Version May 2024
INTRODUCTION — Neuropsychiatric symptoms in Alzheimer disease (AD) and other types of dementia are extremely common and often much more troubling than cognitive symptoms [1]. 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 [2-6]. The presence of neuropsychiatric symptoms leads to greater functional impairment in patients with dementia and cognitive impairment [6,7]. These behaviors often accelerate or lead to nursing home placement [7-11].
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 Alzheimer disease" and "Frontotemporal dementia: Treatment" and "Prognosis and treatment of dementia with Lewy bodies" and "Treatment of vascular cognitive impairment and dementia" and "Management of the patient with 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 [12,13]. Screening for agitation and other neuropsychiatric symptoms in patients with dementia should be done at regular follow-up visits [13]. 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 [10].
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 [11,14-17]. Risk factors include poor light exposure and disturbed sleep [18]. 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 [2]. 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 [10]. 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.
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 [2,10]. 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 (table 2). (See "Drug prescribing for older adults", section on 'Anticholinergic activity'.)
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 [19]. 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 chronic non-cancer 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 [20]:
●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 3) [21].
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 4) [22,23]. 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 [24]. 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 — 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. Phantom boarder syndrome is another delusion that is described in patients with dementia.
If delusions appear to trigger aggression, pharmacologic treatment may be helpful or necessary, but the underlying belief 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 [25-29].
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 5) [13]. 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 [13,30-32].
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 5) [30,32]. 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 [33]. 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 [34]. 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 [34].
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 [35]. 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 [36]. 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 [37-40].
●In preliminary studies, massage and touch therapy appear to be potentially beneficial in the immediate management of agitated behavior and in encouragement to eat [41].
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 chronic non-cancer 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 [42].
One randomized study evaluated a systematic approach to pain evaluation and pharmacologic management in 352 patients with behavioral disturbances and dementia [43,44]. The intervention was a stepwise protocol that followed recommendations of the American Geriatrics Society, consisting of acetaminophen, low-dose morphine, buprenorphine patch, and pregabalin [45]. 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 [46,47]. 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 [48,49]. However, systematic reviews have concluded that studies have not demonstrated a clinically significant effect of memantine for neuropsychiatric symptoms of dementia [46,50,51].
Antidepressant medication — Despite mixed results in clinical trials, we have found selective serotonin reuptake inhibitors (SSRIs) (table 6), 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 [52]. 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 [53].
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 [50,54]. 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 [55-60]. 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 [60]. 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 [55,58,61,62]. (See 'Mortality risk' below.)
Trazodone was compared with placebo in one trial that found no benefit on neuropsychiatric symptoms [63]. Two trials that compared trazodone with haloperidol found no significant relative benefit or harm between these two treatments [63,64]. 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 medications 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 [65]. 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 [66], and a systematic review concluded that there is currently not enough evidence of benefit for carbamazepine to recommend its use for neuropsychiatric symptoms [50].
●Valproate improved aggressive behavior in several earlier reports [67,68]. 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 [50].
●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 [69]. 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 [70-76]. 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 [77].
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 [78]. 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 [79,80].
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 'Mortality risk' below.)
Clinical use — Given the risk of increased mortality associated with the use of atypical neuroleptics in older adults with dementia (see 'Mortality risk' below), we reserve their use for patients who have neuropsychiatric symptoms, particularly psychosis, that are severe, debilitating, or posing safety risks [80]. 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.)
●Initiation of treatment – 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.
•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.
•Pimavanserin is a newer alternative antipsychotic agent with some limited evidence of efficacy in this setting; it is typically started at 34 mg daily. A serotonin-receptor modulator 5HT2A inverse agonist and antagonist with no dopamine D2 affinity, it has also been studied for Parkinson disease-related psychosis. Adverse effects include QT prolongation. (See "Management of nonmotor symptoms in Parkinson disease", section on 'Refractory psychotic symptoms'.)
●Ongoing treatment – 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 [81,82]. 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 [80].
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 [83]. 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. Another randomized trial evaluated 193 patients with dementia-related psychosis who initially responded to treatment with pimavanserin [84]. Patients were randomly assigned to continued treatment with pimavanserin versus placebo. The trial was stopped early for benefit; relapses were less common in pimavanserin versus placebo-treated patients (13 versus 28 percent; hazard ratio [HR] 0.35, 95% CI 0.17-0.73).
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 [85]. Patients with severe baseline irritability/lability and severe auditory hallucinations may be at increased risk for relapse [86].
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 [50].
●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 [50]. A Cochrane review concluded that haloperidol may help control aggression but not other neuropsychiatric manifestations of dementia [87]. 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 [50,88]. 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 [89].
Pimavanserin is a newer antipsychotic agent, a serotonin-receptor modulator 5HT2A inverse agonist and antagonist with no dopamine D2 affinity, which has been studied for Parkinson disease-related psychosis. A trial in 181 patients with dementia due to AD and/or vascular dementia suggested efficacy for pimavanserin at 6 weeks but not at 12 weeks [90]. In a subsequent study, 351 patients with dementia-related psychosis were treated with open-label pimavanserin (20 or 34 mg once daily); 217 had a clinical response that was sustained at 12 weeks [84]. This was followed by a randomized trial of drug continuation versus placebo; a higher relapse rate (13 versus 28 percent) in the placebo-treated patients as noted above provides further evidence of the efficacy of this agent.
There are limited studies regarding the comparative efficacy of these agents. 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 [91].
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 [92]. 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 7). 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 [50,93].
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 [50,88,91,92]. These include extrapyramidal symptoms, confusion, somnolence, falls, and fractures (table 7). 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. These second-generation agents also have a risk of QT prolongation. (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 [94]. Risperidone and the typical antipsychotic agents should not be used in patients who have DLB. (See "Schizophrenia in adults: Guidelines for prescribing clozapine", section on 'Monitoring' and "Prognosis and treatment of dementia with Lewy bodies".)
Mortality risk — 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 [95,96]. Their findings were confirmed in an independently conducted meta-analysis, as well as a subsequent randomized, placebo-controlled study [97,98]. 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 [99,100], 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 [99-106]. Both short-term and long-term treatment is problematic [107], and higher doses are associated with increased risk [102,105]. Concurrent use of nonsteroidal antiinflammatory drugs may also increase risk [108].
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 [105]. 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 [97]. 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) [97], whereas the retrospective study estimated risk of a six-month period [105]. 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 [50,109-111], others have not [112-114]. 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) [113].
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 [115,116]. 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 [117]. 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 [118].
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 [118].
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 [119], 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 [120]. 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 [119]. Small randomized trials have shown that educational interventions for nursing home staff can reduce rates of restraint use while maintaining resident safety [121-124].
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".)
However, older adults who become depressed are at increased risk of having comorbid dementia or of developing dementia in the future [125]. 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 [126].
●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. (See 'Apathy' below and 'Sleep disorders' below.)
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 particular difficulty in patients with vascular dementia (multiple lacunar infarctions), some of whom have relatively mild dementia, often not meeting formal diagnostic criteria, but also have considerable apathy while also reporting depression.
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 [125]. The American Association for Geriatric Psychiatry has proposed diagnostic criteria for depression in patients with AD (table 8) [127]. 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 [128,129]. 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 [130,131]. Options are discussed in detail separately. (See "Diagnosis and management of late-life unipolar depression".)
Selection of a specific SSRI is generally based upon the side effect profile, drug interactions, and cost (table 6). Sertraline (starting at a dose of 25 mg) and citalopram are commonly used in this setting. Citalopram may also improve psychotic and other behavioral 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 [55] (see 'Antidementia drugs' above). The dose of citalopram should not exceed 20 mg daily in older adult patients [52]. 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 [57,132]. However, a study in 131 patients with AD and depression found no efficacy for sertraline after 12 and 24 weeks of therapy [133,134]. Finally, a randomized study comparing sertraline with placebo in 218 patients found no differences in depression scores at 13 or 39 weeks [135]. 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 [136]. 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 [135].
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 [137]. Nortriptyline may be better tolerated than amitriptyline because of fewer anticholinergic effects. (See "Diagnosis and management of late-life unipolar depression".)
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 [138-140]. 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 [141], and smaller studies also suggest that it may improve apathy as well as other outcomes in patients with dementia [142-145]. 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) [143]. 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 [146]. 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 [13]. (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 "Management of the patient with 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 [147-151]. 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 [151-155]. Hormonal agents (eg, medroxyprogesterone acetate, diethylstilbestrol, estrogen, leuprolide) have also been used, with anecdotal reports of efficacy [151,154-156]. 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 [148,154]. One systematic review concluded that the preponderance of anecdotal data provided the most support for antidepressant agents, making these the first drug of choice [155] (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 [151].
SUPPORT FOR CAREGIVERS — Caregivers of patients with dementia can suffer significant stress, particularly as cognitive function declines or behavioral symptoms worsen [157]. Respite care and support groups are available in most areas, often through the local agency on aging. (See "Management of the patient with dementia", section on 'Support for caregivers'.)
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: Caring for someone with Alzheimer disease or dementia (The Basics)")
●Beyond the Basics topics (see "Patient education: Dementia (including Alzheimer disease) (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Screening – 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.)
●Assessment for underlying causes – 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 4). (See 'Evaluation for underlying cause' above.)
●Nonpharmacologic approaches – 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 management – Pain can aggravate 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. (See 'Pain assessment' above.)
Appropriate pain management includes a stepped-care approach, starting low and titrating slowly. (See 'Pain management' above.)
●Role of cholinesterase inhibitors – Cholinesterase inhibitors do not produce clinically significant improvement in neuropsychiatric symptoms in patients with dementia. However, patients are often treated with these drugs because of modest improvement in cognition. (See 'Antidementia drugs' above and "Cholinesterase inhibitors in the treatment of dementia".)
●Depression – 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.)
●Severe or refractory agitation – 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 quetiapine (Grade 2C) after informing families of the mortality risk. 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 – 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 – 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".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael Alexander, MD, who contributed to an earlier version of this topic review.
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