high-dose subgroup compared with the low-dose subgroup.
These estimates are higher than the 1 percent absolute increased risk of death that was found in a 2005 meta-analysis of randomized
placebo-controlled trials [94]. One potential explanation for the difference is that the trials in the meta-analysis were conducted over a
relatively short treatment period (10 to 12 weeks) [94], whereas the retrospective study estimated risk of a six-month period [102]. It is
also possible that methodologic limitations in the retrospective study led to an overestimation of risk, since it is difficult to fully adjust for
factors related to the symptom or behavior that prompted prescription of an antipsychotic drug (which by themselves could be
associated with increased mortality).
The evidence regarding increased stroke risk associated with the use of atypical antipsychotic drugs is conflicting. While several studies
have reported such a link [49,106-108], others have not [109-111]. A large population-based cohort study of adults aged ≥65 years
found a similar risk of ischemic stroke among users of atypical versus typical antipsychotics, even among a subgroup at high risk (those
with atrial fibrillation or prior stroke) [110].
Dextromethorphan-quinidine — Dextromethorphan and quinidine as a combination pill (dextromethorphan-quinidine 20 mg/10 mg)

is approved in the United States and elsewhere for symptomatic treatment of pseudobulbar affect [112,113]. Limited evidence suggests
that it may provide some benefit for severe agitation in patients with dementia. When cost is not prohibitive and other management
strategies have failed, a trial of dextromethorphan-quinidine may be reasonable, at least in outpatients.
In a single trial, 220 patients with probable AD dementia and clinically significant agitation were randomly assigned to receive
dextromethorphan-quinidine or placebo in two consecutive five-week stages [114]. The majority of subjects were outpatients (>90
percent), and most were already taking one or more antidementia drugs, an antidepressant (50 to 60 percent), and an antipsychotic (17
to 23 percent). The primary endpoint was change from baseline on the Neuropsychiatric Inventory (NPI) agitation/aggression domain
(scale range, 0 to 12). In stage 1, mean NPI scores improved in both arms: from 7.1 to 3.8 in the drug therapy group and from 7.0 to 5.3
in the placebo group (between-group difference -1.5, 95% CI -2.3 to -0.7). Effects were similar in stage 2. Most other secondary
endpoints also favored drug therapy, with the exception of quality-of-life indicators. The most common treatment-emergent adverse
effects were falls (9 versus 4 percent), diarrhea (6 versus 3 percent), and urinary tract infection (5 versus 4 percent).
Although statistically significant, the observed between-group difference of 1.5 points on the NPI agitation/aggression domain is of
uncertain clinical significance. The authors of the study powered the trial to detect a mean difference of 2.5 points, which could be
interpreted to mean that the threshold for meaningful benefit was not met. The change in total NPI score, which has been used more
widely as an outcome measure, did not meet the suggested minimum for a clinically important difference [115].
Although dextromethorphan is widely available over the counter in doses used in the study, the dose of quinidine in the combination pill
(10 mg) is much lower than oral formulations of generic quinidine (200 mg). The high cost of dextromethorphan-quinidine as a
combination pill and apparently modest benefits may limit its role until results can be replicated in other studies and more diverse patient
populations.
Dextromethorphan is a low-affinity N-methyl-D-aspartate antagonist, but its mechanism of action for treating agitation is not known.
Proposed mechanisms include nicotinic receptor antagonism, serotonin and norepinephrine reuptake inhibition, and possible analgesic
effect [115].
Use of physical restraints — Physical restraints are rarely indicated in the care of patients with dementia and should be used only
for patients who pose an imminent risk of physical harm to themselves or others [116], with frequent evaluation of continued need.
Reasons for the use of physical restraints must be documented adequately. The use of restraints (both physical and pharmacologic) is
associated with an increased risk of falls, incontinence, and pressure ulcerations [117]. Before resorting to restraints we refer patients to
in-patient geriatric psychiatry programs.
The need for restraints can be decreased by environmental changes that decrease the risk of falls or wandering and by careful
assessment and treatment of possible causes of agitation [116]. Small randomized trials have shown that educational interventions for
nursing home staff can reduce rates of restraint use while maintaining resident safety [118-121].
DEPRESSION
Clinical features and diagnosis — The diagnosis of depression in patients with impaired cognition, or at least symptoms of impaired
cognition, is complicated:
● Patients with depression alone can produce symptoms and signs of cognitive impairment, particularly in older adults, a
phenomenon sometimes called "pseudodementia" or "dementia syndrome of depression." (See "Diagnosis and management of
late-life unipolar depression", section on 'Major depression'.)
However, older adults who become depressed are at increased risk of having comorbid dementia or of developing dementia in the
future [122]. The risk of developing Alzheimer disease (AD) associated with premorbid depression may be higher in men than
women, and it may be independent of vascular disease [123].
● Patients with dementia may develop apathy, sleep impairment, and social withdrawal that suggest the presence of depression, but
that are entirely due to cognitive deficits.
However, patients with dementia may become depressed in reaction to slipping mental capacity or as a direct biologic
consequence of the underlying neurologic disorder.
Further complicating the conundrum, patients with depression or dementia, let alone those with both, often cannot offer much
illumination on their own mood or mental ability.
We have experienced the greatest difficulty in patients with vascular dementia (multiple lacunar infarctions). These patients have
relatively mild dementia, often not meeting formal diagnostic criteria, with considerable apathy, while also reporting depression. (See
"Etiology, clinical manifestations, and diagnosis of vascular dementia".)
Clinical studies to resolve this diagnostic problem have had mixed results, perhaps because of the lack of reliable tools to measure the
relative contributions of depression and dementia in individual patients [122]. The American Association for Geriatric Psychiatry has
proposed diagnostic criteria for depression in patients with AD (table 7) [124]. A therapeutic trial with antidepressant medication may be
the only reasonable diagnostic strategy in difficult cases.
Management — There are relatively few studies to guide selection of an antidepressant medication to treat depression in patients with
dementia [125,126]. We strongly prefer selective serotonin reuptake inhibitors (SSRIs) because of the anticholinergic activity of tricyclic
antidepressants, which are associated with adverse effects in these patients.
Psychotherapy may be a useful but frequently underutilized treatment option in patients with mild to moderate dementia [127,128].
Options are discussed in detail separately. (See "Diagnosis and management of late-life unipolar depression", section on
'Psychotherapy'.)
Selection of a specific SSRI is generally based upon the side effect profile, drug interactions, and cost (table 5). Sertraline (starting at a
dose of 25 mg) and citalopram are commonly used in this setting. Citalopram may also improve psychotic and other behavioral
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symptoms and may be particularly helpful if depression is a likely contributor to the symptoms, or if depression cannot be eliminated as
a contributing factor when no other cause is apparent [54] (see 'Antidementia drugs' above). The dose of citalopram should not exceed
20 mg daily in older adult patients [51]. Fluoxetine has a long half-life and more drug interactions than other SSRIs, making it less
desirable in older adults. Paroxetine is the most anticholinergic of the SSRIs and therefore can also theoretically affect cognition.
Detailed information on drug interactions can be found in the Lexicomp drug interaction program within UpToDate.
Clinical trials of SSRIs for depression in patients with dementia have had somewhat mixed results. Two multicenter trials with citalopram
demonstrated efficacy with reasonably mild side effects [56,129]. However, a study in 131 patients with AD and depression found no
efficacy for sertraline after 12 and 24 weeks of therapy [130,131]. Finally, a randomized study comparing sertraline with placebo in 218
patients found no differences in depression scores at 13 or 39 weeks [132]. A meta-analysis of five studies concluded there was
insufficient evidence to support the use of SSRIs for the treatment of depression in patients with AD, but acknowledged that study
design precluded a conclusion of absence of benefit [133]. In many trials, a high response rate occurs in the placebo group, which may
point to the temporary nature of some of the neuropsychiatric symptoms.
The atypical antidepressants such as venlafaxine and bupropion may also be effective but have not been well studied in AD. In a
randomized trial of 219 patients with depression and AD, mirtazapine was no more effective than placebo after 13 or 39 weeks of
therapy [132].
Tricyclic antidepressants can cause worsening confusion, likely due to their anticholinergic properties, and are not as well tolerated as
SSRIs. In one study, for example, fluoxetine and amitriptyline were equally effective for treating depressive symptoms in patients with
AD, but 58 percent of amitriptyline-treated patients dropped out compared with 22 percent of those treated with fluoxetine [134].
Nortriptyline may be better tolerated than amitriptyline because of fewer anticholinergic effects. (See "Diagnosis and management of
late-life unipolar depression", section on 'Tricyclic and tetracyclic antidepressants'.)
APATHY
Apathy is a common symptom of dementia that can occur with or without comorbid depression. Patients with dementia and apathy are
more likely to have functional impairment in activities of daily living, independent of other factors such as age, cognitive function, and
depression [135-137]. As discussed above, distinguishing apathy from depression can be difficult if not impossible in some cases. (See
'Clinical features and diagnosis' above.)
Management of apathy is challenging, and the symptom may emerge early in the disease course and persist over time.
Nonpharmacologic strategies have not been well studied for this specific symptom. Because the cholinesterase inhibitors may have
some positive effect on apathy, we typically approach the symptom in a stepwise fashion, starting with a cholinesterase inhibitor if the
patient has not yet been exposed to one. (See "Cholinesterase inhibitors in the treatment of dementia".)
If apathy persists despite treatment with a cholinesterase inhibitor and is distressing to the patient or caregiver, pharmacologic options
include a therapeutic trial of an antidepressant and methylphenidate.
Methylphenidate has shown benefit as an adjunctive therapy to citalopram in older adults with major depression [138], and smaller
studies also suggest that it may improve apathy as well as other outcomes in patients with dementia [139-142]. In the largest trial of
methylphenidate in 77 men with mild Alzheimer disease (AD), methylphenidate improved apathy scores compared with placebo over a
12-week treatment period (9.9-point greater improvement on an 18-point scale) [140]. Measures of cognition, functional status,
caregiver burden, and depression also improved more in the methylphenidate group. The mean final dose of methylphenidate was 10
mg twice daily. Treatment was well tolerated, and the number and type of adverse effects were similar between groups.
Because methylphenidate has the potential to precipitate agitation or worsen nighttime sleep, we suggest use of low doses (eg, starting
with 5 mg once daily in the morning, maximum dose 10 mg twice daily, last dose no later than lunchtime) with careful monitoring during
titration.
SLEEP DISORDERS
Sleep disturbances are common in patients with Alzheimer disease (AD), affecting an estimated 25 to 35 percent of patients [143].
Causes are multifactorial, but can include contributions from depression and anxiety, a decrease in daytime physical activity, nocturia,
as well as side effects of medications (eg, vivid dreaming with cholinesterase inhibitors). This is discussed in detail separately. (See
"Sleep-wake disturbances and sleep disorders in patients with dementia", section on 'Sleep changes in aging and dementia'.)
Nonpharmacologic treatment strategies are generally preferred. Many aspects of good sleep hygiene that are emphasized in the
management of insomnia in the general population can be adapted for patients with dementia. Implementing an activity/exercise
program, increasing natural light exposure during the mornings, limiting evening beverages, and eliminating evening alcohol and coffee
are all useful in this patient population [12]. (See "Sleep-wake disturbances and sleep disorders in patients with dementia", section on
'Management'.)
In addition, certain sleep disorders occur with increased prevalence in patients with certain types of dementia. Recognition and
treatment of such disorders, such as restless legs syndrome/Willis-Ekbom disease or rapid eye movement (REM) sleep behavior
disorder (common among patients with Parkinson disease, dementia with Lewy bodies [DLB], and multiple system atrophy) is important
and may result in improved daytime symptoms. (See "Sleep-wake disturbances and sleep disorders in patients with dementia", section
on 'Other disorders'.)
WANDERING
Distractibility and restlessness may lead to wandering. The issue of wandering and becoming lost, with the attendant potential for
physical harm or death, is one of the concerns that often leads families and caregivers to place patients with dementia in nursing
homes. This issue is discussed separately. (See "Safety and societal issues related to dementia", section on 'Wandering and becoming
lost'.)
SEXUALLY INAPPROPRIATE BEHAVIOR
Surveys and observational studies report that a significant number (15 to 25 percent) of patients with dementia exhibit sexually
inappropriate behavior [144-148]. This may be an underestimate, as caregivers may be embarrassed to report this behavior to a
clinician. Examples of sexually inappropriate behavior include inappropriate explicit sex talk and sex acts (grabbing, fondling, public
masturbation, exposing). Other behavioral symptoms (agitation, aggression, and/or depression) are usually present. This problem
occurs in vascular dementia as well as Alzheimer disease (AD) and other neurodegenerative dementias.
A limited number of studies have investigated this problem, almost always in men, and usually in the form of small case series or case
reports. Efficacy has been reported with a variety of psychotropic medications including antidepressants, antipsychotic agents, and
cholinesterase inhibitors, as well as gabapentin, pindolol, and cimetidine [148-152]. Hormonal agents (eg, medroxyprogesterone
acetate, diethylstilbestrol, estrogen, leuprolide) have also been used, with anecdotal reports of efficacy [148,151-153]. However, given
their side effect profile, these are not considered first-line agents.
Given the absence of controlled clinical data, treatment for this problem is necessarily empiric. Behavioral interventions (redirection,
distraction, avoiding stimulants) should be tried first. If this is insufficient, medication trials seem reasonable [145,151]. One systematic
review concluded that the preponderance of anecdotal data provided the most support for antidepressant agents, making these the first
drug of choice [152] (see 'Antidepressant medication' above). Another valid approach may be to examine the context of other behavioral
symptoms that the patient may be experiencing and to try an agent that seems most appropriate for the overall symptom complex [148].
SUPPORT FOR CAREGIVERS
Caregivers of patients with dementia can suffer significant stress, particularly as cognitive function declines or behavioral symptoms
worsen [154]. Respite care and support groups are available in most areas, often through the local agency on aging.
A variety of caregiver intervention studies have been performed, assessing both short-term and long-term outcomes, with mixed results.
Most, but not all, have shown that counseling and support interventions benefit caregivers in the short term as measured by a reduction
in stress and improvement in emotional wellbeing and quality of life [155-157]. As an example, a randomized trial that included 260
caregivers of family members with dementia found that an eight-session educational program was associated with decreased caregiver
anxiety and depression scores and improved quality of life over an eight-month period [157]. A randomized study using a different
intervention (access to a volunteer "befriender" trained to give psychosocial support to caregivers) was less successful, and the majority
of caregivers in the intervention group did not take up the volunteer [156].
Optimizing caregiver support might also help to keep patients with dementia cared for in the home. A meta-analysis of 13 studies of
support programs for caregivers found that interventions designed to provide support for caregivers decreased the odds of
institutionalization [158]. Among the heterogeneous and usually multicomponent interventions used, no specific type stood out as most
effective. However, those that allowed individualization and choice by the caregiver seemed more effective than those that were more
rigorously standardized.
Nationally, information can be obtained from the Alzheimer's Association at 1-800-272-3900, or on the internet at www.alz.org.
Information regarding frontotemporal dementia (FTD) can be found at www.theaftd.org.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately.
(See "Society guideline links: Cognitive impairment and dementia".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces
are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to
12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients.
(You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Dementia (including Alzheimer disease) (The Basics)" and "Patient education: Tips for
caregivers of people with Alzheimer disease (The Basics)")
● Beyond the Basics topics (see "Patient education: Dementia (including Alzheimer disease) (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
● Neuropsychiatric symptoms are common in dementia (table 1) and contribute to nursing home admission and caregiver stress.
Because these symptoms may not be volunteered, clinicians should routinely ask about them. (See 'Symptom assessment' above.)
● When a patient with dementia develops neuropsychiatric symptoms, the first step is to identify precipitating factors and rule out and
treat a medical cause or superimposed delirium (table 3). Agitation and other behavioral abnormalities can arise from a variety of
underlying causes in patients with dementia, and identifying the genesis of the abnormal behavior is critical to effective
management. (See 'Evaluation for underlying cause' above.)
● Environmental, behavioral, and other nonpharmacologic therapies can be effective in this population and, when appropriate, are
preferred over medications, which have a high rate of adverse effects. (See 'Nonpharmacologic therapies' above.)
● Pain is an important source of behavioral disturbances in patients with dementia. Both interview and observation should be used to
determine whether pain reporting represents pain-related suffering, pain perseveration, or a signal of some other type of distress.
Pain management and drug prescribing should be approached pragmatically, using a stepped-care approach and starting low and
titrating slowly. (See 'Pain assessment' above and 'Pain management' above.)
● Cholinesterase inhibitors do not produce clinically significant improvement in neuropsychiatric symptoms in patients with dementia.
However, many such patients are still treated with these drugs because of modest improvement in cognition. (See 'Antidementia
drugs' above and "Cholinesterase inhibitors in the treatment of dementia".)
● A trial of selective serotonin reuptake inhibitors (SSRIs) is suggested for the treatment of depression in Alzheimer disease (AD)
(Grade 2C). Citalopram is often used because of its possible additional benefits for other neuropsychiatric symptoms; the dose of
citalopram should not exceed 20 mg daily in older adult patients. Sertraline is a well-studied alternative to citalopram. Tricyclics
should be avoided because of side effects and drug interactions. (See 'Antidepressant medication' above and 'Depression' above.)
● Antipsychotic agents have limited efficacy and are associated with increased mortality in patients with dementia. However,
alternatives are limited when symptoms are severe, disabling, and/or threatening patient or caregiver safety despite safer
interventions. When antipsychotic drugs are deemed necessary, we suggest low doses of olanzapine or risperidone after informing
families of the mortality risk (Grade 2C). Short-term use when possible, with regular reassessments of risks and benefits, is
advised. (See 'Antipsychotic drugs' above.)
● Patients with dementia with Lewy bodies (DLB) are at especially high risk of severe side effects with neuroleptic medications. When
pharmacotherapy is necessary for treatment of behavioral symptoms in such patients, only very low doses of certain atypical
neuroleptics (eg, quetiapine or clozapine) should be used. (See "Epidemiology, pathology, and pathogenesis of dementia with Lewy
bodies".)
● Physical restraints are rarely indicated in the care of patients with dementia and should be used only for patients who pose an
imminent risk of physical harm to themselves or others. (See 'Use of physical restraints' above.)
● Apathy is a common and challenging symptom of dementia that can exist with and without comorbid depression. Treatment
strategies include a cholinesterase inhibitor, a therapeutic trial of an antidepressant, and low-dose methylphenidate. (See 'Apathy'
above.)
● Sleep disturbances are common in patients with dementia. Nonpharmacologic strategies, including maintaining good sleep
hygiene, maximizing morning natural light, and getting daily exercise, are generally preferred to pharmacotherapy. (See "Sleep-
wake disturbances and sleep disorders in patients with dementia".)
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Topic 5082 Version 55.0
GRAPHICS
Neuropsychiatric symptoms of dementia
Delusions
Hallucinations
Depression
Anxiety
Euphoria
Aggression
Apathy
Irritability
Disinhibition
Wandering or pacing
Sleep disturbances
Graphic 95072 Version 1.0
Approach to agitation in patients with dementia
UTI: urinary tract infection; SSRI: selective serotonin reuptake inhibitor.

* Pharmacologic options for agitation include antipsychotic drugs, citalopram, and
dextromethorphan-quinidine. Atypical antipsychotics may be most appropriate for prominent
and distressing hallucinations or delusions. Antipsychotic drug treatment should be
maintained only if benefits are apparent, and discontinuation should be attempted at regular
intervals, weighing the risk of relapse versus the risk of adverse effects from continued
treatment. Refer to UpToDate topics on management of neuropsychiatric symptoms of
dementia for more details.
Pain Assessment in Advanced Dementia (PAINAD) scale
Items* 0 1 2 Score
Breathing independent of Normal Occasional labored breathing. Noisy labored breathing. Long
vocalization Short period of hyperventilation. period of hyperventilation.
Cheyne-Stokes respirations.
Negative vocalization None Occasional moan or groan. Low- Repeated troubled calling out.
level speech with a negative or Loud moaning or groaning. Crying.
disapproving quality.
Facial expression Smiling or inexpressive Sad. Frightened. Frown. Facial grimacing.
Body language Relaxed Tense. Distressed pacing. Rigid. Fists clenched. Knees pulled
Fidgeting. up. Pulling or pushing away.
Striking out.
Consolability No need to console Distracted or reassured by voice or Unable to console, distract, or

touch. reassure.
Total ¶:
This pain assessment score can be used to assess pain in demented patients. Patients should be observed for 5 minutes prior to performing the assessment.
Total scores range from 0 to 10, with 10 representing severe pain.
* Five-item observational tool.

¶ Total scores range from 0 to 10 (based on a scale of 0 to 2 for 5 items), with a higher score indicating more severe pain (0 = "no pain" to 10 = "severe pain").
Original figure modified for this publication. Warden V, Hurley AC, Volicer L. Development and psychometric evaluation of the pain assessment in advanced dementia
(PAINAD) scale. J Am Med Dir Assoc 2003; 4:9. Illustration used with the permission of Elsevier Inc. All rights reserved.
Common causes of delirium and confusional states
Drugs and toxins

Prescription medications (eg, opioids, sedative-hypnotics, antipsychotics, lithium, skeletal muscle relaxers, polypharmacy)
Nonprescription medications (eg, antihistamines)
Drugs of abuse (eg, ethanol, heroin, hallucinogens, nonmedicinal use of prescription medications)
Withdrawal states (eg, ethanol, benzodiazepines)
Medication side effects (eg, hyperammonemia from valproic acid, confusion from quinolones, serotonin syndrome)
Poisons:
Atypical alcohols (ethylene glycol, methanol)
Inhaled toxins (carbon monoxide, cyanide, hydrogen sulfide)
Plant-derived (eg, Jimson weed, Salvia)
Infections
Sepsis
Systemic infections; fever-related delirium
Metabolic derangements
Electrolyte disturbance (elevated or depressed): sodium, calcium, magnesium, phosphate
Endocrine disturbance (depressed or increased): thyroid, parathyroid, pancreas, pituitary, adrenal
Hypercarbia
Hyperglycemia and hypoglycemia
Hyperosmolar and hypoosmolar states
Hypoxemia
Inborn errors of metabolism: porphyria, Wilson disease, etc
Nutritional: Wernicke encephalopathy, vitamin B12 deficiency, possibly folate and niacin deficiencies
Brain disorders
CNS infections: encephalitis, meningitis, brain or epidural abscess
Epileptic seizures, especially nonconvulsive status epilepticus*
Head injury*
Hypertensive encephalopathy
Psychiatric disorders*
Systemic organ failure

Cardiac failure
Hematologic: thrombocytosis, hypereosinophilia, leukemic blast cell crisis, polycythemia
Liver failure: acute, chronic
Pulmonary disease, including hypercarbia and hypoxemia
Renal failure: acute, chronic
Physical disorders
Burns
Electrocution
Hyperthermia
Hypothermia
Trauma: with systemic inflammatory response syndrome, head injury*, fat embolism
CNS: central nervous system.

* Disorders that, while not truly systemic or "medical," may produce the clinical picture of delirium or confusional state in all other aspects.
Psychosocial interventions for management of behavioral and psychotic symptoms in patients with dementia
Routine activity.
Separate the person from what seems to be upsetting him or her.
Assess for the presence of pain, constipation, or other physical problem.
Review medications, especially new medications.
Travel with them to where they are in time.
Don't disagree; respect the person's thoughts even if incorrect.
Physical interaction: Maintain eye contact, get to their height level, and allow space.
Speak slowly and calmly in a normal tone of voice. The person may not understand the words spoken, but he or she may pick up the tone of the voice behind the
words and respond to that.
Avoid finger-pointing, scolding, or threatening.
Redirect the person to participate in an enjoyable activity or offer comfort food he or she may recognize and like.
If you appear to be the cause of the problem, leave the room for a while.
Validate that the person seems to be upset over something. Reassure the person that you want to help and that you love him or her.
Avoid asking the person to do what appears to trigger an agitated or aggressive response.
Reproduced with permission from: Alzheimer's Association Position Statement on Treatment of BPSD. Copyright © 2014 Alzheimer's Association. All rights reserved.
Available at: https://www.alz.org/national/documents/statements_antipsychotics.pdf (Accessed on July 11, 2018).
Drug properties and doses of antidepressants in older adults and medically ill
Starting
Drug Suggested dose range Precautions* Potential advantages
dose
Selective serotonin reuptake inhibitors (SSRIs) ¶
Escitalopram 5 mg every 5 to 20 mg daily Mild discontinuation symptoms may occur absent Applies to escitalopram and
morning or tapering. citalopram:
every Generally well tolerated. Non-sedating,
evening low risk of sleep disturbance,
Citalopram 10 mg every 10 to 20 mg Δ daily Dose-related risk of QT prolongation ¶ Δ. comparatively few significant drug
morning or interactions.
Mild discontinuation symptoms may occur absent
every tapering. Good choice for initial treatment of
evening depression in most older adults.
Sertraline 12.5 to 25 25 to 200 mg daily More frequent gastrointestinal symptoms including Non-sedating, low risk of insomnia,
mg every diarrhea. Variable oral bioavailability. Oral solution lacks significant cardiovascular effects.
morning contains alcohol. Discontinuation symptoms may occur Good choice for initial treatment of
absent tapering. depression in most older adults.
Fluoxetine 5 to 10 mg 5 to 60 mg daily Activating. Activating effect may be useful for

every Significant drug interactions. treatment of depressed patients with
morning low energy or hypersomnia. Tapering
Prolonged half-life and active metabolites require
upon discontinuation is not needed due
weeks to reach steady state, prolonging time needed to
to long half-life.
evaluate effect of dose adjustment and complicating
wash-out and withdrawal.
Paroxetine 10 mg every 10 to 40 mg every evening Weakly anticholinergic. May cause constipation, dry Useful for patients with insomnia.
evening mouth, or drowsiness. Moderate half-life with no active
Associated with more severe discontinuation symptoms metabolites.
in absence of tapering.
Fluvoxamine 25 mg every 25 to 200 mg every evening Significant drug interactions. Short half-life associated May be useful for patients with
evening with discontinuation symptoms in absence of tapering. insomnia.
Serotonin-norepinephrine reuptake inhibitors (SNRIs) ◊
Venlafaxine 37.5 mg once 75 to 225 mg once daily Applies to venlafaxine and desvenlafaxine: Applies to venlafaxine and
(extended daily Activating. desvenlafaxine:
release) Activating effect may be useful for
May cause dose-dependent increases in blood pressure
Venlafaxine 18.75 to 37.5 75 to 150 mg twice daily (primarily diastolic) and heart rate. Monitor blood treatment of melancholic depressed
(immediate mg every pressure regularly. patients with low energy or
release) morning or hypersomnia.
Gastrointestinal symptoms (eg, nausea) may be more
twice daily Useful for patients with comorbid
prominent with immediate-release venlafaxine.
Desvenlafaxine 50 mg every 50 mg every morning painful conditions such as diabetic
Associated with discontinuation symptoms absent
morning neuropathy.
CrCl <30 mL/min: 50 mg tapering. Taper desvenlafaxine by increasing interval
CrCl <30 every other day between doses.
mL/min: 50
mg every
other day
Duloxetine 10 to 20 mg 20 to 60 mg once daily Significant drug interactions. Mildly sedating. Low risk of insomnia.
daily Useful for patients with comorbid
painful conditions such as diabetic
neuropathy or chronic pain.
Atypical antidepressants ◊
Mirtazapine 7.5 mg every 15 to 60 mg every evening Prolonged half-life and active metabolites. Risk of Sedating. Low risk of sexual
evening accumulation with renal and/or hepatic insufficiency. dysfunction.
Dose reductions necessary. Appetite stimulant and antinausea
Drowsiness, weight gain. Rare reports of effects can be noted within days.
agranulocytosis. Useful for patients with insomnia or
who may benefit from weight gain.
Bupropion 75 mg in 150 mg in morning and Avoid in seizure disorders and depressed patients with Stimulant effect may be useful for
sustained morning midafternoon (twice daily) agitation. Dose-dependent increase in diastolic blood treatment of depressed patients with
release initially then pressure. May worsen insomnia. low energy and apathy. Low risk of
twice daily cognitive toxicity. Dopaminergic action
may be advantageous for depressed
patients with Parkinson disease.
Vilazodone 10 mg once 20 to 40 mg once daily with Take with food to assure bioavailability. Low incidence of weight gain or sexual
daily with food Diarrhea, nausea, vomiting, dizziness, insomnia. dysfunction.
food Role in therapy for treatment of
Significant drug interactions via CYP 3A4 require dose
for seven depressed older adults or adults with
adjustment.
days or more comorbid illness is not yet defined.
Trazodone 12.5 to 25 25 to 100 mg taken 30 to 60 Sedation, orthostatic hypotension, nausea. Residual Used in low doses as adjunct to SSRI
mg taken 30 minutes before bedtime for daytime sedation and cognitive impairment. Reports of for treatment of insomnia.
to 60 minutes hypnotic effects; hyponatremia.
before antidepressant effects require
bedtime for higher doses
hypnotic
effects
Tricyclic antidepressants (TCAs) §
Nortriptyline 10 mg every 10 to 100 mg every evening Applies to nortriptyline and desipramine: Applies to nortriptyline:
evening or in two divided doses May be poorly tolerated by medically ill and older Established therapeutic serum
adults due to anticholinergic effects that include dry concentration 50 to 150 ng/mL.
mouth, constipation, urinary retention, or altered vision Mildly sedating. Taken at bed time for
(eg, avoid in prostatic disease or narrow angle depressed patients with insomnia.
glaucoma).
May be useful for melancholic,
May be fatal in overdose. anxious, depressed patients who have
Potentially cardiotoxic, can cause arrhythmia or not responded to first- and second-line
orthostatic hypotension. antidepressants.
Desipramine 10 mg every 25 to 150 mg every morning Significant drug interactions. Applies to desipramine:
morning or in two divided doses Established therapeutic serum
concentration 125 to 300 ng/mL.
Mild stimulant effects may be useful
for depressed patients with low energy
and hypersomnia who have not
responded to first- and second-line
antidepressants.
CYP: cytochrome.
* Specific interactions of antidepressants with other medications may be determined using the Lexi-Interact™ drug interactions program included with UpToDate.
¶ For additional information refer to topic on unipolar depression in adults and SSRIs.
Δ Maximum recommended daily dose of citalopram is 20 mg for patients >60 years of age, with significant hepatic insufficiency, or taking interacting medications that can
increase citalopram levels.
◊ For additional information refer to topic on SNRIs and other antidepressants for treating depressed adults.
§ For additional information refer to topic on tricyclic and tetracyclic antidepressants for treating depressed adults.
Selected adverse effects of antipsychotic medications for schizophrenia
Weight
Hyper- Prolactin Anticholinergic Orthostatic QTc
gain/diabetes EPS/TD Sedation
cholesterolemia elevation side effects hypotension prolongation
mellitus
First generation agents
Chlorpromazine +++ +++ + ++ +++ +++ +++ +++
Fluphenazine + + +++ +++ + –/+ – –/+*
Haloperidol + + +++ +++ ++ –/+ – Oral: ++

IV: +++
Loxapine ++ ND ++ ++ ++ + + –/+*
Perphenazine ++ ND ++ ++ ++ + – –/+*
Pimozide + ND +++ ++ + + + ++ ¶
Thioridazine Δ ++ ND + +++ +++ ++++ ++++ ++
Thiothixene ++ ND +++ ++ + + + ND
Trifluoperazine ++ ND +++ ++ + + + ND
Second generation agents
Aripiprazole + – + – + – – –/+*
Asenapine ++ – ++ ++ ++ – + +
Brexpiprazole ◊ + + + –/+ + –/+ –/+ –/+*
Cariprazine ◊ + –/+ ++ –/+ + –/+ –/+ –/+*
Clozapine § ++++ ++++ –/+ –/+ +++ +++ +++ ++
Iloperidone ++ ++ –/+ –/+ + + +++ +
Lurasidone –/+ –/+ ++ –/+ ++ – + –/+*
Olanzapine ++++ ++++ + + ++ ++ + ++
Paliperidone +++ + +++ +++ + – ++ +
Pimavanserin + – –/+ – + + ++ +
Quetiapine +++ +++ –/+ –/+ ++ ++ ++ ++
Risperidone +++ + +++ +++ + + + ++
Ziprasidone –/+ –/+ + + + – + +++
Adverse effects may be dose dependent. The QTc classifications are consistent with US Food & Drug Administration (US FDA) guidance. [1] Other sources may
use a different classification system resulting in some agents being classified differently.
EPS: extrapyramidal symptoms; TD: tardive dyskinesia; IV: intravenous; ND: insufficient data.
* Clinically relevant QTc prolongation was not detected in preliminary studies or reported in the manufacturer's labeling.
¶ Although the available evidence concerning the average QTc prolonging effect of pimozide is consistent with a classification of moderate significance (ie, ++), label
warnings have characterized the QTc effect and cardiovascular risks as severe and sudden deaths in patients on pimozide have been reported.
Δ Thioridazine is also associated with dose-dependent retinitis pigmentosa. Refer to UpToDate text.
◊ Based upon limited experience.
§ Clozapine also causes granulocytopenia or agranulocytosis in approximately 1% of patients requiring regular blood cell count monitoring. Clozapine has been associated
with excess risk of myocarditis and venous thromboembolic events including fatal pulmonary embolism. These issues are addressed in the UpToDate topic review of
guidelines for prescribing clozapine section on adverse effects.
Reference:
1. Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs – Questions and Answers; Guidance for Industry US
Food and Drug Administration, June 2017 (revision 2). Available at:
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073161.pdf
With additional data from:
Lexicomp Online. Copyright © 1978-2019 Lexicomp, Inc. All Rights Reserved.
Rummel-Kluge C, Komossa K, Schwarz S. et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of
schizophrenia: a systematic review and meta-analysis. Schizophr Res 2010; 123:225.
Durán CE, Azermai M, Vander Stichele RH. Systematic review of anticholinergic risk scales in older adults. Eur J Clin Pharmacol 2013; 69:1485.
Depression in Alzheimer-type dementia
A. Three or more of the following symptoms, present during the same two-week period, and representing a change from a previous level of functioning. Either item
one or item two must be included:
1. Clinically significant depressed mood
2. Decreased positive affect or pleasure in response to social contacts and usual activities
3. Social isolation or withdrawal
4. Disturbed appetite
5. Disturbed sleep
6. Psychomotor retardation or agitation
7. Irritability
8. Fatigue or loss of energy
9. Feelings of worthlessness, hopelessness, or inappropriate guilt
10. Recurrent thoughts of death or suicidal ideation, plan, or any attempt
B. Meets criteria for Alzheimer-type dementia
C. Depressive symptoms cause clinically significant distress or disruption in function
D. Symptoms do not occur exclusively during an episode of delirium
E. Symptoms are not due to a direct physiologic effect from a substance (medication or drug of abuse)
F. Symptoms are not better accounted for by another condition

Specify if:
Co-occurring onset: onset antedates or co-occurs with AD symptoms
Post-AD onset: onset occurs after AD diagnosis
Specify if:
With psychosis of AD
With other significant behavioral signs or symptoms
With past history of mood disorder
AD: Alzheimer disease.
Contributor Disclosures
Daniel Press, MD Nothing to disclose Michael Alexander, MD Nothing to disclose Kristine Yaffe, MD Consultant/Advisory Boards: Eli Lilly
[Dementia (Data and Safety Monitoring Board)]. Kenneth E Schmader, MD Grant/Research/Clinical Trial Support: GlaxoSmithKline [Herpes zoster
(Zoster vaccine)]. Janet L Wilterdink, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level
review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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Misperception or misunderstanding — There is a hierarchy of causes of misunderstanding.

● Prescribe a trial of scheduled analgesics.

● Use a stepped-care approach to analgesic prescribing.

● Start low, go slowly, but use enough.

Other therapies with possible benefit include:

In general, we prefer one of the following:

Dextromethorphan-quinidine — Dextromethorphan and quinidine as a combination pill (dextromethorphan-quinidine 20 mg/10 mg)

SEXUALLY INAPPROPRIATE BEHAVIOR

SUPPORT FOR CAREGIVERS

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

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Topic 5082 Version 55.0

Neuropsychiatric symptoms of dementia

Graphic 95072 Version 1.0

Approach to agitation in patients with dementia

UTI: urinary tract infection; SSRI: selective serotonin reuptake inhibitor.

Graphic 115346 Version 1.0

Pain Assessment in Advanced Dementia (PAINAD) scale

Facial expression Smiling or inexpressive Sad. Frightened. Frown. Facial grimacing.

Consolability No need to console Distracted or reassured by voice or Unable to console, distract, or

* Five-item observational tool.

Graphic 59509 Version 6.0

Common causes of delirium and confusional states

Drugs and toxins

Nonprescription medications (eg, antihistamines)

Withdrawal states (eg, ethanol, benzodiazepines)

Systemic infections; fever-related delirium

Endocrine disturbance (depressed or increased): thyroid, parathyroid, pancreas, pituitary, adrenal

Hyperglycemia and hypoglycemia

Hyperosmolar and hypoosmolar states

Inborn errors of metabolism: porphyria, Wilson disease, etc

Epileptic seizures, especially nonconvulsive status epilepticus*

Systemic organ failure

Hematologic: thrombocytosis, hypereosinophilia, leukemic blast cell crisis, polycythemia

Liver failure: acute, chronic

Pulmonary disease, including hypercarbia and hypoxemia

Renal failure: acute, chronic

CNS: central nervous system.

Graphic 59893 Version 5.0

Separate the person from what seems to be upsetting him or her.

Assess for the presence of pain, constipation, or other physical problem.

Review medications, especially new medications.

Travel with them to where they are in time.

Don't disagree; respect the person's thoughts even if incorrect.

Avoid finger-pointing, scolding, or threatening.

Graphic 98510 Version 4.0

Selective serotonin reuptake inhibitors (SSRIs) ¶

Fluoxetine 5 to 10 mg 5 to 60 mg daily Activating. Activating effect may be useful for

Serotonin-norepinephrine reuptake inhibitors (SNRIs) ◊

Tricyclic antidepressants (TCAs) §

Graphic 57207 Version 8.0

Selected adverse effects of antipsychotic medications for schizophrenia

First generation agents

Chlorpromazine +++ +++ + ++ +++ +++ +++ +++

Fluphenazine + + +++ +++ + –/+ – –/+*

Haloperidol + + +++ +++ ++ –/+ – Oral: ++

Thioridazine Δ ++ ND + +++ +++ ++++ ++++ ++

Second generation agents