Neuropsychiatric symptoms in dementia

Handbook of Clinical Neurology, Vol. 167 (3rd series) Geriatric Neurology S.T. DeKosky and S. Asthana, Editors https://doi.org/10.1016/B978-0-12-804766-8.00024-8 Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 24

Neuropsychiatric symptoms in dementia 1

REBECCA RADUE1,2, ART WALASZEK3*, AND SANJAY ASTHANA1 Division of Geriatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States

2

Geriatric Research, Education and Clinic Center, William S. Middleton Memorial Veterans Hospital, Madison, WI, United States 3

Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States

Abstract The prevalence of dementia is expected to rise with the aging of our population for decades to come. Neuropsychiatric symptoms of dementia, also known as behavioral and psychologic symptoms of dementia, are extremely common. Symptoms are most prevalent in the moderate stages of the disease, often increase with advancing disease stage, and often more than one symptom is present. These symptoms can cause a great deal of distress for patients and families, and take a toll on society as well. Evaluation and management can be challenging, with nonpharmacologic strategies recommended as first-line approach. There is growing evidence for specific pharmacologic strategies, but these come with significant risk, such that informed consent with the patient and surrogate decision maker is critical. In this chapter, we focus on general principles of etiology, assessment, and management, and then turn to individual symptoms of agitation, psychosis, apathy, sleep disturbance, and feeding and eating problems more specifically. Depression and anxiety are covered elsewhere in this text.

BACKGROUND Epidemiology According to the Alzheimer’s Association, 5.7 million Americans were living with dementia in 2018 (Alzheimer’s Association, 2018). These rates are expected to nearly triple by 2020, with a projected 14 million Americans affected. Neuropsychiatric symptoms (NPS) are more the rule than the exception in dementia, estimated to affect roughly 90% of all patients with Alzheimer’s disease (AD) at some point during the course of their illness, and similar or greater prevalence rates for other forms of dementia. These symptoms, also often referred to as behavioral and psychologic symptoms of dementia (BPSD), broadly include agitation, psychosis, apathy, sleep disturbances, and appetitive changes, as well as depression and anxiety. Most studies of NPS have been conducted in AD or mixed AD and vascular dementia (VD), but the general and

management principles can be applied across etiologies. It should also be noted that though this chapter refers to NPS of dementia, these symptoms are not infrequently present in patients with mild cognitive impairment (MCI, or mild neurocognitive disorder) as well. Some forms of dementia, which the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) refers to as major neurocognitive disorder, contain certain NPS within their diagnostic criteria, such as well-formed and detailed visual hallucinations in dementia with Lewy bodies (LBD). Another example is the behavioral disinhibition and apathy characteristic of behavioral variant frontotemporal dementia (FTD). Across dementia etiologies, NPS tend to be more prevalent with progressive stages of impairment, and peak in prevalence in the moderate stages. Fig. 24.1 highlights the prevalence of NPS during the progressive stages of dementia. It is quite common for a person living with dementia to suffer from more than one NPS at a time, or to have a

*Correspondence to: Art Walaszek, M.D., Department of Psychiatry, University of Wisconsin School of Medicine & Public Health, 6001 Research Park Blvd., Madison, WI 53719, United States. Tel: +1-608-263-6106, Fax: +1-608-261-5653, E-mail: [email protected]

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change in type of symptoms throughout the course of their illness. In general, depression is most common in earlier stages of disease progression. If aggression or apathy is present, they tend to be more likely, than some of the other symptoms, to persist throughout the disease

25.7% 56.0%

course (van der Linde et al., 2016). Fig. 24.2 shows the relative prevalence of each of the core NPS, with apathy being most common overall.

Neurobiology and etiologic theories There are many theories describing the etiologic underpinnings of NPS. Psychologic factors that may play a role include premorbid personality structure, history of trauma, and preexisting psychiatric disorders (Prior et al., 2016). It has been demonstrated that premorbid neuroticism correlates with aggression and mood disturbance (Osborne et al., 2010). Premorbid psychiatric disorders have also been associated with increased risk for developing dementia and NPS—specifically depression, bipolar disorder, schizophrenia, anxiety disorders, and alcohol use disorder (Zilkens et al., 2014). Theoretical frameworks, within which to view NPS, include the behavioral model (Teri et al., 1998), the progressively lowered stress threshold model (Smith et al., 2004), and the unmet needs model (Kovach et al., 2005). Turning to the neurobiologic correlates of NPS (Casanova et al., 2011; Rosenberg et al., 2015a,b; Boublay et al., 2016):

30.4%

54.5% 30.0%

82.3%

31.4%

No symptoms 1–2 symptoms 32.6%

3+ symptoms

30.3% 44.3%

13.3% 4.3%

11.2%

38.2%

15.2%

Normal Mild Mild Moderate Severe cognition cognitive dementia dementia dementia impairment

Fig. 24.1. Prevalence of neuropsychiatric symptoms (NPS) by stage of cognitive impairment. The prevalence of NPS varies by stage of cognitive impairment. The categories in each stage include subjects with no symptoms, one or two symptoms, and three or more symptoms in the last month. Reprinted with permission from Walaszek: Behavioral and Psychology Symptoms of Dementia, (Copyright ©2019). American Psychiatric Association. All Rights Reserved. Adapted from Okura, T., Plassman, B.L., Steffens, D.C., et al., 2010. Prevalence of neuropsychiatric symptoms and their association with functional limitations in older adults in the United States: the Aging, Demographics, and Memory Study. J Am Geriatr Soc 58, 330–337.

1. Apathy has been associated with atrophy, increased amyloid burden, hypoperfusion, and decreased white matter integrity of the anterior cingulate cortex. Additionally, frontal lobe atrophy and damage, and in particular pathologic changes in the orbitofrontal cortex, have been linked with apathy. Studies of apathy

Apathy

49%

Depression

42%

Aggression

40%

Sleep disorder

39%

Anxiety

39%

Irritability

36%

Appetite disorder

34%

Aberrant motor behavior

32%

Delusions

31%

Disinhibition

17%

Hallucinations

16%

Euphoria 7% 0%

10%

20%

30%

40%

50%

60%

Fig. 24.2. Prevalence of specific neuropsychiatric symptoms (NPS). Estimates of prevalence are pooled from 48 studies of NPS in Alzheimer’s disease, using the Neuropsychiatric Inventory. The error bars indicate the 95% confidence interval for each estimate. Adapted from Zhao, Q.-F., Tan, L., Wang, H.-F., et al., 2016. The prevalence of neuropsychiatric symptoms in Alzheimer’s disease: systematic review and meta-analysis. J Affect Disord 190, 264–271.

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2.

3.

that included cerebrospinal fluid analysis have demonstrated increase in tau protein. Vascular risk factors are broadly associated with development of apathy in dementia. Patients with delusions are more likely to have abnormalities in the frontal and anterior cingulate cortices. Also seen with delusions are dopaminergic signaling disturbances and neuronal loss in the parahippocampal gyrus and hippocampus. Agitation has been associated with atrophy of the frontal cortex, insula, cingulate cortex, amygdala, and hippocampus. Neurotransmitter-specific associations have been seen as well, with decreased cholinergic and serotonergic activity widely demonstrated. These neurobiologic associations demonstrate that emotion regulation, threat assessment, and problem-solving areas of the brain are implicated in the neurobiology of agitation.

Effects on patients and care givers The detrimental effects of dementia and NPS on society and individuals affected are severe. It is estimated that a full 30% of the US economic cost of dementia is due to NPS. The toll of NPS on care givers is also grave, with caregiver burnout, increased rates of depression and anxiety, sleep disturbance, and overall distress being high (Sallim et al., 2015; Cheng, 2017). Family or friend care givers who are still working not only have to deal with the financial toll of caring for their loved one, but may also miss out on income due to caregiving interference with employment (Kales et al., 2014). From the caregiver perspective, these factors combine to increase risks of abuse, neglect, and earlier institutionalization of loved ones living with dementia. The greatest toll, however, is often on the patients who suffer with NPS and their quality of life. The fallout includes emotional distress, increased risk of injury and medical complications, accelerated cognitive and functional decline, increased rate of hospitalizations, earlier institutionalization, and increased risks of abuse, neglect, and earlier mortality (Kales et al., 2014).

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of dementia often has bearing on the treatment indicated for broad and specific NPS. The next priority is to characterize the NPS as specifically as possible, including severity, quality, timing, antecedents, consequences, and new or change in NPS. It is also important to screen broadly for NPS, as patients often experience more than one symptom, and symptoms may cluster together (for example, psychosis and agitation commonly present concurrently). Often, because multiple NPS may be present, it can be helpful to have care givers or facilities rank the symptoms present in order of importance. Several methods exist to capture these elements of NPS, including the ABC (antecedents, behaviors, consequences) and DICE methods (Kales et al., 2014). DICE is illustrated in Fig. 24.3. A method for comprehensive assessment and management exists as well, the TIME model, which is discussed further in the section “General management” (Lichtwarck et al., 2018). Rating scales can be helpful in characterizing NPS as well. We recommend the Neuropsychiatric Inventory Questionnaire (NPI-Q) for primary caregivers (Kaufer et al., 2000) and the NPI Nursing Home version (NPI-NH) for long-term care (LTC) facilities (Wood et al., 2000). Another method to capture the specifics and background of NPS is the Wisconsin Star Method, which is illustrated in Fig. 24.4 (Howell, 2015). A crucial step in evaluating NPS is to consider medical etiologies, including toxic, metabolic, infectious, or neurologic illness, as well as medication factors and substances. In terms of medical etiologies, any sudden change in mental status and behavior in a person living with cognitive impairment should be considered possible delirium until proven otherwise. Common infectious causes of delirium or worsening or new NPS include pneumonia and urinary tract infection. Pain is a very important contributor to NPS, and the prevalence of pain in dementia is very high (estimated 47%–68%; Husebo et al., 2016). Other considerations are urinary retention,

Describe the problematic behavior; Investigate possible causes of the behavior;

General assessment The first step in assessing NPS is to characterize the underlying type of dementia, if possible. The primary categories that we are concerned with in this chapter include AD, VD, LBD, Parkinson disease dementia (PDD), and FTD. The primary reasons for this need to determine causative etiology of the dementia driving the NPS are: first, to determine whether any factors contributing may be reversible and, second, because the type

Create a treatment plan; and, Evaluate the outcome of this plan. Fig. 24.3. Dice method for evaluation of neuropsychiatric symptoms. Adapted from Kales, H.C., Gitlin, L.N., Lyketsos, C.G., et al., 2014. Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel. J Am Geriatr Soc 62, 762–769.

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General management

Behavioral and psychological symptoms of dementia

Psychological factors

Social factors

Medical factors

Medications

Fig. 24.4. Wisconsin star method. The Wisconsin Star Method highlights the interrelationships among psychologic factors, social factors, medical factors, and medications in the genesis of BPSD. These may be protective factors or risk factors.

constipation, dehydration, and hunger. Sleep disorders are another not-to-miss consideration. It is also important to screen for sensory impairment, specifically vision and hearing. Medication interactions and adverse effects are common among those living with dementia. Rates of polypharmacy can be high in this population. It is important to screen for use of supplements and over the counter medications. Also important is screening for how medications are managed, especially if the patient is living at home. Important questions to ask include organization of refills and medications, medication administration, how frequently doses are missed or errors are made, and whether and how often medications are refused by the patient. If the patient is living in an LTC facility, it is crucial to obtain an up-to-date medication administration record (MAR) that includes as-needed medication administration. When screening medication regimens for potential contributors to NPS, keeping the Beers Criteria in mind to help identify potential contributing medications can be helpful (American Geriatrics Society 2015 Beers Criteria Update Expert Panel, 2015). Older adults, including those living with dementia, are not immune to substance abuse. It is important to screen for alcohol use, cannabis use, and opioid use. A broad substance use assessment is generally recommended (Ahmed et al., 2015; Han and Moore, 2018). Additional considerations to screen for include new stressors or change in environment, cultural or spiritual beliefs or practices that may play a role, and history of trauma that may influence current symptoms. Finally, screening for caregiver factors is also important. Consider the effect of the NPS on the care givers, whether in-home or institutional, related or professional, paid or unpaid. Screening for elder abuse or neglect is recommended.

While most literature on management of NPS is focused on AD, many principles apply across types of dementia. It should also be noted that some pharmacologic and nonpharmacologic treatment recommendations are specific to certain types of dementia. First and foremost, treating any underlying medical derangements is crucial. Correction of vision and hearing has been shown to reduce NPS in specific populations (Koch et al., 2005; Jorgensen and Messersmith, 2015). All experts and consensus guidelines recommend nonpharmacologic interventions first, prior to consideration of medication intervention, whenever possible. Nonpharmacologic interventions can be especially effective. One of the most important and efficacious interventions, with well-documented supporting evidence, is caregiver education and training (Kales et al., 2015; Vandepitte et al., 2016). In addition, for family or friend in-home care givers, respite care and adult day centers have been shown to reduce behavioral symptoms and may be helpful (Vandepitte et al., 2016). If the patient is living in an LTC facility, the staff should have training in communication skills, behavioral principles, and trauma-informed and person-centered care (Seitz et al., 2012; Scales et al., 2018). Use of the DICE method illustrated previously can be helpful in formulating NPS-specific behavioral interventions. One structured method of assessment and intervention is the TIME method, which is illustrated in Fig. 24.5 (Lichtwarck et al., 2018). Other broad options for nonpharmacologic interventions include scheduled activities and daily structure. People living with dementia often experience boredom and loneliness, and scheduling of activities has been shown to reduce NPS (Livingston et al., 2014). Music therapy has also been shown to be effective in reducing NPS (Scales et al., 2018). Pet therapy is certainly promising, but studies thus far have been inconclusive (Livingston et al., 2014; Scales et al., 2018). Massage and touch have shown mixed results but are generally recommended as options to be tried (Legere et al., 2018; Scales et al., 2018). Aromatherapy has also shown mixed results but is generally thought to be ineffective (Livingston et al., 2014; Brasure et al., 2016; Scales et al., 2018). It should be noted that loss of olfactory sense is considered a likely precursor to dementia (whether prodromal or predisposing) and olfaction is often diminished in older adults. Multiple systematic reviews have concluded that either light therapy for BPSD is ineffective or that evidence is mixed (Gitlin et al., 2012; Livingston et al., 2014; Forbes et al., 2015; Legere et al., 2018; Scales et al., 2018). Nonpharmacologic options are summarized in Fig. 24.6.

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Registration and assessment phase Examine the patient Obtain previous medical records Collect background information Register NPS in detailed 24-h records Guided reflection phase Hold one or more case conferences to apply a “cognitive problem-solving method” to each NPS Include assessed facts, interpretations, staff members’ emotions and reactions, actions to take, and evaluation Action and evaluation phase Implement and evaluate agreed upon actions

Fig. 24.5. Time model for evaluation and management of neuropsychiatric symptoms. Adapted from Lichtwarck, B., Selbaek, G., Kirkevold, Ø., et al., 2018. Targeted interdisciplinary model for evaluation and treatment of neuropsychiatric symptoms: a cluster randomized controlled trial. Am J Geriatr Psychiatry 26, 25–28.

In terms of pharmacologic options for management, the first steps should be to evaluate the patient’s current medication regimen and optimize potential offending medications, as patients with dementia often have significant polypharmacy burden and regimens can frequently be adjusted (Rongen et al., 2016). This includes reducing anticholinergic burden, which has been proven to have benefits for patients with dementia and their care givers (Jaidi et al., 2018). The second step should be to address any underlying pain or suspicion of pain. There is good data to suggest that scheduling acetaminophen up to 3 g per day in divided doses can reduce NPS and pain in patients with dementia (Husebo et al., 2016). The general consensus about NSAIDs is that they should be avoided given gastrointestinal and renal susceptibilities in older adults. Some studies suggest that opioids could be considered, including transdermal preparations (Husebo et al., 2014). We recommend scheduling acetaminophen 3 g daily in divided doses as a general low risk first approach to unexplained NPS, and in general recommend avoiding opioids given risk of delirium, sedation, and falls. In terms of psychotropic medications, at best the data suggest that they have a modest effect (Wang et al., 2015). These medications come with significant risks, including increased mortality with antipsychotics (Reus et al., 2016). There are no medications approved by governmental regulatory bodies in North America, and in Europe only risperidone is approved for NPS (Porsteinsson and Antonsdottir, 2017). All psychotropic

medications carry the general risks of worsening cognitive impairment, falls, sedation, and gastrointestinal effects, including weight loss. Studies suggest that antipsychotics specifically, in addition to increased risk of mortality, may increase the risk of falls and facture by 1.5–2.5 times (Reus et al., 2016). A crucial consideration is the challenge of informed consent in patients with dementia, and it is critical that risks, benefits, and potential adverse effects are discussed thoroughly with the patient or surrogate decision maker (Walaszek, 2011). Our general recommendation is to start with antidepressant medications and proceed from there via the algorithm illustrated in Fig. 24.7. This algorithm covers general management of NPS. With this in mind, antipsychotics have the best evidence base for efficacy. There is an FDA black box warning for increased mortality in older adults with dementia (Schneider et al., 2005). In addition to the risk of mortality, falls, and fracture, other specific risks include neutropenia (especially with clozapine), cerebrovascular events, cardiac events, extrapyramidal side effects (EPSEs, motor side effects associated with dopaminergic blockade), and venous thromboembolism. There are also significant metabolic risks associated with atypical antipsychotics, but their significance in dementia has not been established (Reus et al., 2016). Specific EPSEs of especial concern include akathisia and Parkinsonism, but tardive dyskinesia is also a more long-term concern, with older adults having substantially increased risk compared to younger populations (Jeste et al., 1999).

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R. RADUE ET AL. The most effective interventions for patients are: Structured activities Music therapy Sensory interventions The most effective intervention for families is supporting family caregivers. The most effective interventions for facilities are training programs for formal caregivers. Each of these interventions will require some investment of resources, e.g., training of staff. Since no intervention is effective for all patients, an individualized plan should be developed for each person, and updated over time as circumstances change. Specific behaviors should be targeted, and outcomes of interventions should be measured. Interventions should be culturally sensitive, and may need to be tailored to patients’ and caregivers’ cultural background.

Fig. 24.6. Nonpharmacologic approaches to neuropsychiatric symptom management in dementia. Reprinted with permission from Walaszek: Behavioral and Psychology Symptoms of Dementia, (Copyright ©2019). American Psychiatric Association. All Rights Reserved. Based on a review and summary of the information in these sources: Barrett, C., Crameri, P., 2015. Understanding the experiences and needs of lesbian, gay, bisexual and trans Australians living with dementia, and their partners. Australas J Ageing 34, 34–38; Cooper, C., Tandy, A.R., Balamurali, T.B.S., et al., 2010. A systematic review and meta-analysis of ethnic differences in use of dementia treatment, care, and research. Am J Geriatr Psychiatry 18, 193–203. Legere, L.E., McNeill, S., Martin, L.S., et al., 2018. Nonpharmacological approaches for behavioural and psychological symptoms of dementia in older adults: a systematic review of reviews. J Clin Nurs 27, e1360–e1376; Livingston, G., Kelly, L., Lewis-Holmes, E., et al., 2014. A systematic review of the clinical effectiveness and cost-effectiveness of sensory, psychological and behavioural interventions for managing agitation in older adults with dementia. Health Technol Assess 18, 1–226; Scales, K., Zimmerman, S., Miller, S.J., 2018. Evidence-based nonpharmacological practices to address behavioral and psychological symptoms of dementia. Gerontologist 58, S88–S102; Vandepitte, S., Van Den Noortgate, N., Putnam, K., et al., 2016. Effectiveness of supporting informal caregivers of people with dementia: a systematic review of randomized and non-randomized controlled trials. J Alzheimers Dis 52, 929–965.

In terms of mortality, further study was undertaken that showed the following number needed to harm (NNH): haloperidol NNH was 26, risperidone 27, olanzapine 40, and quetiapine 50 (Maust et al., 2015). Why do antipsychotics carry an increased risk of mortality? The answer seems to lie in cardiac and infectious causes, with QT prolongation (Leucht et al., 2013) and pneumonia (Knol et al., 2008) as most common identified causes of death. Considering all these risks, the atypical antipsychotics are clearly safer than first generation, or typical antipsychotics, so haloperidol should be avoided if possible. Among the atypical antipsychotics, risperidone, olanzapine, and aripiprazole have the most evidence for efficacy in NPS (Maglione et al., 2011; Reus et al., 2016). Summary of antipsychotic treatment recommendations are contained in Table 24.1. Antidepressants may also be effective for NPS, but available data suggest that though they are safer, they

are considerably less efficacious than antipsychotics. Recommended options include citalopram, escitalopram, and trazodone, which have the most evidence base. See Table 24.2 for more details and recommendations. Other options include acetylcholinesterase inhibitors, though evidence is very limited for NPS except in LBD (Wang et al., 2015). There is no supporting evidence for use of memantine for NPS. Prazosin does have some supporting studies, as does the dextromethorphan–quinidine combination treatment (Wang et al., 2009; Cummings et al., 2015a; Chen et al., 2018). Methylphenidate does have some evidence in the treatment of apathy (Ruthirakuhan et al., 2018). Benzodiazepines have very limited efficacy data and should be reserved for emergency cases due to risk of sedation, aspiration, falls, and delirium (Tampi and Tampi, 2014; Davies et al., 2018). Carbamazepine may be effective, but is limited by side effects and drug–drug interactions; valproate

Is there imminent risk of harm to the patient or others? NO

YES

Treat underlying medical causes, including pain*

Instruct caregiver or facility to activate EMS for emergency evaluation and management in safe setting

Discontinue offending medications or substances

Are NPS severely distressing to patient or potentially dangerous or patient or others?

NO

Implement caregiver, behavioral and environmental interventions SEE FIGURE 6

YES Is patient taking a psychotropic medication for NPS?

NO

YES Is the medication at the maximally tolerated or recommended dose?

Recommend SSRI: escitalopram, citalopram or sertraline SEE TABLE 2 or If insomnia is prominent, trazodone or If agitation is prominent, atypical antipsychotic SEE TABLE 1

NO

YES

Obtain informed consent**, titrate medication, monitor outcome*** SEE TABLES 1–3

Obtain informed consent**, start medication, monitor outcome***

What medication is patient currently taking? first SSRI

second SSRI

Switch to another SSRI TABLE 2

Switch to antipsychotic or other agent TABLES 1 and 3

trazodone or other Switch to SSRI or antipsychotic TABLES 1 and 2

antipsychotic Switch to another antipsychotic or other agent TABLES 1 and 3

Obtain informed consent**, switch to new medication, implement caregiver, behavioral, and environmental interventions, and monitor outcome***

Fig. 24.7. Algorithm for responding to neuropsychiatric symptoms (NPS) in dementia. This presumes that an assessment has taken place. These are general guidelines and not meant to replace clinical judgment. *Consider adding acetaminophen 1000 mg two or three times per day, unless contraindicated. **First obtain informed consent from the patient or a proxy decision maker: legal guardian, activated healthcare power attorney, or legal next of kin. ***Schedule an office visit, telemedicine visit, or phone call in 1 week, with instructions to family or staff to call immediately if NPS worsen or intolerable side effects occur. Ineffective medications should be discontinued. Even if a medication appears to be effective, consider tapering off slowly after 4–6 months, especially antipsychotics. Key: EMS, emergency medical services; NPS, neuropsychiatric symptoms; SSRI, selective serotonin reuptake inhibitor. Reprinted with permission from Walaszek: Behavioral and Psychology Symptoms of Dementia, (Copyright ©2019). American Psychiatric Association. All Rights Reserved.

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Table 24.1 Using antipsychotics to address neuropsychiatric symptoms in dementia Medication

Dosing

Aripiprazole first-line agent

Start 2.5 mg at bedtime, increase to 5 mg at bedtime after More likely to cause EPSEs than clozapine, 1 week; may increase to 7.5 mg at bedtime after 2–4 olanzapine and quetiapine; perhaps less sedating weeks, and again to maximum dose of 10 mg at than other antipsychotics; unlikely to cause QT bedtime after another 2–4 weeks prolongation; long half-life could be a problem if patient has intolerable side effects, but could be an advantage if patient intermittently refuses or forgets to take medication Start 6.25–12.5 mg at bedtime; titrate slowly to dose of Requires monitoring of absolute neutrophil count; side effects include sedation, sialorrhea, dry 25–50 mg at bedtime, or divided into twice daily mouth, constipation; caution in patients with dosing cardiac disease; see text for full warnings regarding clozapine Start 0.5 mg once daily, and titrate with caution; Highest risk of mortality among antipsychotics; recommend against use except in emergency highest risk of EPSEs; highest risk of QT situations with appropriate medical monitoring prolongation Start 2.5 mg at bedtime, increase to 5 mg at bedtime after Moderate risk of EPSEs; quite sedating and appetite stimulating 1 week; may increase to 7.5 mg at bedtime after 2–4 weeks, and again to maximum dose of 10 mg at bedtime after another 2–4 weeks; may be divided into twice daily dosing Start 25 mg at bedtime, and increase by 25 mg/d every Effective doses may not be tolerated, due to 2–4 weeks; may be divided into twice daily dosing; sedation, falls, cognitive impairment; least likely target dose of 100–200 mg per day to cause EPSEs (other than clozapine), and so may be first choice in Lewy body disease Start 0.25 mg at bedtime, increase to 0.5 mg at bedtime Doses greater than 1 mg per day associated with EPSEs; avoid in patients with Lewy body after 1 week, may increase to 1 mg at bedtime or disease 0.5 mg twice daily

Clozapine

Haloperidol

Olanzapine first-line agent

Quetiapine first-line agent in patients with parkinsonism Risperidone first-line agent

Cautions (in addition to risk of mortality)

Reprinted with permission from Walaszek: Behavioral and Psychology Symptoms of Dementia, (Copyright ©2019). American Psychiatric Association. All Rights Reserved. Only antipsychotics that have been studied in subjects with dementia are included. They are listed in alphabetic order. In the United States, all antipsychotics have a “black box” label indicating that they should not be used in elderly patients with dementia, due to the risk of mortality. Antipsychotics should be prescribed only after very careful review of risks, benefits, and alternatives. Key: EPSE, extrapyramidal side effect.

should be avoided. Other medication options are summarized in Table 24.3. Our general advice in terms of psychotropic medications is the age old adage: “Start low, go slow, but go.” We generally recommend starting with an antidepressant given its more favorable risk and side effect profile. It is generally best to weigh available evidence with side effect profile, and always important to monitor for any adverse effects. For numerous reasons, taper or gradual dose reduction (GDR) should be planned and attempted when possible, or documentation of reasons why it is contraindicated should be completed.

Variation of neuropsychiatric symptoms by dementia etiology In general, NPS in AD and VD have similar prevalence. LBD and PDD can both manifest visual hallucinations

and delusions. In terms of management, it is broadly recommended for NPS in LBD that donepezil should be first-line treatment given available evidence (Satoh et al., 2010; Stinton et al., 2015). If antipsychotics are needed in LBD or PDD associated NPS, quetiapine or clozapine should be utilized due to sensitivity to EPSEs in this population (Reus et al., 2016). Pimavanserin is approved for psychosis in Parkinson disease, and has an unclear role in LBD. FTD most commonly presents as the behavioral variant, which has behavioral disturbance and apathy as diagnostic criteria. Hyperphagia and hyperorality are also characteristic of the disease. It is important to note that there have been negative studies of acetylcholinesterase inhibitors in this population, and they should be avoided (Young et al., 2018). There have been positive studies of trazodone, SSRIs, and stimulant medications in this population, but data on antipsychotics is limited.

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Table 24.2 Using antidepressants to address neuropsychiatric symptoms in dementia Medication

Dosing

Cautions

Bupropion

Start once-daily formulation (XL) 150 mg at breakfast, then increase to 300 mg at breakfast; after 4 weeks, consider increasing to maximum dose of 450 mg at breakfast

Citalopram first-line agent

Start 10 mg at breakfast for 1 week, then increase to 20 mg at breakfast; after 4 weeks, may increase to 30 mg at breakfast, but will require EKG; may require 9 weeks for full response Start 20 mg at breakfast for 1 week, then increase to 40 mg at breakfast; after 4 weeks, may increase to maximum dose of 60 mg at breakfast

Very limited data on use in dementia; side effects can include seizures, insomnia, weight loss, anxiety, agitation; avoid in patients with epilepsy, head injury, electrolyte disturbances; antidepressant least likely to cause hyponatremia FDA black box warning regarding risk of QT prolongation associated with dose > 20 mg/day in those > 60 years old

Duloxetine

Escitalopram first-line agent

Fluoxetine

Mirtazapine

Paroxetine Sertraline first-line agent in patients with cardiac disease Trazodone

Tricyclic antidepressants Venlafaxine

Only one, unpublished trial of duloxetine for depression in Lewy body disease; avoid in patients with liver disease or excess alcohol consumption Unclear if FDA black box warning regarding citalopram also applies to escitalopram; may be prudent to monitor QT interval at doses >10 mg/day Potential for drug–drug interactions; studies in dementia have been negative

Start 5 mg at breakfast for 1 week, then increase to 10 mg at breakfast; after 4 weeks, may increase to 15 mg at breakfast; after another 4 weeks, may increase to maximum dose of 20 mg at breakfast Start 10 mg at breakfast for 1 week, then increase to 20 mg at breakfast; may increase to maximum dose of 40 mg at breakfast after 4 weeks Common side effects include sedation and Start 15 mg at bedtime and continue for 4 weeks; increased appetite; may be help for insomnia, may increase to 30 mg at bedtime for 4 weeks, but negative studies for depression then maximum dose of 45 mg at bedtime; consider starting at 7.5 mg at bedtime if concern about tolerability Recommend against use in dementia because of anticholinergic side effects and risk of worsening cognition After initially positive studies, more recent studies Start 25 mg at breakfast for 1 week, then increase to have been negative; safer than citalopram in 50 mg at breakfast; after 4 weeks, may increase to patients with cardiac disease 100 mg at breakfast; after another 4 weeks, may increase to maximum dose of 200 mg at breakfast Monitor for orthostatic hypotension, excess Start trazodone 25–50 mg at bedtime; may titrate by sedation, falls; strongest evidence for efficacy is 50 mg/day increments as tolerated, up to a in FTD, though some evidence for insomnia maximum of 250 mg/day; usually dosed at night, in AD but could consider dividing into two to three doses per day Recommend against use in dementia because of anticholinergic side effects, risk of worsening cognition, and QT prolongation Monitor blood pressure; gastrointestinal side Start once-daily formulation (XR) 37.5 mg at effects may be especially common; breakfast for 1 week, then increase to 75 mg at discontinuation can be difficult due to serotonin breakfast; after 4 weeks, may increase to 150 mg withdrawal symptoms; little evidence at breakfast; after another 4 weeks, may increase supporting efficacy in dementia to maximum dose of 225 mg at breakfast

Reprinted with permission from Walaszek: Behavioral and Psychology Symptoms of Dementia, (Copyright ©2019). American Psychiatric Association. All Rights Reserved. Medications are listed in alphabetical order; only antidepressants that have been studied in subjects with dementia are included. All antidepressants except bupropion carry risk of hyponatremia in older adults, especially women and those on diuretics. Key: AD, Alzheimer’s disease; EKG, electrocardiogram; FTD, frontotemporal dementia.

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Table 24.3 Other pharmacologic approaches to neuropsychiatric symptoms in dementia Medication

Dosing

Cautions

Acetaminophen 1000 mg twice daily or three times daily Avoid in patients with hepatic disease or significant consider for all patients alcohol consumption who may have pain Carbamazepine Start 100 mg at bedtime; increase by 100 mg/day per Monitor drug level, absolute neutrophil count, week; target blood level of 5–8 mcg/mL sodium, liver function tests; high potential for drug–drug interactions Clonazepam Start 0.5 mg at bedtime; if not effective, may increase Only for use in REM behavior disorder; monitor to 1 mg at bedtime for sedation, falls, cognitive impairment, disinhibition, respiratory suppression Dextromethorphan– Start 20/10 mg of dextromethorphan/quinidine in the Most common side effects were falls, diarrhea, quinidine morning; after 1 week, increase to twice daily; UTI, and dizziness; monitor for cardiac side second-line agent after another 2 weeks, increase to 30/10 mg twice effects; mean increase of QT interval was 5 ms daily Donepezil and other For donepezil: start 5 mg at breakfast; after 1 month, Can cause or exacerbate insomnia, weight loss, cholinesterase increase to 10 mg at breakfast; 23 mg/day dose hallucinations, bradycardia, falls; do not dose in inhibitors unlikely to offer additional benefit; consider the evening, as it may cause insomnia or first-line agent for LBD starting at 2.5 mg at breakfast if tolerability a nightmares or PDD concern Gabapentin Doses of 200–1200 mg/day have been reported in Monitor for dizziness, sedation and gait instability; very limited evidence to support efficacy case series; consider starting at 100 mg at bedtime or 100 mg bid, and titrating by 100 mg/day weekly Lorazepam Recommend against use except in emergency Monitor for sedation, falls, cognitive impairment, situations or to reduce anxiety for procedures disinhibition, respiratory suppression Melatonin 1–3 mg 2–3 h before bedtime Low potential for side effects, but also unlikely to be effective for insomnia in dementia; may be helpful for RBD Memantine (once daily formulation) 7 mg per day for 1 week, Generally well tolerated; unlikely to have much benefit for BPSD, but perhaps less likely than then 14 mg per day for 1 week, then 21 mg per day cholinesterase inhibitors to cause or exacerbate for 1 week, then 28 mg per day thereafter BPSD (twice daily formulation) 5 mg in morning for 1 week, then 5 mg twice a day for 1 week, then 10 mg in the morning and 5 mg at bedtime for 1 week, then 10 mg twice a day thereafter Monitor blood pressure and heart rate; avoid in Start 5 mg twice daily (morning and noon); after Methylphenidate patients with cardiac arrhythmias; can cause 2 weeks, may titrate to 10 mg twice daily (morning use only in patients with weight loss and insomnia apathy and noon) Prazosin Start 1 mg at bedtime, titrating by 1 mg/day per week Monitor for dizziness, falls, sedation, and hypotension second-line agent up to a maximum of 2 mg in the morning and 4 mg at bedtime 34 mg per day is both the initial and target dose May be associated with higher risk of mortality; Pimavanserin can cause QT prolongation; potential for drug– use only in patients with psychosis due to drug interactions; mixed data on efficacy Parkinson disease Valproate Not recommended, due to risk of side effects including brain atrophy Reprinted with permission from Walaszek: Behavioral and Psychology Symptoms of Dementia, (Copyright ©2019). American Psychiatric Association. All Rights Reserved. Only medications, other than antidepressants and antipsychotics that have been studied in subjects with dementia are included. They are listed in alphabetical order. See text for detailed discussion and references. Key: RBD, REM behavior disorder; UTI, urinary tract infection.

NEUROPSYCHIATRIC SYMPTOMS IN DEMENTIA

SPECIFIC NEUROPSYCHIATRIC SYMPTOMS Agitation CLINICAL PRESENTATION The neuropsychiatric symptom of agitation can be considered on a continuum in terms of both verbal and physical manifestations. Verbally, the more benign end of the spectrum may include repetitive verbal statements (questions or repeated phrases), calling out or yelling, pathologic laughing or crying (pseudobulbar affect) and in more severe forms may escalate to verbal aggression such as threats or derogatory remarks. The same can be said of repetitive physical behaviors escalating to physical aggression. Patients may be fidgety or restless, may have purposeless repetitive behaviors (hand banging, for example), may pace excessively, may refuse medications or care, or may hoard or hide objects (including food items). Patients may also repeatedly call emergency services or family members for help. Physical aggression can manifest toward objects (wringing or banging hands, throwing things) but often involves people (hitting, kicking, punching, or attempts to strangle). Some patients may also display sexually inappropriate behaviors, either verbal (inappropriate comments or suggestions) or physical (grabbing others, public masturbation) (De Giorgi and Series, 2016). Wandering affects about 10%–20% of patients living with dementia and is a subset of agitation that can be considered as a repetitive physical behavior within this continuum (van der Linde et al., 2016). It is important to note that agitation is often the most distressing, and potentially dangerous, NPS for care givers and patients. At times it can be fueled by anxiety (discussed elsewhere) or psychosis (discussed in the following text), but can also be without clear underlying contributors.

ASSESSMENT General principles of assessment apply to agitation as with all forms of NPS, and it may be helpful to visit that portion of the chapter. As discussed previously, ABC or DICE models may be particularly helpful in characterizing the contributing and surrounding factors of agitation. It is especially important to consider the context in which behaviors are occurring, for example, whether the agitation occurs with personal care or whether wandering occurs at a particular time of day.

MANAGEMENT The first consideration should be safety. If the patient poses a severe and immediate danger to self or others

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through their aggression (which may include psychosis, discussed next), and nonpharmacologic and pharmacologic interventions fail, then immediate steps should be taken to ensure safety. Always as a last resort, a change of venue should be considered with a move to a higher level of care if necessary, such as an emergency department or inpatient medical or psychiatric unit for further evaluation and management. Such a move usually only needs to be temporary, and once the crisis has passed and the patient is stabilized, they can often return to their previous living situation, or at least to a lower level of care. It will be important to consider the legal statutes surrounding care for those with dementia with or without surrogate decisions makers as pertains to psychiatric treatment in your practice location. You may need to involve local law enforcement or a local crisis agency. In terms of nonpharmacologic management, the general principles discussed previously do apply. Some considerations specific to wandering include alarms and electronic tagging or monitoring (for example, a wander guard) (Cipriani et al., 2014). Some considerations specific to sexually inappropriate behaviors include arranging for conjugal visits, changing gender of care givers, avoiding overstimulating television or radio programs, and general redirection techniques (De Giorgi and Series, 2016). In terms of pharmacologic management, as discussed previously the best evidence for efficacy is for the antipsychotics. Even so, randomized control trials have shown only modest benefit in reduction of psychosis and agitation (Jeste et al., 2008). In head-to-head analysis, olanzapine was shown most effective for agitation, risperidone was effective, and aripiprazole was less effective (Maglione et al., 2011). One study found that risperidone 1 mg daily was successful in decreasing wandering (Cipriani et al., 2014). Quetiapine has not been shown superior to placebo in randomized control trials examining agitation, but it does have a place in treatment of LBD and PDD agitation as discussed previously due to lower risk of EPSEs (Reus et al., 2016). While haloperidol is effective for agitation, there are far more pressing safety concerns and there also appears to be a greater risk of mortality. Recall that one study showed a number needed to harm (NNH) of 26 with haloperidol in terms of mortality, compared to 40 for olanzapine (Maust et al., 2015). We recommend avoiding haloperidol for these reasons. We additionally recommend avoiding intramuscular (IM) preparations whenever possible given increased risk of adverse effects in older adults with dementia. Table 24.1 highlights the recommended dosing for antipsychotic medications for agitation and/or psychosis in dementia. As discussed previously, it holds true for agitation that antidepressants are likely less effective than antipsychotics,

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but are generally considered a safer option and therefore are recommended first line. Potential adverse effects that are of particular concern in older adults include gastrointestinal side effects and hyponatremia. If one serotonergic antidepressant leads to hyponatremia, other serotonergic agents seem just as likely to do so. The exceptions among antidepressants are bupropion, which unfortunately does not have evidence of benefit in agitation, and mirtazapine, which, though less likely to cause hyponatremia, can still do so in some cases, and has only minimal evidence of benefit for agitation (De Picker et al., 2014; Viramontes et al., 2016). Trazodone may also be less likely to cause hyponatremia, in spite of serotonergic properties. Among the antidepressants, the available evidence best supports the use of citalopram, escitalopram, and trazodone. Among these, citalopram has the most supporting evidence but is associated with QT prolongation (Farina et al., 2017). Escitalopram may be less likely to cause this side effect and has good cardiac safety data thus far. Among the other SSRIs, paroxetine is contraindicated due to anticholinergic burden, and fluoxetine is not recommended due to long half-life, drug–drug interaction risk, and activating properties that sometimes lead to akathisia as a side effect in vulnerable patients. Sertraline has an excellent side effect profile, a wide dose range, and is generally well tolerated, but unfortunately it has not been examined for agitation and studies of depression in dementia have been negative (Farina et al., 2017). We would in general not recommend SNRIs or TCAs—venlafaxine due to lack of evidence, HTN, and withdrawal risks and TCAs due to anticholinergic burden. Duloxetine has been studied in DLB for depression, but may be trialed for agitation in this population (Stinton et al., 2015). There is good evidence to suggest that trazodone is effective for agitation in FTD, though it has not been widely studied for other etiologies (Herrmann et al., 2012; Nardell and Tampi, 2014). Table 24.2 summarizes dosing recommendations for antidepressants in NPS. Certain other psychotropics have demonstrated potential benefit for agitation in dementia. One study of propranolol augmentation showed modest short-term benefit, but this was not sustained in the long-term (Peskind et al., 2005). A study of prazosin showed that it was well tolerated and effective (Wang et al., 2009). One study of dextromethorphan–quinidine combination demonstrated efficacy at reducing agitation (Cummings et al., 2015a,b), and a case series in FTD showed the same (Chen et al., 2018). There is some evidence for gabapentin for agitation in DLB as well (Stinton et al., 2015). Serotonergic antidepressants, anticonvulsants such as carbamazepine or gabapentin, and hormonal blockade (medroxyprogesterone, finasteride, oral or transdermal estrogen, and leuprolide) have been shown to be effective at managing sexually inappropriate

behaviors (De Giorgi and Series, 2016). Table 24.3 summarizes recommendations for use of other psychotropics.

Psychosis CLINICAL PRESENTATION Psychotic symptoms that present in association with cognitive impairment most commonly include auditory and visual hallucinations and delusions. It is important to note that these symptoms in and of themselves do not necessarily merit treatment; rather, there must be enough distress or danger present to warrant intervention. Common visual hallucinations can range from the often benign hallucinations as in LBD of animals or small children, to more disturbing hallucinations of malevolent beings (robbers, spies, or past abusers or people related to traumatic events such as soldiers). Auditory hallucinations are less common, but can range from benign music to malevolent conversations or derogatory diatribes. Delusions in dementia are often “paramnestic,” or related to memory loss, for example, patients may misplace items and accuse others of stealing them, or may not recognize a loved one and believe there is a stranger in their home. The most common delusions in dementia are related to these, and include delusions of theft, delusions of infidelity, delusions that one’s home is not one’s own, delusions of being harmed, and misidentification delusions (where a patient may believe that loved ones have been replaced with imposters, as in Capgras syndrome).

ASSESSMENT The general principles discussed previously apply to assessment of psychosis as well. It is important to determine the level of distress that hallucinations cause the patient and care givers. Treatment is often less effective for psychotic symptoms than for agitation, and therefore risks may be higher, so the mandate of treating only when necessary is important to remember. Another important component of assessment can be determining the veracity of statements, for example, does the patient have a delusional belief that their care giver is trying to harm them, or is their care giver in fact engaging in elder abuse? This can be difficult to determine, and may necessitate consultation with or referral to adult protective services agencies or law enforcement. Hallucinations can also be present in delirium, or in visual impairment with Charles Bonnet syndrome, and these etiologies should be considered.

MANAGEMENT Nonpharmacologic management includes first and foremost caregiver education on appropriate response to hallucinations, and especially delusions. These NPS can be

NEUROPSYCHIATRIC SYMPTOMS IN DEMENTIA extremely distressing to care givers. Imagine your partner you are working hard to care for wrongfully accusing you of infidelity, or your parent you are working hard to care for wrongfully insisting that you are stealing from them. Providing education and training to care givers is of paramount importance. It is best for care givers to use redirection and distraction techniques when these things come up, or simply provide reassurance. When these techniques fail and there is significant distress or impairment, medications can sometimes help alleviate symptoms. Antipsychotics are certainly the most intuitive class to utilize for these symptoms, but unfortunately are less effective for psychotic symptoms in dementia than for other NPS. An Agency for Healthcare Research and Quality comparative effectiveness review demonstrated that risperidone was effective, aripiprazole less so but still effective, and olanzapine was only equivocal at treating psychosis in dementia (Maglione et al., 2011). Pimavanserin is a novel agent that was recently approved for PD psychosis. It is a 5-HT2A inverse agonist with no dopaminergic activity. It has modest evidence for the indicated symptoms, though there is a risk of drug–drug interactions and QT prolongation, and the drug is quite expensive (Bozymski et al., 2017). One trial in AD patients found benefit at 6 weeks but not at 12 weeks (Ballard et al., 2018). As discussed previously, DLB and PDD psychosis should be treated differently, with quetiapine or clozapine ideally, though pimavanserin could be considered. The best evidence for efficacy is with clozapine, but certainly given the risks and need for monitoring, it may be best advised to trial quetiapine first (Connolly and Lang, 2014).

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ASSESSMENT General approaches to assessment as discussed previously also apply to apathy. Apathy is among the most purely biologically based NPS, but it is important to distinguish hypoactive delirium, depression, and normal progression of dementia from apathy.

MANAGEMENT Nonpharmacologic management is first line. There is evidence to support the use of music therapy, multisensory interventions, and pet therapy (Scales et al., 2018). For patients with MCI and still living at home, it can be helpful for loved ones to collaboratively create “to-do” lists or structured schedules such that necessary activities are completed. In terms of pharmacologic options, although apathy is the most common NPS, there is a relative dearth of study and intervention. Methylphenidate may be helpful in apathy associated with AD, but can be limited by hypertension and tachycardia (Ruthirakuhan et al., 2018). One study found an 18 mmHg increase in blood pressure with 10 mg of immediate release methylphenidate dosed twice daily (Padala et al., 2018). Stimulants may also be useful in VD and poststroke apathy (Dolder et al., 2010). One study of dextroamphetamine 20 mg daily was shown to be helpful with apathy in FTD (Nardell and Tampi, 2014). There have also been case reports of bupropion use for apathy in FTD, and it has been used in cases of other dementias owing to its dopaminergic activity and theoretical benefit. Keep in mind the risks of insomnia, worsening anxiety or agitation, weight loss, and lowering of the seizure threshold with bupropion.

Apathy CLINICAL PRESENTATION Apathy is the most common form of NPS, and can be prominent in any form of dementia. It is best described as a significant decrease in motivation and interest. Patients may have less goal-directed activity, and may be content to sit and do little with their time. They may not engage in activities or complete necessary tasks without prompting. They may also be less emotional or affectionate than they once were, and less interested in the activities of loved ones. It can be difficult to distinguish progression of dementia, apathy, and depression. The worthlessness, hopelessness, and guilt associated with depression are usually not present in apathy or dementia. Apathy is usually far less bothersome, if at all, to the sufferer and far more distressing to loved ones, so patients with dementia who are less able to engage in previously pleasurable activities will usually express frustration with this, while those with apathy will usually not.

Sleep disturbance CLINICAL PRESENTATION Circadian rhythm disturbances and alterations of the sleep–wake cycle are common in dementia. AD pathology is known to lead to degeneration of the suprachiasmatic nucleus and thus the circadian rhythm regulation commonly goes awry. Sleep fragmentation becomes common, and nighttime awakening may come with wandering or other problem behaviors. Other patients may experience day–night reversal, leading to significant issues for care givers and facilities where staffing ratios are typically smaller overnight. Another related phenomenon is worsening of behaviors or cognition in the late afternoon and evening hours, commonly referred to as “sundowning.”

ASSESSMENT Sleep assessment should include thorough medical investigation. While primary sleep disorders are commonly

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comorbid in dementia patients, medications, substances, and medical conditions such as benign prostatic hypertrophy or lower extremity edema can contribute to sleep disturbance (via nocturia for both conditions mentioned here). Untreated or undertreated sleep apnea may present as or contribute to apathy.

MANAGEMENT Starting with nonpharmacologic management, it should be noted that behavior programs including sleep hygiene and environment modification can be effective (McCurry et al., 2005). Medications in general have very limited effect and behavioral interventions are recommended as first line. Patients with dementia, especially those with limited mobility, may suffer from boredom during the daytime and be more likely to nap, thus disturbing nighttime sleep. Keeping patients awake, engaged, and exposed to daylight during daytime hours is strongly encouraged, wherever possible. Pharmacologic recommendations for sleep fragmentation or general insomnia include trazodone. One study of 50 mg at bedtime showed good effect for insomnia in dementia in a Cochrane Review (McCleery et al., 2016). A Cochrane review of melatonin and ramelteon for persons with dementia and a sleep disorder concluded that these agents were ineffective (McCleery et al., 2016), though one study of melatonin in nursing home residents, most of whom had dementia, showed some benefit for sleep (Riemersma-van der Lek et al., 2008). There are no randomized control trials for benzodiazepines or other sedative hypnotics in dementia, and they should generally be avoided due to risk of adverse effects including sedation, falls, and delirium. Light therapy has failed to demonstrate efficacy (McCleery et al., 2016). DLB or PDD are not uncommonly accompanied by REM sleep behavior disorder. Treatment with clonazepam or melatonin may be effective (Jung and St Louis, 2016). When it comes to obstructive sleep apnea (OSA), the mainstay of CPAP or BiPAP holds true, and has been found effective for sleep and mood improvement in dementia (Cooke et al., 2009). Restless leg syndrome (RLS) is one area that has not been studied in dementia populations. It should be noted that many commonly used psychotropics can worsen or cause RLS. It is reasonable to trial standard therapies for RLS such as pramipexole or ropinirole, but it should be noted that these may worsen other NPS and risks and benefits should be weighed carefully.

Appetitive disturbance CLINICAL PRESENTATION From failure to thrive and malnutrition to the hyperphagia and hyperorality of FTD, feeding and eating

disturbances are common in dementia, and can be a cause of increased morbidity and mortality. Patients with dementia are more likely to have olfactory deficits as discussed previously, and foods may not have an appealing taste for them any longer. Thirst drives also have a tendency to decrease with age, making those with dementia especially vulnerable to dehydration. As dementia progresses, patients may gradually lose the ability to cook for themselves and be more likely to rely on bland or unvaried diets. As amnestic deficits progress, people living with dementia may forget that they have eaten or drunk and ask to do so again, or conversely may believe they have consumed a meal or drunk sufficient fluids when in fact they have not. People with FTD may display specific patterns of food consumption, craving sweets and carbohydrates, consuming food rapidly or excessively and posing a choking risk, having rigid food preferences, or attempting to consume nonfood objects.

ASSESSMENT This is another area of NPS where thorough medical evaluation cannot be stressed enough. Common medical conditions such as severe GERD, dental problems, or constipation can lead to decreases in appetite or eating. Many medications, including acetylcholinesterase inhibitors, can lead to nausea, decreased appetite, and weight loss as side effects.

MANAGEMENT As discussed, it is crucial to address medical concerns including pain, nausea, and constipation. It is also important to discontinue offending medications that may correlate with change in appetite and feeding or eating problems. Some nonpharmacologic interventions with supporting evidence include high calorie dietary supplements, increased protein intake, and physical activity (Droogsma et al., 2015). Pharmacologic options, when all else is optimized, include mirtazapine for weight gain and topiramate for hyperorality and hyperphagia. One small positive study of mirtazapine looked at doses of 30 mg daily and found association with 1.9 kg weight gain over 3 months and 2.1 kg at 6 months. In this retrospective study, patients with lower baseline BMI gained more weight (Segers and Surquin, 2014). It should be noted that given the histaminergic profile of mirtazapine, lower doses (7.5–15 mg daily) are more likely to stimulate appetite than higher doses. Finally, feeding tubes are associated with worse outcomes and we strongly recommend against placing them (Palacek et al., 2010).

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CONCLUSION In conclusion, neuropsychiatric symptoms are nearly ubiquitous in dementia, and the vast majority of people living with dementia will experience at least one NPS during the course of their illness. These common symptoms can have significant impacts on quality of life, and contribute to morbidity and mortality for people living with dementia, and significant stress and burden for their care givers as well as significant cost to society. Careful assessment of NPS includes detailed documentation of symptoms and contributors as well as thorough medical assessment to investigate potential cause of new or changing symptoms. Nonpharmacologic interventions are recommended as first line, and include caregiver training and education, as well as music therapy and other sensory modalities and regular engagement of patients in activities. Pain is very common among those living with dementia, and should always be a consideration. We do recommend scheduling 3 g of acetaminophen daily in divided doses, where not contraindicated, as a general first approach for problem NPS. Other pharmacologic strategies should be used with caution and tailored to individual dementia etiology and specific NPS. In general, atypical antipsychotics are more effective than antidepressants, but come with greater risk. In LBD, acetylcholinesterase inhibitors (namely, donepezil, as it is best tolerated) should be considered for NPS given the evidence base. A thorough conversation and informed consent should be had and documented with patients and their surrogate decision makers before proceeding with psychotropic treatment, and frequent consideration of gradual dose reduction should take place.

REFERENCES Ahmed AIA, van der Marck MA, van den Elsen GAH et al. (2015). Cannabinoids in late-onset Alzheimer’s disease. Clin Pharmacol Ther 97: 597–606. Alzheimer’s Association (2018). 2018 Alzheimer’s disease facts and figures. Alzheimers Dement 14: 367–429. American Geriatrics Society 2015 Beers Criteria Update Expert Panel (2015). American Geriatrics Society 2015 updated beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 63: 2227–2246. Ballard C, Banister C, Khan Z et al. (2018). Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer’s disease psychosis: a phase 2, randomised, placebo-controlled, double-blind study. Lancet Neurol 17: 213–222. Boublay N, Schott AM, Krolak-Salmon P (2016). Neuroimaging correlates of neuropsychiatric symptoms in Alzheimer’s disease: a review of 20 years of research. Eur J Neurol 23: 1500–1509. Bozymski KM, Lowe DK, Pasternak KM et al. (2017). Pimavanserin: a novel antipsychotic for Parkinson’s disease psychosis. Ann Pharmacother 51: 479–487.

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Brasure M, Jutkowitz E, Fuchs E et al. (2016). Nonpharmacologic interventions for agitation and aggression in dementia, Comparative Effectiveness Review No. 177. (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-2012-00016-I.) AHRQ Publication No.16-EHC019-EF, Agency for Healthcare Research and Quality, Rockville, MD. Casanova MF, Starkstein SE, Jellinger KA (2011). Clinicopathological correlates of behavioral and psychological symptoms of dementia. Acta Neuropathol 122: 117–135. Chen Q, Calcagno HE, Shad M (2018). Efficacy of dextromethorphan/quinidine for patients with psychosis-related aggression: a retrospective case series. Prim Care Companion CNS Disord 20 (3): pii: 18m02284. https:// doi.org/10.4088/PCC.18m02284. Cheng S-T (2017). Dementia caregiver burden: a research update and critical analysis. Curr Psychiatry Rep 19: 64. https://doi.org/10.1007/s11920-017-0818-2. Cipriani G, Lucetti C, Nuti A et al. (2014). Wandering and dementia. Psychogeriatrics 14: 135–142. Connolly BS, Lang AE (2014). Pharmacological treatment of Parkinson disease: a review. JAMA 311: 1670–1683. Cooke JR, Ayalon L, Palmer BW et al. (2009). Sustained use of CPAP slows deterioration of cognition, sleep, and mood in patients with Alzheimer’s disease and obstructive sleep apnea: a preliminary study. J Clin Sleep Med 5: 305–309. Cummings JL, Lyketsos CG, Peskind ER et al. (2015a). Effect of dextromethorphan-quinidine on agitation in patients with Alzheimer disease dementia: a randomized clinical trial. JAMA 314: 1242–1254. Cummings J, Mintzer J, Brodaty H et al. (2015b). Agitation in cognitive disorders: international psychogeriatric association provisional consensus clinical and research definition. Int Psychogeriatr 27: 7–17. Davies SJ, Burhan AM, Kim D et al. (2018). Sequential drug treatment algorithm for agitation and aggression in Alzheimer’s and mixed dementia. J Psychopharmacol 32 (5): 509–523. https://doi.org/10.1177/0269881117744996. De Giorgi R, Series H (2016). Treatment of inappropriate sexual behavior in dementia. Curr Treat Options Neurol 18: 41. De Picker L, Van Den Eede F, Dumont G et al. (2014). Antidepressants and the risk of hyponatremia: a class-byclass review of literature. Psychosomatics 55: 536–547. Dolder CR, Davis LN, McKinsey J (2010). Use of psychostimulants in patients with dementia. Ann Pharmacother 44 (10): 1624–1632. https://doi.org/10.1345/aph.1P341. Droogsma E, van Asselt D, De Deyn PP (2015). Weight loss and undernutrition in community-dwelling patients with Alzheimer’s dementia: from population based studies to clinical management. Z Gerontol Geriatr 48: 318–324. Farina N, Morrell L, Banerjee S (2017). What is the therapeutic value of antidepressants in dementia? A narrative review. Int J Geriatr Psychiatry 32: 32–49. Forbes D, Forbes SC, Blake CM et al. (2015). Exercise programs for people with dementia. Cochrane Database Syst Rev (4): CD006489. https://doi.org/10.1002/14651858. CD006489.pub4.

452

R. RADUE ET AL.

Gitlin LN, Kales HC, Lyketsos CG (2012). Nonpharmacological management of behavioral symptoms in dementia. JAMA 308: 2020–2029. Han BH, Moore AA (2018). Prevention and screening of unhealthy substance use by older adults. Clin Geriatr Med 34 (1): 117–129. https://doi.org/10.1016/j.cger.2017. 08.005. Herrmann N, Black SE, Chow T et al. (2012). Serotonergic function and treatment of behavioral and psychological symptoms of frontotemporal dementia. Am J Geriatr Psychiatry 20: 789–797. Howell T (2015). The Wisconsin Star method: understanding and addressing complexity in geriatrics. In: ML Malone, E Capezuti, RM Palmer (Eds.), Geriatrics models of care: bringing ‘best practice’ to an aging America, Springer International Publishing 87–94. Husebo BS, Ballard C, Cohen-Mansfield J et al. (2014). The response of agitated behavior to pain management in persons with dementia. Am J Geriatr Psychiatry 22: 708–717. Husebo BS, Achterberg W, Flo E (2016). Identifying and managing pain in people with Alzheimer’s disease and other types of dementia: a systematic review. CNS Drugs 30: 481–497. Jaidi Y, Nonnonhou V, Kanagaratnam L et al. (2018). Reduction of the anticholinergic burden makes it possible to decrease behavioral and psychological symptoms of dementia. Am J Geriatric Psychiatry 26: 280–288. Jeste DV, Lacro JP, Bailey A et al. (1999). Lower incidence of tardive dyskinesia with risperidone compared with haloperidol in older patients. J Am Geriatr Soc 47: 716–719. Jeste DV, Blazer D, Casey D et al. (2008). ACNP white paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology 31: 957–970. Jorgensen LE, Messersmith JJ (2015). Impact of aging and cognition on hearing assistive technology use. Semin Hear 36: 162–174. Jung Y, St Louis EK (2016). Treatment of REM sleep behavior disorder. Curr Treat Options Neurol 18: 50. Kales HC, Gitlin LN, Lyketsos CG et al. (2014). Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel. J Am Geriatr Soc 62: 762–769. Kales HC, Gitlin LN, Lyketsos CG (2015). Assessment and management of behavioral and psychological symptoms of dementia. BMJ 350: h369. Kaufer DI, Cummings JL, Jetchel P et al. (2000). Validation of the NPI-Q, a brief clinical form of the neuropsychiatric inventory. J Neuropsychiatry Clin Neurosci 12: 233–239. Knol W, van Marum RJ, Jansen PA et al. (2008). Antipsychotic drug use and risk of pneumonia in elderly people. J Am Geriatr Soc 56: 661–666. Koch JM, Datta G, Makhdoom S et al. (2005). Unmet visual needs of Alzheimer’s disease patients in long-term care facilities. J Am Med Dir Assoc 6: 233–237. Kovach CR, Noonan PE, Matovina Schlidt A et al. (2005). A model of consequences of need-driven dementiacompromised behavior. J Nurs Scholarsh 37: 134–140.

Legere LE, McNeill S, Martin LS et al. (2018). Nonpharmacological approaches for behavioural and psychological symptoms of dementia in older adults: a systematic review of reviews. J Clin Nurs 27: e1360–e1376. Leucht S, Cipriani A, Spineli L et al. (2013). Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 382: 951–962. Lichtwarck B, Selbaek G, Kirkevold Ø et al. (2018). Targeted interdisciplinary model for evaluation and treatment of neuropsychiatric symptoms: a cluster randomized controlled trial. Am J Geriatr Psychiatry 26: 25–28. Livingston G, Kelly L, Lewis-Holmes E et al. (2014). A systematic review of the clinical effectiveness and cost-effectiveness of sensory, psychological and behavioural interventions for managing agitation in older adults with dementia. Health Technol Assess 18: 1–226. Maglione M, Ruelaz Maher A, Hu J et al. (2011). Off-label use of atypical antipsychotics: an update, Comparative Effectiveness Review No. 43. (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA290-2007-10062-1.), Agency for Healthcare Research and Quality, Rockville, MD. Maust DT, Kim HM, Seyfried LS et al. (2015). Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm. JAMA Psychiat 72: 438–445. McCleery J, Cohen DA, Sharpley AL (2016). Pharmacotherapies for sleep disturbances in dementia. Cochrane Database Syst Rev 11: CD009178. McCurry SM, Gibbons LE, Logsdon RG et al. (2005). Nighttime insomnia treatment and education for Alzheimer’s disease: a randomized, controlled trial. J Am Geriatr Soc 53: 793–802. Nardell M, Tampi RR (2014). Pharmacological treatments for frontotemporal dementias: a systematic review of randomized controlled trials. Am J Alzheimers Dis Other Demen 29: 123–132. Osborne H, Simpson J, Stokes G (2010). The relationship between pre-morbid personality and challenging behaviour in people with dementia: a systematic review. Aging Ment Health 14: 503–515. Padala PR, Padala KP, Lensing SY et al. (2018). Methylphenidate for apathy in community-dwelling older veterans with mild Alzheimer’s disease: a double-blind, randomized, placebocontrolled trial. Am J Psychiatry 175: 159–168. Palacek EJ, Teno JM, Casarett DJ et al. (2010). Comfort feeding only: a proposal to bring clarity to decision-making regarding difficulty with eating for persons with advanced dementia. J Am Geriatr Soc 58: 580–584. Peskind ER, Tsuang DW, Bonner LT et al. (2005). Propranolol for disruptive behaviors in nursing home residents with probable or possible Alzheimer disease: a placebocontrolled study. Alzheimer Dis Assoc Disord 19: 23–28. Porsteinsson AP, Antonsdottir IM (2017). An update on the advancements in the treatment of agitation in Alzheimer’s disease. Expert Opin Pharmacother 18: 611–620.

NEUROPSYCHIATRIC SYMPTOMS IN DEMENTIA Prior J, Abraham R, Nicholas H et al. (2016). Are premorbid abnormal personality traits associated with behavioural and psychological symptoms in dementia? Int J Geriatr Psychiatry 31: 1050–1055. Reus VI, Fochtmann LJ, Eyler AE et al. (2016). The American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. Am J Psychiatry 173: 543–546. Riemersma-van der Lek RF, Swaab DF, Twisk J et al. (2008). Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA 299: 2642–2655. Rongen S, Kramers C, O’Mahony D et al. (2016). Potentially inappropriate prescribing in older patients admitted to psychiatric hospital. Int J Geriatr Psychiatry 31 (2): 137–145. https://doi.org/10.1002/gps.4302. Rosenberg PB, Drye LT, Porsteinsson AP et al. (2015a). Change in agitation in Alzheimer’s disease in the placebo arm of a nine-week controlled trial. Int Psychogeriatr 27: 2059–2067. Rosenberg PB, Nowrangi MA, Lyketsos CG (2015b). Neuropsychiatric symptoms in Alzheimer’s disease: what might be associated brain circuits? Mol Aspects Med 43–44: 25–37. Ruthirakuhan MT, Herrmann N, Abraham EH et al. (2018). Pharmacological interventions for apathy in Alzheimer’s disease. Cochrane Database Syst Rev 5: CD012197. https://doi.org/10.1002/14651858.CD012197.pub2. Sallim AB, Sayampanathan AA, Cuttilan A et al. (2015). Prevalence of mental health disorders among caregivers of patients with Alzheimer disease. J Am Med Dir Assoc 16: 1034–1041. Satoh M, Ishikawa H, Meguro K et al. (2010). Improved visual hallucination by donepezil and occipital glucose metabolism in dementia with Lewy bodies: the Osaki-Tajiri project. Eur Neurol 64: 337–344. Scales K, Zimmerman S, Miller SJ (2018). Evidence-based nonpharmacological practices to address behavioral and psychological symptoms of dementia. Gerontologist 58: S88–S102. Schneider LS, Dagerman K, Insel P (2005). Risk of death with atypical antipsychotic drug treatment for dementia: metaanalysis of randomized placebo-controlled trials. JAMA 294: 1934–1943. Segers K, Surquin M (2014). Can mirtazapine counteract the weight loss associated with Alzheimer disease? A retrospective open-label study. Alzheimer Dis Assoc Disord 28: 291–293. Seitz DP, Brisbin S, Herrman N et al. (2012). Efficacy and feasibility of nonpharmacological interventions for neuropsychiatric symptoms of dementia in long term care: a systematic review. JAMDA 13: 503–506. Smith M, Gerdner LA, Hall GR et al. (2004). History, development, and future of the progressively lowered stress threshold: a conceptual model for dementia care. JAGS 52: 1755–1760.

453

Stinton C, McKeith I, Taylor J-P et al. (2015). Pharmacological management of Lewy body dementia: a systematic review and meta-analysis. Am J Psychiatry 172: 731–742. Tampi RR, Tampi DJ (2014). Efficacy and tolerability of benzodiazepines for the treatment of behavioral and psychological symptoms of dementia: a systematic review of randomized controlled trials. Am J Alzheimers Dis Other Demen 29: 565–574. Teri L, Logsdon RG, Weiner MF et al. (1998). Treatment for agitation in dementia patients: a behavior management approach. Psychotherapy 35: 436–443. van der Linde RM, Dening T, Stephan BCM et al. (2016). Longitudinal course of behavioural and psychological symptoms of dementia: systematic review. Br J Psychiatry 209: 366–377. Vandepitte S, Van Den Noortgate N, Putnam K et al. (2016). Effectiveness of supporting informal caregivers of people with dementia: a systematic review of randomized and non-randomized controlled trials. J Alzheimers Dis 52: 929–965. Viramontes TS, Truong H, Linnebur SA (2016). Antidepressantinduced hyponatremia in older adults. Consult Pharm 31: 139–150. Walaszek A (2011). Ethical issues in the care of individuals with dementia. In: P McNamara (Ed.), Dementia. Praeger 123–150. Wang LY, Shofer JB, Rohde K et al. (2009). Prazosin for the treatment of behavioral symptoms in patients with Alzheimer disease with agitation and aggression. Am J Geriatr Psychiatry 17: 744–751. Wang J, Yu J-T, Wang H-F et al. (2015). Pharmacological treatment of neuropsychiatric symptoms in Alzheimer’s disease: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 86: 101–109. Wood S, Cummings JL, Hsu MA et al. (2000). The use of the neuropsychiatric inventory in nursing home residents. Characterization and measurement. Am J Geriatr Psychiatry 8: 75–83. Young JJ, Lavakumar M, Tampi D et al. (2018). Frontotemporal dementia: latest evidence and clinical implications. Ther Adv Psychopharmacol 8: 33–48. Zilkens RR, Bruce DG, Duke J et al. (2014). Severe psychiatric disorders in mid-life and risk of dementia in late-life (age 65-84 years): a population based case-control study. Curr Alzheimer Res 11: 681–693.

FURTHER READING American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders, fifth edn. American Psychiatric Publishing, Arlington, VA. Kales HC, Gitlin LN, Stanislawski B et al. (2018). Effect of the WeCareAdvisorTM on family caregiver outcomes in dementia: a pilot randomized controlled trial. BMC Geriatr 18: 113.

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R. RADUE ET AL.

Katz IR, Rupnow M, Kozma C et al. (2004). Risperidone and falls in ambulatory nursing home residents with dementia and psychosis or agitation: secondary analysis of a double-blind, placebo-controlled trial. Am J Geriatr Psychiatry 12: 499–508. Konovalov S, Muralee S, Tampi RR (2008). Anticonvulsants for the treatment of behavioral and psychological symptoms of dementia: a literature review. Int Psychogeriatr 20: 293–308. Lonergan E, Luxenberg J (2009). Valproate preparations for agitation in dementia. Cochrane Database Syst Rev 3: CD003945. https://doi.org/10.1002/14651858.CD003945. pub3. Moretti R, Torre P, Antonello RM et al. (2005). Olanzapine as a possible treatment of behavioral symptoms in vascular dementia: risks of cerebrovascular events. A controlled, open-label study. J Neurol 252: 1186–1193. Schneider LS, Dagerman K, Insel P (2006). Efficacy and adverse effects of atypical antipsychotics or dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry 14: 191–210. Scoralick FM, Louzada LL, Quintas JL et al. (2017). Mirtazapine does not improve sleep disorders in Alzheimer’s disease: results from a double-blind, placebo-controlled pilot study. Psychogeriatrics 17: 89–96.

Sparks MB (2008). Inpatient care for persons with Alzheimer’s disease. Crit Care Nurs Q 31: 65–72. Sultana J, Chang CK, Hayes RD et al. (2014). Associations between risk of mortality and atypical antipsychotic use in vascular dementia: a clinical cohort study. Int J Geriatr Psychiatry 29: 1249–1254. Van Leeuwen E, Petrovic M, van Driel ML et al. (2018). Withdrawal versus continuation of long-term antipsychotic drug use for behavioural and psychological symptoms in older people with dementia. Cochrane Database Syst Rev 3: CD007726. https://doi.org/10.1002/14651858.CD007726. pub3. Vigen CL, Mack WJ, Keefe RS et al. (2011). Cognitive effects of atypical antipsychotic medications in patients with Alzheimer’s disease: outcomes from CATIE-AD. Am J Psychiatry 168: 831–839. Woerner MG, Correll CU, Alvir JM et al. (2011). Incidence of tardive dyskinesia with risperidone or olanzapine in the elderly: results from a 2-year, prospective study in antipsychotic-naı¨ve patients. Neuropsychopharmacology 36: 1738–1746. Zhao Q-F, Tan L, Wang H-F et al. (2016). The prevalence of neuropsychiatric symptoms in Alzheimer’s disease: systematic review and meta-analysis. J Affect Disord 190: 264–271.