Behavioral and psychological symptoms in Alzheimer's dementia and vascular dementia

Handbook of Clinical Neurology, Vol. 165 (3rd series) Psychopharmacology of Neurologic Disease V.I. Reus and D. Lindqvist, Editors https://doi.org/10.1016/B978-0-444-64012-3.00002-2 Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 2

Behavioral and psychological symptoms in Alzheimer’s dementia and vascular dementia WILLIAM JAMES DEARDORFF AND GEORGE T. GROSSBERG* Department of Psychiatry and Behavioral Neuroscience, St. Louis University School of Medicine, St Louis, MO, United States

Abstract Behavioral and psychological symptoms of dementia (BPSD) are highly prevalent and represent a significant burden for patients and their caregivers. Early recognition and management of these symptoms is crucial as they are associated with increased risk of institutionalization, impairments in daily functioning, reduced quality of life, and more rapid progression to severe dementia. This chapter will discuss the pathophysiology, proposed diagnostic criteria, clinical features, and management of BPSD, including apathy, depression, agitation/aggression, psychosis, and sleep disturbances. Apathy and depression are the most common overall, and apathy is associated with high symptom severity likely because of its greater persistence. Symptoms such as agitation, aggression, hallucinations, and delusions may be especially distressing and dangerous to patients and caregivers. Nonpharmacologic management should be considered first-line therapy in most cases due to the modest and inconsistent evidence base for pharmacologic agents and greater risk of harm. However, the judicious use of pharmacologic agents may be warranted when symptoms are dangerous and/or severely distressing.

BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS IN ALZHEIMER’S DISEASE The core clinical criteria for the diagnosis of Alzheimer’s disease (AD) focus on the presence of cognitive or behavioral symptoms that interfere with daily functioning and represent a decline from previous levels of functioning (McKhann et al., 2011). These cognitive or behavioral impairments must span a minimum of two domains, such as impaired ability to remember new information, impaired reasoning, or changes in personality and behavior. While cognitive symptoms are frequently considered the hallmark feature of AD, patients often display a broad range of behavioral and psychological symptoms of dementia (BPSD), such as hyperactivity (agitation and irritability), psychosis (delusions and hallucinations), affective symptoms (depression and anxiety), and apathy (Table 2.1) (Aalten et al., 2007). Cross-sectional studies estimate that behavioral symptoms are highly prevalent,

with 96% of patients displaying at least one among six European memory clinics’ symptoms (Petrovic et al., 2007). They are associated with increased risk of institutionalization, difficulties in daily functioning, and increased caregiver burden (Clyburn et al., 2000; Yaffe et al., 2002). Apathy and depression are the most prevalent behavioral symptoms in patients with AD, and apathy tends to have the greatest degree of severity due to its high persistence (Aalten et al., 2005; Steinberg et al., 2008). The strong connection between behavioral symptoms and AD may be explained as a psychologic reaction to the experience of cognitive decline or may reflect the underlying neurodegenerative process as brain structures important in behavior and emotion are affected (Geda et al., 2013). Regardless, early identification and treatment of these symptoms in AD is crucial to allow patients and their caregivers an acceptable level of well-being and functioning (Volicer, 2018).

*Correspondence to: George T. Grossberg, MD, St. Louis University School of Medicine, Department of Psychiatry and Behavioral Neuroscience, St. Louis University School of Medicine, 1438 South Grand, St Louis, MO 63104, United States. Tel: +1-314-977-4829, Fax: +1-314-977-4878, E-mail: [email protected]

6

W.J. DEARDORFF AND G.T. GROSSBERG

Table 2.1 Common behavioral and psychological symptoms in patients with Alzheimer’s disease

Symptom

Prevalencea

Clinical features

Apathy

49% (ranging from 19% to 88%)

Depression

42% (ranging from 19% to 78%)

Agitation and aggression

40% (ranging from 11% to 68%)

Psychosis

Delusions: 31% (ranging from 9% to 59%) Hallucinations: 16% (ranging from 6% to 41%)

Sleep disturbances

39% (ranging from 14% to 69%)

Loss of or diminished motivation Less likely to initiate conversation Less interested and/or enthusiastic in usual interests Reduced participation in social activities Loss of spontaneous emotion or less emotional response to positive or negative events Depressed mood (sad, hopeless) Reduced pleasure in usual activities Social isolation or withdrawal Disrupted sleep or appetite Psychomotor agitation or retardation Irritability, fatigue Thoughts of death, feelings of worthlessness Hitting others or self, kicking, biting Throwing things or slamming doors Screaming, using profanity, shouting Restlessness, pacing, fidgeting Repetitive mannerisms Delusions: belief that he/she is in danger, belief that caregivers are imposters, belief that caregivers will abandon him/her Hallucinations: talking to people who are not there, seeing objects or people who are not there, tasting things or smelling odors that are not present Excessive nighttime awakening Increased sleep latency Early morning awakening Excessive day-time sleepiness Napping more frequently during the day

a

Nonpharmacologic management

Pharmacologic managementb

Cognitive-behavioral approaches, music therapy, cognitive stimulation programs, creative activities

No consistent evidence for any agent. Antidepressants, ChEIs, memantine, and methylphenidate may be options

Psychotherapy (e.g., CBT, PST, IPT, PATH), music therapy

Antidepressants such as SSRIs or SNRIs may be tried, although their effect is inconsistent in clinical trials

Behavioral management (caregiver training, dementia-care mapping, personcentered care), music therapy

Possible small benefit with antipsychotics if necessary. Mixed evidence with antidepressants, ChEIs, memantine, and anticonvulsants

Address possible precipitating factors, caregiver training, environmental modifications

Antipsychotics, possibly ChEIs and memantine

Education (sleep hygiene), physical activity, cognitive behavioral therapy in those who can participate, limited evidence for bright light therapy

Insufficient evidence for melatonin or ramelteon; possible benefit with trazodone. Avoid benzodiazepines and nonbenzodiazepine hypnotics due to risk of harm

Prevalence data comes from Zhao et al. (2016). Pharmacologic agents should be considered as a second-line treatment if nonpharmacologic methods fail due to their limited evidence of benefit with risk of harm. There are some circumstances where their use may be appropriate urgently, such as when the patient poses a risk of significant harm to self and/or others. Abbreviations: CBT, cognitive behavioral therapy; ChEIs, cholinesterase inhibitors; IPT, interpersonal therapy; PATH, problem adaptation therapy; PST, problem-solving therapy; SNRIs, serotonin-norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors.

b

BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS

Framework for the evaluation of patients with behavioral and psychological symptoms When evaluating a patient who presents with BPSD, the “DICE” mnemonic, which stands for Describe, Investigate, Create, and Evaluate, serves as a useful framework for implementing nonpharmacologic strategies (Kales et al., 2014). Clinicians are encouraged to first ask the patient or caregiver to describe the symptoms or behaviors, identify precipitants and the environment in which they occur, and label what aspect of the symptoms are most distressing or problematic. In the second step, the clinician must investigate the potential causes of the behavior, such as new medications, untreated pain, underlying infections, medical conditions, caregiver stress, poor communication, or environmental factors. For example, agitation may result from difficulty swallowing hard food or lack of routine. Rating scales may be used to assess the severity of these symptoms. Table 2.2 describes some of the commonly encountered rating scales used in clinical trials. Unfortunately, many of these rating scales are too lengthy to be used in clinical practice. However, knowledge of the questions that these scales address can help clinicians to adopt a more complete assessment. For example, the Neuropsychiatric Inventory-Clinician rating scale (NPI-C) is a comprehensive scale assessing BPSD (de Medeiros et al., 2010). The Neuropsychiatric Inventory-Questionnaire (NPI-Q) is a short form of the NPI which may be filled out by an informant in 5 min or less and covers 12 domains (Kaufer et al., 2000). Informants rate the severity of symptoms as well as the distress that the symptoms impose on the informant, giving an idea of which symptoms are most important to address. In the third step, a treatment plan is created in collaboration with the caregiver and patient. Behavioral and environmental modifications should play an integral role in this process as they may reduce the frequency and severity of BPSD with effect sizes similar to pharmacotherapy (Brodaty and Arasaratnam, 2012). Finally, during follow-up visits, the clinician must evaluate which strategies were effective and assess any misunderstandings or difficulties in performing certain interventions. If nonpharmacologic methods fail or the symptoms are severe enough at presentation, pharmacologic agents may be warranted.

Apathy Apathy is the most common BPSD and is characterized primarily by a loss of motivation. The prevalence of apathy varies from 19% to 88% across individual studies, with one meta-analysis reporting a pooled prevalence

7

of 49% (Zhao et al., 2016). Apathy is prominent across all stages of AD, an independent contributor to decreased functional status in patients with AD, and may increase the risk of conversion to AD in patients with mild cognitive impairment (MCI) (Robert et al., 2008; You et al., 2015). Compared with psychotic symptoms and anxiety, which tend to have low to moderate persistence over the course of dementia, apathy has a relatively high level of persistence (van der Linde et al., 2016). The proposed diagnostic criteria from the 2009 International Apathy Workgroup characterize apathy as a syndrome with a core feature of loss of or diminished motivation in comparison to the previous level of functioning and not consistent with the patient’s age or culture (Robert et al., 2009). At least one symptom from two out of three domains must be present most of the time for a period of at least 4 weeks. The three domains include: goal-directed behavior, such as initiation and engagement with the environment; goal-directed cognitive activity, such as environment-stimulated curiosity and interest; and emotion, such as responsiveness to positive or negative stimuli. Symptoms must cause clinically significant impairment in important areas of functioning, such as personal, social, or occupational. Apathy and depression represent two distinct syndromes, although distinguishing between the two can be challenging. Certain features may overlap, such as diminished interest, psychomotor retardation, and fatigue. However, symptoms that might be more unique to depression include pessimism, poor appetite with weight loss, disturbed sleep, crying spells, hopelessness, and feelings of guilt (Ishii et al., 2009). Neuroimaging studies have correlated symptoms of apathy with alterations in both the structure and functional activity of frontal-subcortical circuits, such as the anterior cingulate circuit (involved in motivation) and the medial orbitofrontal circuit (involved in integration of visceral–amygdala functions) (Bonelli and Cummings, 2007; Theleritis et al., 2014). Both these regions play an important role in decision-making and response initiation (Marshall et al., 2007). In a structural MRI study, reduced initiative was associated with atrophy of the anterior cingulate and ventrolateral orbitofrontal cortex (Stanton et al., 2013). Management of apathy should begin with nonpharmacologic methods, which have been studied in mostly small open label studies or randomized controlled trials (RCTs) with methodological limitations. In one literature review, the only intervention with sufficient quality studies was therapeutic activity, which represents a heterogeneous group of interventions including cognitive stimulation programs, creative activities, cooking, and behavioral elements (Brodaty and Burns, 2012). Other categories with low quality evidence demonstrating

Table 2.2 Commonly used rating scales in clinical trials Scale Name Cognitive scales Alzheimer’s Disease Assessment Scale—Cognitive Subscale (ADAS-Cog) (Rosen et al., 1984) Mini-Mental State Examination (MMSE) (Folstein et al., 1975)

Description

Time

Scoring

Direction

Comments

11 items related to memory, orientation, praxis, and language 11 items assessing cognitive domains such as orientation, attention, memory, and language

30 min

70-Point scale

5–10 min

30-Point scale

Higher scores indicate more cognitive impairment Lower scores indicate more cognitive impairment

Limited utility in mild and severe AD due to ceiling and floor effects, respectively. Does not assess frontal/executive functioning Limited in mild and severe AD due to ceiling and floor effects, respectively. Primarily used as criteria for eligibility in clinical trials. Definition varies, but generally mild AD 21–26, moderate AD 10–20, and severe AD <10 Preferred scale for trials with severe AD. Questions related to language (most heavily weighted), memory, praxis, visuospatial ability, attention, orientation, social interaction, and construction Specifically developed as a brief screening tool for mild cognitive impairment and mild Alzheimer’s disease, using a cutoff score of 26

Severe Impairment Battery (SIB) (Saxton and Swihart, 1989)

40 items assessing several cognitive domains

20–30 min

100-Point scale

Lower scores indicate more cognitive impairment

Montreal Cognitive Assessment (MOCA) (Nasreddine et al., 2005)

Items assess visuospatial and executive functioning, attention, language, recall

10 min

30-Point scale

Lower scores indicate more cognitive impairment

Global measure using a 7-point categorical scale with questions focusing on cognition, behavior, and social and daily functioning Global measure using a 5-point categorical scale. Overall score calculated through algorithm

20 min

7-Point score

1: marked improvement 4: no change 7: marked worsening

40 + min

0 ¼ no dementia 0.5 ¼ very mild dementia 1 ¼ mild dementia 2 ¼ moderate dementia 3 ¼ severe dementia

Questions related to memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care

26 items rated on 0–3 point scale covering behavioral symptoms

20 min

75-Point scale

Questions related to delusions, hallucinations, aggressiveness, activity disturbances, diurnal rhythm disturbances, anxiety, and phobias. Does not assess apathy, irritability, or disinhibition

Global scales Alzheimer’s Disease Cooperative Study—Clinical Global Impression of Change (ADCS-CGIC) Clinical Dementia Rating Scale (CDR)

Behavioral scales Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD)

Higher scores indicate greater severity of behavioral symptoms

Quantifies the degree of change from baseline based on a global assessment

Neuropsychiatric inventory (NPI)

12 items covering behavioral symptoms based on severity (scores 1–3) and frequency (1–4)

25–30 min

144-Point scale

Higher scores indicate higher frequency/ severity of behavioral symptoms

Behavior Rating Scale for Dementia of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD-BRSD) Cohen-Mansfield Agitation Inventory (CMAI)

46 items on 0–5 point scale covering behavioral symptoms

40 min

148-Point scale

29 items on a 7-point scale covering aggression and agitation

15 min

203-Point scale

Higher scores indicate greater severity of behavioral symptoms Higher scores indicate greater agitation/ aggression

Cornell Scale for Depression in Dementia (CSDD)

19 items rated on 0–2 point scale covering depressive symptoms

20 min

38-Point scale

Abbreviations: AD, Alzheimer’s disease.

Higher scores indicate greater depressive symptoms

Maximum score of 12 (frequency  severity) per item. Questions related to hallucinations, delusions, agitation/ aggression, anxiety, apathy, disinhibition, sleep behavior, and others. The NPI-Q is a self-administered version of the NPI which takes 5 min for the informant to complete Questions related to depressive features, psychotic symptoms, self-regulation, irritability/agitation, vegetative features, apathy, aggression, and affective lability Questions related to physically aggressive, physically nonaggressive (pacing, restlessness, hiding things), verbally aggressive, and nonverbally aggressive behaviors (strange noises, negativism) Uses two semi-structured interviews with patient and informant

10

W.J. DEARDORFF AND G.T. GROSSBERG

positive results include music therapy, exercise, pet therapy, and special care programming. To give an example of some of these programs, one cognitive-behavioral approach asked subjects about their perceived ability to carry out common daily tasks, and whether they considered certain chores important in their daily life (Lam et al., 2010). An occupational therapist subsequently focused on training the participant in these self-identified important skills. In another study, an intervention consisted of “biographically oriented mobilization” (Treusch et al., 2015). Activities were planned based on individually identified information about the residents’ biography or their current interests. For example, one woman who formerly worked at a bank was given coins and sorted them, while another woman, who used to bake for her family, was asked to recall ingredients and show how to mix ingredients together. Providing opportunities to engage in meaningful and emotionally impactful activities based on personalized assessments may be enough to improve symptoms of apathy. Similarly, programs that combine activating strategies (development of a daily structure and pleasant activities plan), psychotherapy, and medication may also improve symptoms of apathy (Leontjevas et al., 2013). There is limited evidence for the use of pharmacologic agents to treat apathy in patients with AD (Sepehry et al., 2017; Theleritis et al., 2017). Several small trials have studied the effects of antidepressants, such as citalopram, trazodone, and fluvoxamine, in patients with AD and/or frontotemporal dementia (Berman et al., 2012). Generally, these studies did not specifically select patients with apathy and did not demonstrate statistically significant improvements on apathy scores compared with placebo. Evidence regarding the efficacy of cholinesterase inhibitors (ChEIs), such as donepezil, rivastigmine, and galantamine, in improving symptoms of apathy is conflicting, primarily because the results are based on secondary endpoints and involve patients not recruited due to symptoms of apathy (Table 2.3) (Harrison et al., 2016). A meta-analysis involving donepezil and galantamine did not find a significant treatment effect (Hedges’ g ¼  0.055; 95% CI 0.322, 0.213; P ¼ 0.687; n ¼ 4), where most studies used the NPI-apathy subscale (Sepehry et al., 2017). In a study that specifically recruited patients with marked neuropsychiatric symptoms at baseline (NPI total score > 11), patients were treated openly with donepezil for 12 weeks before being randomized to either placebo or 10 mg donepezil daily (Holmes et al., 2004). At 12 weeks following randomization, patients treated with 10 mg/day donepezil showed significant decreases in NPI total scores compared with placebo (2.9 vs 3.3 points; P ¼ 0.02). Differences between baseline and week 12 on the NPI-apathy subscale during the open-label donepezil treatment phase

reached statistical significance (P < 0.0001, corrected for multiple comparisons). In another post hoc analysis of two RCTs in which no corrections for multiple comparisons were made, treatment with donepezil compared with placebo resulted in a significant reduction in the emergence of apathy as defined by a composite score incorporating frequency and severity (Waldemar et al., 2011). Results for all other NPI items were nonsignificant, except for aberrant motor behavior. Other openlabel studies involving galantamine and rivastigmine have demonstrated improvements in apathy scores (Cummings et al., 2005; Gauthier et al., 2010). Like ChEIs, evidence for the N-methyl-D-aspartate (NMDA) receptor antagonist, memantine, in the acute management of apathy is weak. In one meta-analysis, no statistically significant benefit with memantine on the NPI-apathy subscale was seen among a group of four heterogeneous studies (Hedges’ g ¼ 0.092; 95% CI 0.134, 0.318; P ¼ 0.423) (Sepehry et al., 2017). One prospective, open-label 12-month study randomized 177 patients with AD to 1 of 4 treatment arms (memantine, donepezil, rivastigmine, or galantamine) (Cumbo and Ligori, 2014). The memantine, donepezil, and rivastigmine (but not galantamine) groups demonstrated statistically significant improvements from baseline to 12 months on NPI and Behavioral pathology in the AD (BEHAVE-AD) total score, with mean differences on NPI total score ranging from 3.67 to 3.79 points. However, no statistically significant improvements were seen in the apathy subscale of the NPI in any of the groups. Because the preliminary data suggest that apathy in AD may be associated with dysfunctions in the dopaminergic brain reward system, methylphenidate and modafinil were proposed to improve symptoms of apathy by increasing dopamine (Lanctot et al., 2008). In an RCT involving 23 participants with mild-to-moderate AD who were already stabilized on a ChEI medication, treatment with modafinil 200 mg/day for 8 weeks did not result in a significant difference in apathy scores based on the Frontal Systems Behavior Scale compared with placebo (Frakey et al., 2012). A large placebo response and small sample size limit its interpretability. Methylphenidate has been studied in two RCTs and one open-label trial (Herrmann et al., 2008; Padala et al., 2010; Rosenberg et al., 2013). Apathy in Dementia Methylphenidate Trial (ADMET) was the first parallel group, multicenter, RCT of a medication intervention specifically designed to assess apathy in AD (Drye et al., 2013). Patients were excluded if they had a diagnosis of a major depressive episode. At the end of 6 weeks, treatment with 20 mg/day methylphenidate (n ¼ 29) compared with placebo (n ¼ 31) demonstrated a nonstatistically significant difference of 2.5 points (95% CI 6.5, 1.6; P ¼ 0.23) on the 18-item Apathy

Table 2.3 Commonly encountered medications in the management of behavioral and psychological symptoms

Medication

Class

Starting dose

Donepezil

Cholinesterase inhibitor

5 mg/day

Rivastigmine

Cholinesterase inhibitor

Galantamine

Cholinesterase inhibitor NMDA receptor antagonist

1.5 mg BID orally or 4.6 mg/24 h patch 4 mg BID IR or 8 mg/day ER 5 mg/day IR or 7 mg/day ER

Memantine

Recommended dose range 5 mg, 10 mg, and 23 mg/day available 6–12 mg/day orally or 9.5–13.3 mg/24 patch 16–24 mg/day

Gastrointestinal side effects (nausea, vomiting, and diarrhea), insomnia, weight loss, dizziness, bradycardia, syncope

Headache, dizziness

Risperidone

Atypical antipsychotic

0.25–0.5 mg/day

10–20 mg/day IR or 28 mg/day ER 0.5–2 mg/day

Olanzapine

Atypical antipsychotic

1–2.5 mg/day

5–10 mg/day

Quetiapine

Atypical antipsychotic

25 mg/day

25–300 mg/day

Aripiprazole

Atypical antipsychotic Antidepressant (SSRI)

2 mg/day

2–10 mg/day

5–10 mg/day

10–20 mg/day

Escitalopram

Antidepressant (SSRI)

5 mg/day

10 mg/day

Sertraline

Antidepressant (SSRI) Antidepressant (SSRI)

12.5–25 mg/day

50–200 mg/day

5–10 mg/day

10–40 mg/day

37.5 mg/day

75–300 mg/day

Trazodone

Antidepressant (SNRI) Antidepressant

50 mg/day

50–300 mg/day

Mirtazapine

Antidepressant

7.5–15 mg/day

15–45 mg/day

Methylphenidate

CNS stimulant

5 mg/day

10–20 mg/day administered BID

Citalopram

Fluoxetine

Venlafaxine

Notable side effects and comments

Higher EPS than other atypical antipsychotics; weight gain, elevated prolactin; black-box warning for increased risk of cerebrovascular events including stroke and mortality in patients with dementia for all antipsychotics EPS, higher weight gain, and hypercholesterolemia than other atypical antipsychotics, anticholinergic side effects EPS, weight gain, higher anticholinergic side effects and orthostatic hypotension than other atypical antipsychotics, sedation EPS, less metabolic side effects than others Nausea/vomiting, insomnia, sexual dysfunction, hyponatremia, may impair platelet aggregation. Administer in evening due to sedating properties. Dose-dependent QTc prolongation (maximum recommended dose is 20 mg/day in patients >60 due to risk of abnormal heart rhythm) Side effects similar to citalopram. Not currently available as generic. Dose-dependent QTc prolongation (maximum recommended dose is 20 mg/day in patients >60 due to risk of abnormal heart rhythm) Side effects similar to citalopram. Administer in morning due to activating properties Side effects similar to citalopram, but insomnia and agitation may be more frequently encountered. Should generally be avoided due to long half-life and drug–drug interactions Side effects similar to citalopram, but also dosedependent elevations in blood pressure Sedation, nausea, orthostatic hypotension, dizziness, priapism Increased appetite, weight gain, drowsiness, anticholinergic effects (constipation, xerostomia). May be associated with sedation at lower doses (H1 antagonism) and activation at higher doses (a2 antagonism) Decreased appetite, weight loss, irritability/ anxiety, headache, insomnia, and increased risk of cardiovascular events

Abbreviations: CNS, central nervous system; EPS, extrapyramidal symptoms; ER, extended release; IR, immediate release; NMDA, N-methyl-Daspartate; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

12

W.J. DEARDORFF AND G.T. GROSSBERG

Evaluation Scale (scores range from 18 to 72 and higher scores indicate more severe apathy) (Rosenberg et al., 2013). On the Alzheimer’s Disease Cooperative StudyClinical Global Impression of Change (ADCS-CGIC), which was a co-primary outcome, 21% of patients treated with methylphenidate showed moderate or marked improvement at 6 weeks compared with 3% of placebo patients (odds ratio (OR) of 3.7; 95% CI 1.3–10.8; P ¼ 0.02, favoring methylphenidate.) On the NPI-apathy subscale, the estimated treatment difference favored methylphenidate over placebo by 1.8 points (95% CI 3.4, 0.3; P ¼ 0.02). Potential safety problems included higher rates of weight loss and anxiety. A larger study, ADMET2, is currently in process with an estimated primary completion date of August 2019 (ClinicalTrials. gov identifier NCT02346201). The trial differs from ADMET in that the co-primary outcome measures are the NPI-apathy subscale and ADCS-CGIC. Bupropion, which acts as a dopamine and norepinephrine reuptake inhibitor, has also been studied for the treatment of apathy of AD although the results are not yet available (ClinicalTrials.gov identifier NCT01047254). The combined evidence remains too weak to recommend any pharmacologic agent as first-line therapy for the treatment of apathy (Ruthirakuhan et al., 2018). This may be due to methodological issues, such as largely relying on the apathy subscale of the NPI, which may not capture the full spectrum of the apathy syndrome. In clinical practice, patients with AD often receive a ChEI and/or memantine because of their benefits on cognition and function. This combination may also help to decrease symptoms of apathy (Atri et al., 2017). However, it remains unclear how best to manage patients, who present with symptoms of apathy and who either have persistent symptoms while on maximally tolerated doses of ChEIs and/or memantine or are not currently taking one or either medication because of a history of intolerable side effects or a perceived lack of benefit. Treatment of apathy in this patient population should involve nonpharmacologic methods as first-line therapy. For patients who display persistent symptoms of apathy after a variety of nonpharmacologic interventions have been employed, a trial of methylphenidate may be an option. While more definitive evidence will be obtained from the ADMET2 trial, results from the ADMET trial, in which statistical significance was achieved on the NPIapathy subscale as well as the ADCS-CGIC, provide some preliminary evidence that methylphenidate may provide modest benefits (difference in NPI-apathy score of 1.8 points favoring methylphenidate from a mean baseline of 7 points). The lack of statistical significance on the Apathy Evaluation Scale, which was a co-primary outcome, may be because of a lack of power in the study or lack of precision in the instrument. The long-term use

of methylphenidate is not currently recommended in the absence of more compelling evidence because of concerns regarding decreased appetite, weight loss, and increased anxiety.

Depression The prevalence of depression in AD ranges from 19% to 78% with a pooled prevalence of 42% (Zhao et al., 2016). Depression is associated with an overall increased risk of developing AD in the general population as well as an increased risk of progression to dementia in patients with MCI (Cherbuin et al., 2015; Mourao et al., 2016). One key question that remains to be elucidated is whether depression itself is a risk factor for dementia or whether it is part of the prodromal symptoms of dementia (Byers and Yaffe, 2011). Evidence from a recently published cohort study, in which depressive symptoms during late life, but not midlife, were associated with increased risk for dementia, suggests depression may be a prodromal feature of dementia or that the two arise from common pathophysiologic pathways and risk factors (SinghManoux et al., 2017). Proposed pathways that link depression with dementia include vascular disease, increased cortisol leading to hippocampal atrophy, and increased amyloid-b production initiated via a stress response from increased glucocorticoids (Byers and Yaffe, 2011; Taylor et al., 2013). In a meta-analysis of neuroimaging studies, both AD and late-life depression were associated with a reduction in bilateral hippocampal volume (Boccia et al., 2015). However, it is unclear whether hippocampal atrophy seen in patients with late-life depression serves as a direct risk factor for AD or is part of the prodrome of AD. In 2002, the National Institute of Mental Health (NIMH) prepared provisional diagnostic criteria for depression in AD (Olin et al., 2002). These criteria reflect subtle differences between late-life depression in patients without cognitive impairment and depression in AD. For example, patients with AD often present with milder symptoms such as social isolation, withdrawal, and irritability and may not develop major depressive episodes. The clinician must decide which symptoms are likely due to depression and which may be a direct result of non-mood-related dementia symptoms (e.g., significant weight loss secondary to dysphagia). Like major depressive disorder (MDD), a diagnosis of depression in AD must only be made in the presence of either clinically significant depressed mood or decreased positive affect/ pleasure in response to usual activities. Many of the other criteria are similar, except for the inclusion of irritability and social isolation/withdrawal and the requirement that only three or more symptoms be present for a 2-week period. Some individuals, such as those with a history

BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS of recurrent major depressive episodes prior to the onset of AD, may be better classified as having both AD and MDD. While effective in late-life depression, antidepressants have demonstrated mostly negative results in trials involving patients with AD (Leong, 2014; Farina et al., 2017). Commonly used rating scales in trials involving patients with depression include the Montgomery–Asberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HAM-D). However, these scales may not be appropriate in individuals with dementia. The Cornell Scale for Depression in Dementia (CSDD) may demonstrate higher sensitivity and specificity in patients with dementia because of its greater emphasis on function and input from both the caregiver and patient (Korner et al., 2006). Several meta-analyses have been performed previously, and all of them have commented on the significant methodologic limitations of the RCTs, including inadequate power and small sample sizes (Bains et al., 2002; Thompson et al., 2007; Nelson and Devanand, 2011; Sepehry et al., 2012). Clinical trials involving citalopram, escitalopram, sertraline, fluoxetine, venlafaxine, and mirtazapine have been performed. In one meta-analysis, a nonstatistically significant benefit was seen for antidepressants compared with placebo in the odds of response (OR ¼ 2.12; 95% CI 0.95, 4.70; P ¼ 0.07; n ¼ 6), where response was generally defined as 50% improvement on the scale used (Nelson and Devanand, 2011). Pooled response rates were 53.3% and 38.9% in the drug and placebo groups, respectively. Perhaps the two most well-known recent trials are the Depression in Alzheimer’s Disease-2 (DIADS-II) study and the Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia (HTA-SADD) study (Rosenberg et al., 2010; Banerjee et al., 2011). In DIADS-II, 131 participants with mildto-moderate AD and depression in AD (based on the consensus criteria discussed above) were randomized to sertraline (targeted dose of 100 mg/day) or placebo (Rosenberg et al., 2010). At the study’s endpoint of 12 weeks, the OR of being at or better than a given category on the modified ADCS-CGIC was 1.01 (95% CI 0.52, 1.97; P ¼ 0.98). The median CSDD score difference at 12 weeks was 1.2 points (95% CI -1.65, 4.05; P ¼ 0.41), indicating no statistically significant benefit with sertraline. Interestingly, caregivers from both groups received a psychosocial intervention (20–30 min counseling sessions at every study visit), which may partially account for the high placebo response. Diarrhea, indigestion, dry mouth, and dizziness were more common in the sertraline-treated group. In the HTA-SADD trial, 326 participants were randomized to sertraline (target dose 150 mg/day; mean dose 70 mg/day), mirtazapine (target

13

dose 45 mg/day; mean dose 24 mg/day), or placebo (Banerjee et al., 2011). Inclusion criteria included probable or possible AD, and depression for greater than 4 weeks. At the 13-week primary endpoint, the difference in mean CSDD score (where higher scores indicate increased depressive symptoms) comparing sertraline to placebo was 1.17 points (95% CI 0.23, 2.58; P ¼ 0.10), comparing mirtazapine to placebo was 0.01 points (95% CI 1.37, 1.38; P ¼ 0.99), and comparing sertraline to mirtazapine was 1.16 (95% CI 0.25, 2.57; P ¼ 0.11). Results were nonsignificant even at 39 weeks. These two trials imply that the use of antidepressants as first-line therapy in patients with dementia and clinically significant depression should be reconsidered. The high response rates in both placebo and antidepressant-treated groups in most clinical trials suggests that supportive care should play an important role and antidepressants may be reserved for those with more severe depression or recurrent depressive symptoms. In late-life depression, psychotherapy demonstrates statistically significant improvements in depressive symptoms over control groups (Huang et al., 2015). The effect size varies based on the type of control group, such as treatment-as-usual, supportive therapy, or waitlist. A variety of interventions specifically targeting patients with dementia and depression have been described, such as cognitive behavioral therapy (CBT), reminiscence group therapy, problem-solving therapy (PST), and interpersonal psychotherapy (IPT) (Wilkins et al., 2010; Orgeta et al., 2014; Apostolo et al., 2016). With CBT, significant adaptations may need to be made for patients with dementia to participate meaningfully (Chand and Grossberg, 2013). Examples include encouraging participants to take notes during sessions, frequent summaries, and incorporating caregivers if consent is given. IPT sessions can focus on the role transitions that both the patient and caregiver will experience (Miller and Reynolds, 2007). For example, patients will need to cope with a loss of independence while the caregiver may need to take on a role more like a parent as the patient requires assistance with activities of daily living (ADLs). Interventions focused on PST may also reduce depressive symptoms in patients with evidence of executive dysfunction or cognitive impairment (Arean et al., 2010; Kiosses et al., 2011). For example, problem adaptation therapy (PATH) is a home-based intervention with a PST framework that focuses on solving problems that contribute to the patient’s depression and impaired functioning by utilizing tools such as environmental adaptations, notebooks, and calendars. Interventions are personalized based on the severity of cognitive impairment and the patient’s home environment. Caregivers learn how to help the individual avoid negatively charged situations, shift the individual’s attention within

14

W.J. DEARDORFF AND G.T. GROSSBERG

a situation, or change how the individual thinks about the situation. A recent RCT was performed comparing home-delivered PATH to home-delivered supportive therapy for cognitively impaired patients (ST-CI), which teaches techniques such as highlighting positive experiences and imparting optimism (Kiosses et al., 2015). At the 12-week endpoint, PATH participants (n ¼ 37) reported a greater improvement in depressive symptoms as measured by the MADRS total score (Cohen’s d ¼ 0.60, 95% CI 0.13, 1.06) and disability as measured by World Health Organization Disability Assessment Schedule-II total score (Cohen’s d ¼ 0.67, 95% CI 0.20, 1.14) compared with ST-CI (n ¼ 37). Remission rates, defined as MADRS scores 7, were significantly greater in the PATH group at week 12 compared with ST-CI (37.84% vs 13.51%, respectively; P ¼ 0.02). Implementation of the PATH program may not be possible in resource limited areas. However, half of the therapists in this trial were social workers who may have administered it via home health care organizations. Another nonpharmacologic therapy is music therapy, which may be classified as receptive/passive, where participants listen to music played or selected by the therapist, and active, where participants are actively involved in playing instruments and/or singing. In a recent Cochrane review of 17 studies, music therapy reduced depressive symptoms but had little to no effect on agitation or aggression (van der Steen et al., 2018). Among the nine studies which assessed depressive symptoms (measured by the Geriatric Depression Scale (GDS) or subscales of BEHAVE-AD or NPI), the standardized mean difference (SMD) from placebo was 0.28 (95% CI 0.48, 0.07). This is comparable to the SMD reported with antidepressant treatment in patients with dementia (0.29, 95% CI 0.02, 0.60) (Nelson and Devanand, 2011). Further research is needed to determine whether there are differences between active and receptive music therapy and whether a trained therapist is needed for benefits to be seen. Nonpharmacologic methods, if available, should be first-line for depression in patients with AD as they have demonstrated modest benefits in RCTs with limited harm. When nonpharmacologic methods have failed, antidepressants may be considered. However, it should be emphasized that antidepressants are not without harm in this population and may be associated with anticholinergic and gastrointestinal side effects, increased risk of bleeding, and hyponatremia (Anglin et al., 2014). The effect of certain antidepressants on falls and fractures is unclear (Gebara et al., 2015). Factors that may favor a therapeutic trial with an antidepressant include symptoms that are clearly distressing to the patient and/or caregiver, persistent symptoms despite the use of environmental changes and symptoms specific to depression

such as anhedonia (vs symptoms such as decreased motivation which may be more consistent with apathy) (Lenze, 2011). For clinicians wishing to discontinue antidepressants in this population, symptoms should be monitored closely and nonpharmacologic interventions should be provided, as discontinuation has been shown to increase depressive symptoms compared with patients continued on antidepressant therapy (Bergh et al., 2012).

Agitation and aggression Agitation and aggression are often distressing to both the patient and caregiver, associated with shorter survival time from mild AD to severe AD and/or death, and increase the risk of institutionalization (Okura et al., 2011; Peters et al., 2015). The prevalence of aggression across 29 heterogeneous studies ranges from 11% to 68%, with a pooled prevalence of 40% (Zhao et al., 2016). A consensus definition for agitation was provided by the Agitation Definition Working Group (ADWG) of the International Psychogeriatric Association (IPA) (Cummings et al., 2015b). The core criterion includes behaviors that are associated with evidence of emotional distress (rapid changes in mood, irritability, outbursts) that have been persistent or recurrent for a minimum of 2 weeks. Examples include excessive motor activity (pacing, rocking, restlessness), verbal aggression (yelling, screaming), and/or physical aggression (grabbing, scratching, slamming doors). Behaviors must cause significant impairments in interpersonal relationships, aspects of social functioning, and/or ability to perform or participate in daily living activities. This definition implies that agitated behaviors serve as an expression of an emotional state of distress. Therefore, a patient would not meet diagnostic criteria if the aggressive behaviors did not cause distress or if the behavior is only upsetting to someone else but not the patient. A patient could meet criteria for agitation without demonstrating aggression. Common clinical scales used to measure symptoms of agitation and aggression are the agitation/ aggression subscale of the NPI, BEHAVE-AD, and the Cohen-Mansfield Agitation Inventory (CMAI) (Cohen-Mansfield, 1996). Based on neuroimaging studies, agitation is associated with volume loss in the frontal cortex, anterior cingulate cortex, posterior cingulate cortex, insula, amygdala, and hippocampus (Rosenberg et al., 2015). Agitation is also associated with hypoperfusion in the left anterior temporal cortex, bilateral dorsofrontal cortex, and right parietal cortex (Hirono et al., 2000). Neurochemically, agitation is associated with decreased cholinergic activity in the frontal and temporal cortex and decreased serotonin. The circuits that are involved in these brain regions include those that control

BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS maladaptive responses to uncertainty about future threat, such as inflated estimates of threat cost and hypervigilance (Grupe and Nitschke, 2013). This suggests that agitation is a hyperreactive state that involves a miscalculation of potential threats in addition to increased vigilance and heightened reactivity to threat uncertainty (Rosenberg et al., 2015). Treatment of agitation and aggression in AD is challenging as the symptoms may be very distressing to both the patient and caregiver. A variety of nonpharmacologic interventions have been tested that demonstrate some efficacy in clinical trials, such as music therapy and behavioral management techniques encompassing caregiver training and dementia-care mapping (Chenoweth et al., 2009; Millan-Calenti et al., 2016). Dementia-care mapping is a person-centered approach whereby observers track people with dementia throughout the day and note positive events and personal detractions (i.e., staff behaviors that might undermine the personhood of those with dementia) (Brooker, 2005). Training sessions are held to explore how actions of the staff members may contribute to the behavior of residents and encourage staff members to build meaningful relationships with the persons with dementia. While designed for a nursing home, the techniques involved may be taught to caregivers in a home setting. Music therapy has also shown efficacy, even in patients with moderateto-severe AD, and its effects may be enhanced when the intervention is individualized and interactive (e.g., clapping, singing, and dancing) (Millan-Calenti et al., 2016). However, a meta-analysis of 12 studies did not report a significant difference from placebo on symptoms of agitation or aggression (SMD ¼  0.08; 95% CI 0.29, 0.14; 515 participants) (van der Steen et al., 2018). Evidence for bright light therapy and aromatherapy is limited (Livingston et al., 2014). While some of these interventions are more difficult to implement and require adequate training, others such as music therapy are relatively easy to implement. Caregivers should be counseled on identifying potential precipitating factors, establishing structured routines for the patient, and improving communication skills by speaking in a calm, reassuring voice and avoiding negative words (Kales et al., 2014). It is important for caregivers to recognize that the patient’s behaviors are often not intentional. An incredible burden is often placed on caregivers and their well-being should also be addressed by recommending that they participate in support groups, find time for themselves, and seek out medical help when necessary. While there currently are no FDA approved drugs for agitation in AD, antipsychotics are commonly prescribed despite a black-box warning for increased risk of cardiovascular events and mortality in patients with dementia

15

(Ballard and Waite, 2006; Maust et al., 2015). The increased risk of mortality is seen with both typical and atypical antipsychotics and even when only used for brief periods of time. The OR for mortality in one meta-analysis was 1.54 (95% CI 1.06, 2.23; P ¼ 0.02), where most studies were 8–12 weeks in duration. This corresponds to an absolute risk difference of 1% excess deaths (95% CI 0.4, 2%; P ¼ 0.01) (Schneider et al., 2005). A 3.5% greater mortality (95% CI 0.5, 6.5%; P ¼ 0.02) was reported when comparing low vs high dose groups in one retrospective case–control study (based on haloperidol-equivalent dosages of <1.5 mg/day vs 3.0 mg/day) (Maust et al., 2015). In addition, data from clinical trials and observational studies have identified an increased risk of acute myocardial infarction, hip fracture, extrapyramidal symptoms, and somnolence with antipsychotics (Farlow and Shamliyan, 2017). The efficacy of antipsychotics in clinical trials is modest, with smaller effect sizes seen for those with more severe dementia and outpatients (Schneider et al., 2006a; Gentile, 2010). For example, the effect size among RCTs with 6–12 weeks of follow-up on a measure of total global score (which includes symptoms such as delusions, hallucinations, anxiety, agitation, hostility, and others) reached statistical significance for aripiprazole (SMD 0.20; 95% CI 0.04, 0.35; n ¼ 3), olanzapine (SMD 0.12; 95% CI 0, 0.25; n ¼ 4), and risperidone (SMD 0.19, 95% CI 0, 0.38; n ¼ 6) but not quetiapine (SMD 0.11; 95% CI 0.02, 0.24; n ¼ 4) (Maher et al., 2011). The point estimates are small and the confidence intervals include values that are negligible to modest. On measures of agitation, the pooled SMD among atypical antipsychotics was 0.20 (95% CI 0.12, 0.27). Perhaps the most well-known study entitled Clinical Antipsychotic Trials of Intervention EffectivenessAlzheimer’s Disease (CATIE-AD) involved 421 outpatients with AD and delusions, hallucinations, aggression, or agitation severe enough to disrupt their functioning (Schneider et al., 2006b). Participants were randomized to olanzapine, quetiapine, risperidone, or placebo. The primary outcome was time to discontinuation of treatment, which served as a pragmatic measure that incorporates the perceptions of the clinician, caregiver, and patient regarding the drug’s benefits vs risks. Treatment could be discontinued by the physician at any time after 2 weeks if the patient’s response was not adequate. The study did not find a statistically significant difference in time to discontinuation between treatment groups for any reason (median time to discontinuation ranged from 5.3 weeks to 8.1 weeks). When assessing median time to discontinuation due to lack of efficacy, significant differences from placebo (9.0 weeks) were seen with the olanzapine group (22.1 weeks) and risperidone group (26.7 weeks). Patients receiving an antipsychotic were significantly more likely to discontinue

16

W.J. DEARDORFF AND G.T. GROSSBERG

treatment due to intolerance, adverse effects, or death compared with placebo. Common adverse events with antipsychotics included extrapyramidal symptoms, sedation, and confusion or changes in mental status. One limitation regarding efficacy was that the quetiapine group achieved a lower mean dose (56.5 mg/day) than typically seen in clinical practice due to the protocol committee’s concern regarding excess sedation with higher doses. The results of this trial suggest that any potential benefits seen with antipsychotics are often offset by adverse events that limit their tolerability. The newer antipsychotics aripiprazole and brexpiprazole are currently involved in phase 3 trials to receive an FDA indication for the treatment of agitation associated with AD (ClinicalTrials.gov identifier NCT02168920 and NCT01862640). Results from two Phase 3 trials involving brexpiprazole were recently reported with mixed results on the primary endpoint of CMAI total scores. While nonpharmacologic methods should be first-line therapy, there may still be certain situations in which atypical antipsychotics are appropriate, such as continued agitation despite adequate trials of nonpharmacologic methods or when symptoms of agitation are severe (e.g., causing impairment in eating), dangerous to the patient or others, and/or cause significant distress to the patient (Jennings and Grossberg, 2013; Reus et al., 2016). For patients who fail to respond to nonpharmacologic interventions, the results of the CATIE-AD study show that there may be some benefit if patients can tolerate their side effects. Atypical antipsychotics would be preferred to typical antipsychotics given similar efficacy but greater risk of harm with typical antipsychotics (particularly extrapyramidal symptoms and possibly increased risk of all-cause mortality compared with atypical antipsychotics) (Farlow and Shamliyan, 2017). Patients should be initiated on the lowest dose range and titrated upward. Examples of daily dose ranges for geriatric patients include 2–10 mg/day for aripiprazole, 5–10 mg/day for olanzapine, 25–300 mg/day for quetiapine, and 0.5–2.0 mg/day for risperidone (Table 2.3). When initiated, patients should be monitored for certain common side effects, such as extrapyramidal symptoms, weight gain, impaired glucose tolerance, orthostatic hypotension, and QTc prolongation. Another finding of concern of the CATIE-AD study was that use of atypical antipsychotics was associated with worsening cognitive function, with an average decline of 2.46 points greater on the 30 point MMSE scale compared with placebo patients over 36 weeks (Vigen et al., 2011). If the patient’s symptoms have not improved after a 2–4 week trial, the agent should be tapered and withdrawn. If an adequate response has been seen, the

American Psychiatric Association (APA) recommends that attempts to discontinue the medication within 4 months of initiation should be made because of the risk of adverse events, unless the patient has experienced a recurrence of symptoms during prior attempts at tapering the medication (Reus et al., 2016). Discontinuation can be effected safely without detrimental effects on behavior, although the risk of relapse appears higher in certain patient populations such as more severe behavioral symptoms at baseline (e.g., severe mood disorder with psychotic features) (Ballard et al., 2008; Declercq et al., 2013). However, the multicenter Antipsychotic Discontinuation in Alzheimer’s Disease (ADAD) trial did report a statistically significant increase in the risk of relapse following discontinuation of risperidone compared with continued risperidone therapy among patients with symptoms of psychosis and/or agitation/aggression who achieved an adequate response after 16 weeks with risperidone treatment (Devanand et al., 2012). The implications of this study will be discussed further in the section on psychosis, but the results suggest that clinicians will need to have detailed discussions with patients and their caregivers regarding their preferences and concerns given the unclear ratio of benefit to harm. Several antidepressants, including citalopram, sertraline, and trazodone, have been studied in RCTs involving patients with clinically significant agitation (Seitz et al., 2011). When compared to placebo in two studies, sertraline and citalopram were both associated with significant reductions in symptoms of agitation. Other studies comparing sertraline or citalopram to antipsychotics demonstrated similar efficacy between the two classes. Regarding trazodone, one study found no statistically significant difference in CMAI total scores compared to placebo. Two other studies comparing trazodone to haloperidol failed to detect any difference in CMAI total scores. The recently completed Citalopram for Agitation in Alzheimer Disease Study (CitAD) demonstrated that the addition of citalopram (majority received 30 mg/day) to a psychosocial intervention resulted in significantly reduced symptoms of agitation and caregiver distress (Porsteinsson et al., 2014). Participants were included if they had clinically significant agitation and excluded if they had a major depressive episode or psychosis requiring antipsychotic treatment. On the co-primary outcome measures, the treatment difference on the 18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) at week 9 was 0.93 points favoring citalopram (95% CI 1.80, 0.06; P ¼ 0.04), and the OR of being at or better than a given modified ADCS-CGIC category was 2.13 (95% CI 1.23, 3.69; P ¼ 0.01). Forty percent of patients receiving citalopram displayed moderate or marked improvement from baseline compared with 26% of patients receiving

BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS placebo. Interestingly, effects with citalopram were statistically significant for NPI total score (6.03 points, 95% CI 10.75, 1.32; P ¼ 0.013) but not the NPI agitation subscale (0.78 points, 95% CI 1.77, 0.21; P ¼ 0.123). Some possible safety concerns included worsening of cognition on the 30 point MMSE (difference from placebo of 1.05 points, 95% CI 1.97, 0.13; P ¼ 0.03) and QT interval prolongation (difference from placebo of 18.1 ms, 95% CI 6.1, 30.1; P ¼ 0.004) with citalopram treatment. In a post hoc multivariate method to assess heterogeneity of response, participants with milder cognitive impairment, treated as outpatients, and with moderate to moderately severe agitation scores demonstrated the greatest response (Howard, 2016; Schneider et al., 2016). Placebo was most effective for long-term care residents with moderate to severe cognitive impairment (MMSE 20) and moderately severe to severe agitation scores. While these types of analyses may help to identify specific patient populations in which treatment may be most beneficial, they have limited power given the small numbers of patients within each subgroup/decile and should be considered exploratory. However, these results do suggest that the risks of worsening cognition, prolongation of QTc, and other possible adverse effects of SSRIs (hyponatremia, falls) may outweigh the minimal benefits seen with patients with more severe cognitive impairment living in long-term care (Coupland et al., 2011). Given the FDA’s warning about using doses of citalopram or escitalopram higher than 20 mg/day in patients over 60 years of age, the 30 mg/day dose should be avoided. A trial with escitalopram for agitation in AD is planned with an estimated completion date of December 2020 (ClinicalTrials.gov identifier NCT03108846). The ChEIs and memantine have also been studied in patients with AD and agitation. The most well-known trial was the CALM-AD trial, which examined the use of donepezil vs placebo for 12 weeks in 272 patients with AD who had evidence of clinical agitation and were not receiving neuroleptic agents or ChEIs at the time of the enrollment (Howard et al., 2007). Most participants received a psychosocial treatment program for up to 4 weeks prior to randomization and were only randomized if their CMAI score was 39 or more after the psychosocial treatment. Randomization could also be immediate if the agitation was severe enough to warrant drug treatment. The majority (>90%) of participants lived in a residential care facility and had moderate-tosevere AD. Only 53 of the 387 participants (13.7%) who entered the psychosocial-treatment phase had sufficient improvement in their CMAI score to not proceed to randomization, demonstrating the difficulty in managing these symptoms with nonpharmacologic therapy. At the 12-week endpoint, no significant difference from

17

baseline on CMAI score was detected between placebo and the donepezil treated groups (0.06; 95% CI 4.35, 4.22). This trial provides high quality evidence that donepezil does not result in clinically significant improvements in agitation compared to placebo among a population with mostly severe AD living in residential care facilities. A similar trial involving memantine was performed in patients with moderate-to-severe AD who presented with agitation, although participants were living in the community and on a stable dose of ChEI therapy for at least three months prior to screening (Herrmann et al., 2013). This trial underwent several protocol amendments and was ultimately underpowered because of recruitment issues and premature termination. At the 24-week endpoint, no significant differences between memantine and placebo groups were seen in mean change from baseline in NPI total score (1.23 points favoring placebo; 95% CI 1.75, 4.21; P ¼ 0.42) or SIB total scores (0.48 points favoring placebo; 95% CI 2.30, 1.34; P ¼ 0.60). These results are consistent with another trial involving institutionalized patients which did not find a benefit with memantine on CMAI total scores compared to placebo (Fox et al., 2012). Overall, the evidence suggests that ChEIs and memantine are likely not beneficial for the acute management of agitation and aggression given the negative trials in which patients were specifically recruited because of symptoms of agitation and aggression. However, benefits may arise from either delaying the emergence of or preventing the clinical worsening of agitation and aggression (Gauthier et al., 2002; Cummings et al., 2004). This is supported mostly by reductions in behavioral symptoms seen with open-label studies and RCTs (usually measured with the NPI as a secondary outcome) and post hoc analyses, which examine symptom clusters such as agitation/aggression (Gauthier et al., 2008; Wilcock et al., 2008; Herrmann et al., 2011). The combination of memantine and a ChEI may help to reduce symptoms of agitation over a 6-month period, based on an analysis of three trials in which patients already stabilized on a ChEI received either memantine or placebo (Atri et al., 2017). At week 24, benefits were seen with combination therapy on NPI total score as well as on many subdomains, such as agitation, delusions, irritability, anxiety, and apathy/indifference. Caregiver burden related to these symptoms was also decreased. Effect sizes were modest, with values of Cohen’s d ranging from 0.19 to 0.36. Other medications that may be considered for agitation in AD include melatonin, benzodiazepines, and anticonvulsant medications. The principle behind the use of melatonin to treat agitation in AD is that disturbed sleep patterns may be an underlying precipitant for agitated

18

W.J. DEARDORFF AND G.T. GROSSBERG

behavior (Gehrman et al., 2009; de Jonghe et al., 2010). In one systematic review, two RCTs demonstrated improvements in sundowning/agitated behavior with melatonin compared to placebo, one RCT demonstrated no significant improvement, and five case series reported improvement (de Jonghe et al., 2010). Benzodiazepines should generally be avoided because of their lack of established efficacy and well-documented side effects, such as increased risk of falls and fractures, sedation, cognitive impairment, prolonged reaction times, paradoxical agitation, and hallucinations (Tampi and Tampi, 2014). A meta-analysis of studies involving valproate demonstrated no improvement in agitation, with an increase in adverse events compared with placebo control, and valproate was ineffective in delaying or preventing the emergence of agitation and psychosis (Lonergan and Luxenberg, 2009; Tariot et al., 2011). Small clinical studies involving carbamazepine have demonstrated positive results, although issues with tolerability (e.g., drowsiness, ataxia, and hyponatremia) and drug–drug interactions limit its use (Gallagher and Herrmann, 2014). It may be useful in refractory patients who are not responding to antipsychotics (Olin et al., 2001). Other notable experimental therapies currently involved in Phase II and III clinical trials include dextromethorphan/quinidine (AVP-786), pimavanserin, lumateperone (ITI-007), and the cannabinoid nabilone (Garay et al., 2016). Dextromethorphan acts as an uncompetitive NMDA receptor antagonist, sigma-1 receptor agonist, and a3b4 nicotinic acetylcholine antagonist (Taylor et al., 2016). The addition of quinidine increases the exposure to dextromethorphan by acting as a CYP2D6 inhibitor. The combination is currently FDA approved for pseudobulbar affect. A 10-week phase II trial enrolled mostly outpatients with AD and clinically significant agitation (Cummings et al., 2015c). The trial utilized a two-stage approach whereby placebo nonresponders after the first 5 weeks were rerandomized. At the end of the first 5 weeks, dextromethorphan/quinidine demonstrated statistically significant benefits over placebo on the NPI agitation/aggression score with a least squares mean difference (LSMD) of 1.5 points (95% CI 2.3, 0.7; P < 0.001). A similar effect size was seen in the second 5-week stage. Its use is not currently recommended because of the high cost, need for confirmatory Phase III trials, and an effect size that is of questionable clinical significance (the trial was powered to detect a mean difference of 2.5 points, and the protocol notes that this study should be considered an exploratory trial with a purpose to design subsequent studies). Two phase III trials are currently running (ClinicalTrials.gov identifier NCT02442765 and NCT02442778). Pimavanserin is a selective

serotonin inverse agonist targeting 5-HT2A receptors and is FDA approved for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. It is currently involved in a Phase II trial for the treatment of agitation and aggression in AD (ClinicalTrials.gov identifier NCT02992132). Lumateperone (ITI-007), whose mechanism of action includes serotonin 5-HT2A receptor antagonism and D2 receptor modulation, is involved in a Phase III trial for the treatment of agitation in patients with dementia (ClinicalTrials.gov identifier NCT02817906).

Psychosis Psychotic symptoms, including delusions and hallucinations, are associated with increased risk of institutionalization, increased caregiver distress, impaired functional status, and aggression (Magni et al., 1996; Rapoport et al., 2001; Yaffe et al., 2002). The estimated prevalence of delusions in AD ranges from 9% to 59% with a pooled prevalence of 31% (Zhao et al., 2016). The estimated prevalence of hallucinations in AD ranges from 6% to 41% with a pooled prevalence of 16%. A large cohort of outpatients with MCI or AD found an overall incidence of psychosis of 10% per year (Weamer et al., 2016). The incidence of psychosis was two- to threefold higher in AD subjects with moderate-to-severe cognitive impairment compared with mild impairment. Importantly, psychosis is consistently associated with more rapid cognitive decline (Wilson et al., 2000). Neuroimaging studies demonstrate an association between psychosis and atrophy in the lateral frontal, lateral parietal, and anterior cingulate gyrus (Rafii et al., 2014). This corresponds with studies demonstrating decreased regional perfusion in bilateral dorsolateral frontal regions and the left anterior cingulate gyrus (Mega et al., 2000). These regions are involved in the cortico-subcortical network, which plays a role in regulating complex human behaviors. As many of these imaging studies involving patients with psychotic symptoms did not exclude patients with agitation, there is a great deal of overlap between the imaging findings with these two symptoms (Rosenberg et al., 2015). Proposed diagnostic criteria for psychosis of AD include the presence of symptoms such as visual or auditory hallucinations and/or delusions, evidence that these symptoms were not present prior to the onset of the symptoms of dementia, symptom duration for longer than 1 month, symptoms severe enough to cause disruption in functioning, and the absence of delirium (Jeste and Finkel, 2000). The clinician must also exclude other causes of psychotic symptoms, such as schizophrenia, mood disorder with psychotic features, medications, other general medical conditions, and substance abuse.

19 BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS Paranoid and persecutory delusions are the most com(Katz et al., 2007; Maher et al., 2011). For example, data monly encountered delusions in patients with AD pooled from five RCTs using the psychosis subscale of (Binetti et al., 1993; Bassiony and Lyketsos, 2003; the NPI found an effect size of Cohen’s d ¼ 0.20 (95% Kwak et al., 2013). Misidentification, which is a false CI 0.05, 0.36) (Maher et al., 2011). An effect size of belief that the identity of a person or object has somehow 0.20 is considered small and the upper limit of the conchanged or been altered, is also common due to difficulty fidence interval includes an effect that is only moderate. in recognizing family members and friends. It is imporEffect sizes for aripiprazole (three trials), olanzapine tant to distinguish between delusions that cause distress (five trials), and quetiapine (three trials) did not to the patient and those that may be considered as reach statistical significance when analyzed specifically “comfort phenomena” (Ballard et al., 1995). One study using psychosis subscales. Among three head-to-head reported that 40% of delusions did not result in discomtrials, no statistically significant differences were fort to the patient (Cohen-Mansfield et al., 2016). Deluobserved between the antipsychotics. sions of abandonment, danger, and infidelity were more In patients who are started on an antipsychotic for often associated with discomfort compared with other symptoms of psychosis, attempts should be made to disdelusions. Some delusions, such as imagining that one’s continue their use once symptoms have resolved because deceased spouse is still alive, may elevate mood. This has of the risk of adverse events as discussed previously. One important implications for treatment as no intervention trial that is of concern, entitled Antipsychotic Disconmay be necessary other than educating caregivers about tinuation in Alzheimer’s Disease (ADAD), provides how best to respond to the delusion. The most frequently evidence that patients may be at greater risk of relapse encountered questionnaires for assessing psychotic once an antipsychotic is discontinued (Devanand et al., symptoms include the BEHAVE-AD, the NPI-Psychosis 2012). In this trial, 180 participants with AD and symptoms of psychosis and/or agitation/aggression received subscale, the Behavior Rating Scale for Dementia open-label risperidone (initiated at 0.25–0.5 mg/day; (BRSD), and the Columbia University Scale for mean dose achieved was 0.97 mg/day) for 16 weeks. Psychopathology in Alzheimer’s Disease (CUSPAD) A hundred and ten patients who responded to treatment (Cohen-Mansfield and Golander, 2011). at 16 weeks were then randomized to one of three groups: Treatment of psychotic symptoms begins with addressing potential contributing factors, ruling out medical risperidone for 32 weeks, risperidone for 16 weeks causes, and attempting specific behavioral and environfollowed by placebo for 16 weeks, or placebo for mental modifications (Cohen-Mansfield, 2003; Cohen32 weeks. Among the participants randomized, 80% Mansfield et al., 2014). It is important to recognize that had psychosis and 81% had agitation/aggression. Mean some delusions may in fact be misinterpretations or an MMSE scores ranged from 13.4 to 15.5 among the groups attempt to compensate for disorientation to person, place, and about half lived at home and half at an assisted-living or time (Cohen-Mansfield et al., 2017). For example, a facility or nursing home. At 16 weeks post randomization, delusion of theft may be a response to the person’s inability the placebo group had a significantly higher risk of relapse to remember where they left an object. The common “one’s compared to the other two groups receiving risperidone house is not one’s home” delusion is often related to disori(hazard ratio ¼ 1.94; 95% CI 1.09, 3.4; P ¼ 0.02). Sixty entation to place. In the absence of significant distress from percent (24 of 40) of patients in the placebo group relapsed the patient, caregivers should be counseled that these delucompared with 33% (23 of 70) in the other two groups. sions may be an adaptive response. In cases where patients These results were similar during the second 16-week have fears of abandonment, attempts should be made to period with an increased risk of relapse in the group provide more frequent contact with loved ones. Improving switching from risperidone to placebo at 16 weeks post sensory function with hearing aids, glasses, and adequate randomization compared with the risperidone group (hazlighting may help. Multicomponent interventions, such ard ratio ¼ 4.88; 95% CI 1.08, 21.98; P ¼ 0.02). Imporas a combination of music therapy, painting activities, tantly, discontinuation rates with risperidone were 38% and physical activities, may also reduce the severity of in the open-label period, 68% in the risperidone group psychotic symptoms (Chen et al., 2014). treated for 32 weeks, and 29% in the risperidone group Pharmacologic therapies are sometimes necessary if treated for 16 weeks. Taken together, the high rate of either nonpharmacologic methods fail and/or psychotic symprelapse or discontinuation even in the risperidone groups toms cause significant distress or harm to the patient emphasizes its limited effectiveness. In a planned post hoc and/or others. Antipsychotics have been the subject analysis of this trial, the presence of severe hallucinations of several clinical trials (Ballard and Waite, 2006; (NPI domain score of 7–12) was significantly associated Tampi et al., 2016). Risperidone is the antipsychotic with an increased risk of relapse when compared to the with perhaps the most evidence, demonstrating a group with no hallucinations (hazard ratio ¼ 2.70; 95% superior efficacy to placebo based on meta-analyses CI 1.19, 6.12; P < 0.02) (Patel et al., 2017).

20

W.J. DEARDORFF AND G.T. GROSSBERG

The results of this study provide clinicians with some guidance when speaking with patients and their caregivers about decisions to discontinue antipsychotics. The optimal duration of antipsychotic use remains unclear. In an APA survey of experts, 33.5% reported that they would maintain a patient who presented with dangerous psychosis on an antipsychotic for 4–6 months before trying to taper and withdraw it; 26.1% responded that they would maintain the dose for 1–3 months before tapering; and 10.1% responded that they would maintain the dose without any specific target date to taper. The APA recognizes that the recommendation to attempt a taper within 4 months is based on low strength of evidence and longer treatment periods may be justified (Reus et al., 2016). Patients who initially presented with symptoms of hallucinations graded as severe may be at a particularly high risk of relapse. Frequent monitoring following discontinuation is essential and nonpharmacologic methods will need to be continued during this vulnerable period. Caregivers must be counseled on behavioral and environmental modifications as discussed in the section on agitation. As with the other symptoms discussed here, the evidence for ChEIs and memantine comes from either open-label trials or from secondary endpoints on RCTs not specifically designed to assess the efficacy of these medications on psychosis (Barak et al., 2001; Fischer et al., 2006; Gauthier et al., 2008; Clerici et al., 2012). For example, a pooled analysis of six RCTs reported statistically significant differences with memantine treatment compared with placebo at week 12 on the NPI delusions score (P ¼ 0.007) and NPI hallucinations score (P ¼ 0.037) (Gauthier et al., 2008). At weeks 24/28, statistical significance was seen with delusions (P ¼ 0.001) but not hallucinations. Given that post hoc analyses often make no adjustment for multiple comparisons and analyses of open-label trials may be biased (e.g., regression to the mean and selective attrition), it remains unclear whether ChEIs or memantine may be used specifically as a treatment for psychosis of AD. However, greater adherence and treatment persistence with these medications may be useful in delaying the emergence of these symptoms. In terms of investigational therapies, results from a Phase II trial involving pimavanserin in patients with Alzheimer’s disease psychosis were recently reported. Pimavanserin showed statistically significant improvements on the NPI-NH psychosis scale compared with placebo at the 6-week point (3.76 point improvement with pimavanserin vs 1.93 point improvement for placebo; P ¼ 0.0451) but not at the 12-week endpoint. Despite having a mechanism of action different than most antipsychotics, pimavanserin still carries a black-box

warning for risk of increased mortality in elderly patients with dementia-related psychosis and is only FDA approved for Parkinson’s disease psychosis.

Sleep disturbances The prevalence of sleep disorders in AD ranges from 14% to 69% with a pooled prevalence of 39% (Zhao et al., 2016). The most frequently encountered sleep impairments include excessive awakening, early morning awakening, excessive day-time sleepiness, and napping more than an hour a day (Urrestarazu and Iriarte, 2016). Importantly, sleep problems such as longer sleep latency and decreased sleep efficiency are correlated with cognitive dysfunction and behavioral symptoms such as aggressiveness (Moran et al., 2005; Shin et al., 2014). The pathogenesis of sleep disturbances in patients with AD is multifactorial, and a bidirectional relationship between AD and sleep quality has been proposed (Ju et al., 2014; Lim et al., 2014). The changes in sleep architecture among patients with AD are like those encountered in normal aging, including increased sleep latency, decreased slow-wave sleep, and early morning awakenings (Urrestarazu and Iriarte, 2016). However, the magnitude is more than expected based on age. Disruptions in sleep patterns, characterized by decreased slowwave sleep, often precede the onset of cognitive symptoms and may promote amyloid-b deposition via the excessive neuronal firing that can result from poor-quality sleep. Deposition of amyloid plaques in regions of the brain that control sleep promotes decreased quality of sleep, and alterations in the circadian rhythm result from degeneration of neurons in the suprachiasmatic nucleus and disruptions in melatonin secretion (Weldemichael and Grossberg, 2010). τ-Hyperphosphorylation and intracellular aggregation also contributes to sleep disruption (Holth et al., 2017). Other factors, such as anxiety, medications, inadequate daylight exposure, sleep apnea, and increased age, can also contribute to problems with sleep. Proposed diagnostic criteria for sleep/wake cycle disturbances in patients with AD involve a complaint of insomnia and/or excessive daytime sleepiness that was not present before the onset of the dementia (Yesavage et al., 2003). There should be evidence via polysomnography, actigraphy, or structured sleep log observation of a disturbance of sleep/wake cycle based on at least two of the following four characteristics: increased wake after sleep onset occurring often or long enough to affect function or well-being, decreased total sleep time, poor daytime wake continuity with an increase in the number and/or duration of naps, and desynchronization of the sleep/wake rhythm.

BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS The first step in the evaluation of a patient with sleep complaints is to characterize the nature of the disturbances and identify any environmental or behavioral problems that may be contributing. Patients and their caregivers should be asked about habits surrounding bedtime, amount of activity during the day, nocturnal noise, and time spent in bed. Comorbidities such as polyuria from diabetes, depression, or obstructive sleep apnea may be contributing factors. ChEIs, in particular donepezil, are also associated with insomnia and switching them to morning administration may help to improve sleep. There is limited high-quality evidence regarding the use of nonpharmacologic interventions (Brown et al., 2013). Interventions include nonlight-based interventions (e.g., music, exercise, transcutaneous electrical nerve stimulation, individualized activities, and sleep hygiene) and light-based interventions. Light-based interventions may promote synchronization of the internal circadian rhythms with the environment and may be performed in several different ways, such as light boxes placed close to participants, bright light visors, or ceiling mounted light fixtures. One intervention within nursing homes involved daytime physical activity, attempts to keep participants out of bed, evening bright light exposure, and strategies to avoid nighttime noise or interruptions (Ouslander et al., 2006). No significant effect was reported on nighttime sleep quality (measured with actigraphy and polysomnography) or mood and behavior (measured with the GDS and NPI). Another trial in four nursing homes which investigated the effect of increased daily sunlight exposure, increased physical activity, andefforts to decrease nighttime noise and light also found no significant effects on percentage of nighttime sleep or number of nighttime awakenings (Alessi et al., 2005). However, both these trials reported significant decreases in daytime sleeping, and one reported increased participation in activities among participants assigned to the intervention. These results are consistent with a Cochrane review that found no effect of light therapy on cognitive function, sleep, challenging behaviors, or psychiatric symptoms in patients with dementia (Forbes et al., 2014). Another trial with strong methodological quality found that institutional respite care demonstrated significant improvements in sleep quality among caregivers but a significant worsening of sleep measures in patients (Lee et al., 2007). CBT has demonstrated modest benefits for sleep problems in elderly adults without dementia and/or depression, but its effect in patients with AD is not well studied (Montgomery and Dennis, 2003). In sum, the evidence base for nonpharmacologic methods is weak. Despite the negative results, it is still worthwhile to counsel patients on sleep hygiene techniques, such as

21

developing a structured bedtime routine, encouraging daytime light exposure and physical activities, and limiting the number of daytime naps. Commonly used pharmacologic agents for sleep disturbances in AD include melatonin, the melatoninreceptor agonist ramelteon, sedating antidepressants such as mirtazapine and trazodone, antipsychotics, and hypnotics. A Cochrane review of pharmacotherapies for sleep disturbances in dementia identified six RCTs for inclusion (McCleery et al., 2016). No published RCTs involving benzodiazepines and nonbenzodiazepine hypnotics were identified, despite their widespread use. One trial was conducted using zolpidem but the results were not reported. Treatment with melatonin from two studies (dose range 2–10 mg/day) was not associated with significant effects, compared with placebo, on total nocturnal sleep time, ratio of daytime sleep to nighttime sleep, caregiver rated sleep quality, cognition, or ADLs. The largest study involving melatonin also reported no statistically significant differences in objective sleep measures (Singer et al., 2003). When used in combination with whole-day bright or dim light, melatonin may have benefits on improving both cognitive and noncognitive (e.g., sleep efficiency, nocturnal restlessness) symptoms of dementia (Riemersma-van der Lek et al., 2008). One trial involving 30 community-dwelling participants with moderate-to-severe AD randomly assigned to receive 50 mg/day trazodone or placebo at night for two weeks demonstrated statistically significant increases in nocturnal sleep time (mean difference ¼ 42.46 min; 95% CI 0.9, 84.0) and sleep efficiency (Camargos et al., 2014). No significant benefit was found on number of nocturnal awakenings, amount of time spent asleep during the day, number of daytime naps, cognitive measures, ADL performance, or caregiver rated assessment of sleep. The evidence was judged as low quality from the Cochrane reviewers, because of the wide confidence intervals and limited number of participants. One unpublished Phase II trial involving ramelteon was also included in this review. Seventy-four participants with mild to moderately severe AD were randomized to treatment with ramelteon 8 mg/day or placebo for 8 weeks. On the primary outcome, no statistically significant difference was seen in mean nocturnal total sleep time at week 1 (LSMD ¼ 18.2 min; 95% CI 7.8, 44.3; P ¼ 0.167) or week 8. Since the publication of the Cochrane review, a small pilot study with mirtazapine 15 mg/day or placebo for two weeks was performed in 14 community-dwelling AD patients with sleep disorders (Scoralick et al., 2017). Eleven participants were randomized to mirtazapine and three were randomized to placebo, with the use of 14 historical controls added to the placebo group. The trial reported increased daytime sleep duration in the

22

W.J. DEARDORFF AND G.T. GROSSBERG

mirtazapine group (68.4 min; 95% CI 35.0, 101.9; P ¼ 0.00), without improvements in nighttime duration of sleep (mean difference ¼ 55.3 min; 95% CI 4.6, 115.1; P ¼ 0.27) or efficiency. The small sample size and use of historical controls limits any definitive conclusion. Overall, benzodiazepines and nonbenzodiazepine hypnotics should be avoided because of the lack of evidence and potential for serious adverse events. Because of the relatively low risk of harm, melatonin may be offered at doses between 2 and 10 mg/day. While the evidence is of low quality, trazodone may be an option. Tricyclic antidepressants and antihistamine medications should be avoided because of their anticholinergic side effects and increased incidence of daytime somnolence. The practice of administering sedating antipsychotics to treat sleep disturbances should be avoided in view of the risks of adverse events without evidence of benefit. There is some evidence that ChEIs alter sleep architecture (Moraes Wdos et al., 2006). This effect may be different with donepezil, compared to rivastigmine or galantamine, although the administration schedules might explain some of the difference (Cooke et al., 2006). Taking the ChEIs, donepezil and galantamine, in the morning as opposed to the evening may improve the sleep states of patients with AD, as reported in one study using a visual analogue scale to assess sleep quality and daytime drowsiness (Song et al., 2013). Some preliminary evidence from pilot studies supports a preference for using galantamine over donepezil if the goal is to improve sleep quality (Ancoli-Israel et al., 2005; Naharci et al., 2015). However, larger studies will need to be performed to confirm this association.

Other behaviors Other behaviors sometimes seen in patients with AD include inappropriate sexual behaviors (ISBs), wandering, and anxiety. ISBs may include inappropriate sex talk, sexual acts (touching, grabbing, exposing, masturbating), or implied sexual acts (openly reading pornographic material) (Ozkan et al., 2008). A proposed definition of ISBs in dementia includes a behavior that is explicitly sexual or perceived to be sexual by others, which is inappropriate for reasons such as occurring in a public place, directed at a person who finds it unacceptable, or directed toward a person who is unwilling or unable to consent (Sachdev, 2017). In one sample of 195 patients in which 48.7% were women, ISBs were detected in 17.9% (Canevelli et al., 2017). Verbal behaviors, such as sexual comments, and physical behaviors, such as kissing other persons, were the most commonly encountered behaviors. The underlying neurobiology is

likely related to disruptions in one or more of four major brain areas, including the frontal lobe, temporal–limbic system, striatum, and hypothalamus. Nonpharmacologic methods, such as redirection, behavioral modifications with positive and negative reinforcement, removal of precipitating factors, distraction (e.g., engaging in activities that involve the hands to minimize inappropriate fondling), and supportive psychotherapy (particularly for the caregiver or spouse), are recommended (Cipriani et al., 2016). While there are no RCTs of pharmacologic agents in the treatment of ISBs, case reports and case series have demonstrated some success with antidepressants (e.g., trazodone, citalopram), ChEIs, cimetidine, hormonal agents (e.g., medroxyprogesterone or conjugated estrogen in males), and anticonvulsant medications (e.g., gabapentin, carbamazepine). Antidepressants may have the most evidence (albeit still limited), with the least risk of harm (Guay, 2008). One common source of anxiety among caregivers is the possibility of their loved one wandering and becoming lost. This scenario occurs even for persons living in a nursing home or other caregiving facility (Rowe et al., 2004). Becoming lost is a highly unpredictable event, with 65% of cases occurring while the person with dementia was in the presence of a caregiver. Clinicians should educate caregivers of this risk and may consider recommending programs such as Safe Return, a service by the Alzheimer’s Association that provides an identification bracelet, necklace, or clothing tag to help facilitate the return of the person.

BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS IN VASCULAR DEMENTIA Vascular dementia (VaD) is part of the broader category of vascular cognitive impairment (VCI), which includes both mild VCI and major VCI. VaD is classified into four main subtypes: poststroke dementia, subcortical ischemic vascular dementia, multi-infarct (cortical) dementia, and mixed dementia (VCI/AD, VCI/DLB, and others) (Skrobot et al., 2016). Based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), patients diagnosed with a major vascular neurocognitive disorder must first meet criteria for a major neurocognitive disorder (i.e., evidence of significant cognitive decline in one or more cognitive domains whereby the cognitive deficits interfere with independence in everyday activities) (American Psychiatric Association, 2013). The clinical features must also be consistent with a vascular etiology, as evidenced by either an onset of cognitive deficits that is temporally related to a cerebrovascular event or evidence for decline that is prominent in complex attention and frontal-executive function.

BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS There is a large degree of overlap in neuropsychiatric features between AD and VaD. Based on one study of 180 patients, those with VaD had a significantly higher prevalence of agitation (40% vs 15%) and sleep disturbances (57% vs 32%) than patients with AD and significantly higher prevalence of depression (48% vs 20%) and aberrant motor behavior (31% vs 13%) than patients with mixed AD/VaD (Anor et al., 2017). However, differences in medication usage such as antipsychotics may explain some of these results. In one postmortem study, no significant differences in behavioral symptoms were found between patients with AD or VaD (Echavarri et al., 2013). Apathy appears to be the most common behavioral symptoms in both dementias (Kazui et al., 2016). Higher levels of disease severity in patients with VaD are associated with increased severity of apathy, irritability, and sleep disturbances and increased frequency of delusions, agitation, apathy, aberrant motor behavior, and sleep disturbances. Patients with VaD may also impose a greater burden on caregivers at earlier stages of the disease compared with patients with AD (Vetter et al., 1999). Higher levels of behavioral symptoms, particularly apathy, are associated with increased functional impairment in patients with VaD following a stroke (Zawacki et al., 2002; Brodaty et al., 2005). Compared with AD, there are very few clinical trials investigating the treatment of BPSD in VaD. The ChEIs and memantine have been the most extensively studied pharmacologic agents. The rationale behind the use of ChEIs is that preclinical and clinical data suggest that the cognitive impairment in patients with VaD may be partially attributed to a cholinergic deficit (Amenta et al., 2002). However, this association may be confounded by the presence of mixed AD/VaD pathology as patients with “pure” VaD have significantly less cholinergic deficits compared with patients with AD or mixed AD/VaD (Perry et al., 2005). Nevertheless, studies involving galantamine, rivastigmine, and donepezil have displayed small beneficial effects on cognition (difference from placebo of around 2 points on the ADAS-cog) with inconsistent effects on global scales, ADLs, and BPSD (Malouf and Birks, 2004; Birks and Craig, 2006; Birks et al., 2013). Two studies with galantamine have been performed, although one included patients with VaD or AD with radiologic evidence of cerebrovascular disease on neuroimaging (Erkinjuntti et al., 2002; Auchus et al., 2007). One reported nonstatistically significant benefits in favor of galantamine on the NPI (mean difference from placebo of 2.10 points; 95% CI 4.77, 0.57) while the other reported statistically significant benefits with placebo (mean difference from placebo of 1.80 points; 95% CI 0.31, 3.29) (Kavirajan and Schneider, 2007). Baseline scores on the NPI in these studies were relatively low, which may limit its ability to

23

detect a significant difference. Two clinical trials involving memantine reported positive benefits on cognitive but not global outcome measures (Orgogozo et al., 2002; Wilcock et al., 2002). The ChEIs and memantine are not FDA approved for the treatment of vascular dementia. While there is some evidence for significant benefits on cognitive outcomes, the clinical relevance of a 2-point difference on the 70-point ADAS-Cog, in the absence of any effect on global outcome measures, is unclear. Given the multitude of side effects with ChEIs, such as nausea, vomiting, diarrhea, weight loss, bradycardia, and syncope, their use in vascular dementia cannot be recommended. A series of clinical trials in European countries, involving a once-daily formulation of 240 mg ginkgo biloba extract (EGb 761), has been performed in patients with probable AD, possible AD with cerebrovascular disease, or probable VaD. Many of these trials specifically enrolled patients with BPSD (Gauthier and Schlaefke, 2014). In one trial of 410 outpatients, roughly half were characterized as possible AD with cerebrovascular disease and 18% with probable VaD (Ihl et al., 2011). At the 24-week endpoint, patients in the ginkgo biloba group demonstrated improvements in NPI total score (3.2 points) compared to no change in the placebo group from baseline (0.0 points, P < 0.001). A broad range of symptoms showed improvement in individual NPI items, such as apathy/indifference and depression/dysphoria (Bachinskaya et al., 2011). In another study involving patients with AD (52% of patients), AD with cerebrovascular disease (38%), or VaD (10%) presenting with BPSD, NPI total score at week 24 decreased by 4.6 points in the ginkgo biloba treated group compared with a 2.1-point decrease in the placebo-treated group (P < 0.001) (Herrschaft et al., 2012). In a third study where nearly half of the 400 patients were diagnosed with VaD, NPI total scores in the ginkgo biloba group decreased from a baseline score of 21.3  9.5 points to an end-point score of 14.7  9.5 points, while those in the placebo group saw an increase in NPI scores from a baseline of 21.6  9.9 points to endpoint score of 24.1 12.8 (P < 0.001) (Napryeyenko et al., 2007; Scripnikov et al., 2007). The improvement in NPI total scores were significant and similar in both the VaD and AD subgroups (Napryeyenko et al., 2009). A pooled analysis of these trials demonstrated a LSMD on the NPI-total score of 3.85 points favoring ginkgo biloba treatment (95% CI -4.50, 3.21; P < 0.001; Cohen’s d ¼ 0.56) (von Gunten et al., 2016). Treatment with ginkgo biloba was also associated with significant benefits on measures of cognition, ADLs, and global scales. The relatively large effect sizes seen in these studies across multiple measures should be interpreted with caution, as other studies have

24

W.J. DEARDORFF AND G.T. GROSSBERG

demonstrated unreliable and inconsistent benefits (Birks and Grimley Evans, 2009). Ginkgo biloba is generally well tolerated, although there is a wide variation in the quality of preparations. Because of an increased risk of bleeding, it should be used with caution in patients taking anticoagulants. Its use is not typically recommended for patients with dementia because of a lack of regulation in its preparation, inconsistent effect sizes, and low methodological quality among many of the trials (Yang et al., 2016). The calcium channel blocker nimodipine has been studied in several older RCTs involving patients with AD, VaD, or mixed AD/VaD with some evidence of short-term benefit on cognitive functioning and global measures, but one study was not able to report a benefit on behavioral symptoms or ADLs (Lopez-Arrieta and Birks, 2002). A large trial involving amlodipine in patients, specifically with vascular dementia, will measure noncognitive dementia symptoms as a secondary endpoint (Greenan et al., 2016) but the trial status is currently reported as “stopped” (ISRCTN registry, 2016 from http://www.isrctn.com/ISRCTN31208535). Cerebrolysin, which is a peptide preparation produced from purified pig brain proteins and administered by intravenous infusion, may have some benefit on cognitive and global functioning in patients with VaD (Chen et al., 2013). However, there is insufficient evidence to recommend its use, given the limited number of trials and demanding treatment schedule. There is a relatively greater amount of evidence, albeit still limited, for the management of poststroke depression (PSD) and apathy, which are highly prevalent in stroke survivors (both around 33%) and associated with declines in physical function and health (Brodaty et al., 2005; Mayo et al., 2009; Withall et al., 2011; van Dalen et al., 2013; Ferro et al., 2016). Predictors of behavioral and psychological symptoms following stroke include stroke severity at admission and medial temporal lobe atrophy, which is a marker often associated with AD (Wong et al., 2016). Poststroke apathy and depression are considered distinct conditions as concomitant depression is present in only 40% of patients with apathy (van Dalen et al., 2013). SSRIs are the most extensively studied medications for poststroke behavioral symptoms and have been shown to reduce the risk of dependency, reduce disability scores, and improve symptoms of depression and anxiety (Mead et al., 2012). Most trials included in one meta-analysis were conducted with fluoxetine. Others used citalopram, sertraline, and paroxetine. However, a large amount of heterogeneity and methodological limitations limit the strength of their recommendation. Larger effect sizes were seen among trials that specifically included patients with depression at recruitment. A statement from the American Heart Association and American Stroke Association concluded that

antidepressant medications may be effective in treating PSD, but further research is needed (Towfighi et al., 2017). While one Cochrane review concluded that there was no strong evidence to support psychotherapy in PSD, a series of trials since its publication suggest that brief psychosocial–behavioral interventions may be useful (Hackett et al., 2008). For example, one nurse-delivered intervention involved nine sessions over 8 weeks to discuss problem-solving approaches and how best to view depressive symptoms (Mitchell et al., 2009). Benefits were seen at both the 9-week and 12-month follow-up periods. In poststroke apathy, one RCT among patients within 3 months of an index stroke, without apathy at initial evaluation, reported that either escitalopram or problem-solving therapy was more effective than placebo in preventing new onset of apathy (Mikami et al., 2013). The nootropic nefiracetam was studied in a RCT of 13 patients who met criteria for apathy 8 weeks after a stroke (Starkstein et al., 2016). No statistically significant differences between the nefiracetam and placebo-treated groups at week 12 were seen on the Apathy Scale score, although the trial was likely underpowered (122 patients were expected to participate). As poststroke apathy may be related to dopaminergic pathways, treatment with dopamine agonists may help to improve symptoms such as lack of motivation (Murakami et al., 2013). Case reports and case series have suggested some benefit with ropinirole, bromocriptine, and methylphenidate (van Dalen et al., 2013). However, these agents must be used with caution until further data is available, as they are associated with orthostatic hypotension, nausea, dyskinesia, and hallucinations. Given the lack of evidence, it seems reasonable to treat BPSD in patients with VaD in a manner similar to treating BPSD in patients with AD, especially considering the high degree of mixed pathology. Aggressive management of vascular risk factors, such as smoking, obesity, hypertension, diabetes, and hyperlipidemia, is recommended. Nonpharmacologic management of BPSD in VaD is once again considered first-line therapy. A trial of ChEIs and/or memantine may be warranted, especially given that it is often difficult to distinguish between VaD and AD. However, their use in VaD is off-label. Use of antidepressants for symptoms of depression and apathy may also be considered.

CONCLUSION BPSD in patients with AD and VaD are associated with multiple adverse outcomes, including increased risk of institutionalization, increased patient and caregiver distress, and a shorter survival time. The management of these symptoms in patients with AD and VaD is challenging because of the limited effectiveness of both

BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS nonpharmacologic and pharmacologic therapies. This can partially be attributed to a limited understanding of the underlying mechanisms for these behaviors. Despite a high prevalence of BPSD, there are currently no FDA approved medications for this indication and commonly used medications such as antipsychotics are often associated with serious adverse events. Future research will need to focus on understanding the relevant brain circuits involved, identifying prominent risk factors, and better defining the natural progression of these symptoms. To identify patients with these symptoms early, better screening tools will need to be developed that can be used quickly in a busy clinic setting. Clinical trials face many methodological challenges, including the absence of a gold standard outcome measure, whether to include or exclude patients using concomitant medications that may be psychoactive, and the optimal duration of treatment, given the oftentimes fluctuating course of these symptoms (Cummings et al., 2015a). Research should assess which clinical rating measures are most appropriate to capture subtle changes in symptomatology to maximize power in clinical trials. Ultimately, a major priority for clinical research is the development of interventions that combine environmental and behavioral modifications, caregiver education, and pharmacologic agents.

REFERENCES Aalten P, de Vugt ME, Jaspers N et al. (2005). The course of neuropsychiatric symptoms in dementia. Part I: findings from the two-year longitudinal Maasbed study. Int J Geriatr Psychiatry 20: 523–530. Aalten P, Verhey FR, Boziki M et al. (2007). Neuropsychiatric syndromes in dementia. Results from the European Alzheimer disease consortium: part I. Dement Geriatr Cogn Disord 24: 457–463. Alessi CA, Martin JL, Webber AP et al. (2005). Randomized, controlled trial of a nonpharmacological intervention to improve abnormal sleep/wake patterns in nursing home residents. J Am Geriatr Soc 53: 803–810. Amenta F, Di Tullio MA, Tomassoni D (2002). The cholinergic approach for the treatment of vascular dementia: evidence from pre-clinical and clinical studies. Clin Exp Hypertens 24: 697–713. American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders, American Psychiatric Association, Washington, DC. Ancoli-Israel S, Amatniek J, Ascher S et al. (2005). Effects of galantamine versus donepezil on sleep in patients with mild to moderate Alzheimer disease and their caregivers: a double-blind, head-to-head, randomized pilot study. Alzheimer Dis Assoc Disord 19: 240–245. Anglin R, Yuan Y, Moayyedi P et al. (2014). Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal antiinflammatory use: a systematic review and meta-analysis. Am J Gastroenterol 109: 811–819.

25

Anor CJ, O’Connor S, Saund A et al. (2017). Neuropsychiatric symptoms in Alzheimer disease, vascular dementia, and mixed dementia. Neurodegener Dis 17: 127–134. Apostolo J, Bobrowicz-Campos E, Rodrigues M et al. (2016). The effectiveness of non-pharmacological interventions in older adults with depressive disorders: a systematic review. Int J Nurs Stud 58: 59–70. Arean PA, Raue P, Mackin RS et al. (2010). Problem-solving therapy and supportive therapy in older adults with major depression and executive dysfunction. Am J Psychiatry 167: 1391–1398. Atri A, Grossberg G, Hendrix S et al. (2017). Memantine added to background cholinesterase-inhibitors reduces agitation and neuropsychiatric symptoms in Alzheimer’s disease (P3.082). Neurology 88. Supplement P3.082. Auchus AP, Brashear HR, Salloway S et al. (2007). Galantamine treatment of vascular dementia: a randomized trial. Neurology 69: 448–458. Bachinskaya N, Hoerr R, Ihl R (2011). Alleviating neuropsychiatric symptoms in dementia: the effects of Ginkgo biloba extract EGb 761. Findings from a randomized controlled trial. Neuropsychiatr Dis Treat 7: 209–215. Bains J, Birks J, Dening T (2002). Antidepressants for treating depression in dementia. Cochrane Database Syst Rev (1): CD003944. Ballard C, Waite J (2006). The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer’s disease. Cochrane Database Syst Rev 92: CD003476. Ballard CG, Bannister CL, Patel A et al. (1995). Classification of psychotic symptoms in dementia sufferers. Acta Psychiatr Scand 92: 63–68. Ballard C, Lana MM, Theodoulou M et al. (2008). A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial). PLoS Med 5e76. Banerjee S, Hellier J, Dewey M et al. (2011). Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial. Lancet 378: 403–411. Barak Y, Bodner E, Zemishlani H et al. (2001). Donepezil for the treatment of behavioral disturbances in Alzheimer’s disease: a 6-month open trial. Arch Gerontol Geriatr 33: 237–241. Bassiony MM, Lyketsos CG (2003). Delusions and hallucinations in Alzheimer’s disease: review of the brain decade. Psychosomatics 44: 388–401. Bergh S, Selbaek G, Engedal K (2012). Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): double blind, randomised, parallel group, placebo controlled trial. BMJ 344e1566. Berman K, Brodaty H, Withall A et al. (2012). Pharmacologic treatment of apathy in dementia. Am J Geriatr Psychiatry 20: 104–122. Binetti G, Bianchetti A, Padovani A et al. (1993). Delusions in Alzheimer’s disease and multi-infarct dementia. Acta Neurol Scand 88: 5–9. Birks J, Craig D (2006). Galantamine for vascular cognitive impairment. Cochrane Database Syst Rev 4: CD004746.

26

W.J. DEARDORFF AND G.T. GROSSBERG

Birks J, Grimley Evans J (2009). Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev (5): CD003120. Birks J, McGuinness B, Craig D (2013). Rivastigmine for vascular cognitive impairment. Cochrane Database Syst Rev 4: CD004744. Boccia M, Acierno M, Piccardi L (2015). Neuroanatomy of Alzheimer’s disease and late-life depression: a coordinatebased meta-analysis of MRI studies. J Alzheimers Dis 46: 963–970. Bonelli RM, Cummings JL (2007). Frontal-subcortical circuitry and behavior. Dialogues Clin Neurosci 9: 141–151. Brodaty H, Arasaratnam C (2012). Meta-analysis of nonpharmacological interventions for neuropsychiatric symptoms of dementia. Am J Psychiatry 169: 946–953. Brodaty H, Burns K (2012). Nonpharmacological management of apathy in dementia: a systematic review. Am J Geriatr Psychiatry 20: 549–564. Brodaty H, Sachdev PS, Withall A et al. (2005). Frequency and clinical, neuropsychological and neuroimaging correlates of apathy following stroke—the Sydney stroke study. Psychol Med 35: 1707–1716. Brooker D (2005). Dementia care mapping: a review of the research literature. Gerontologist 45 Spec No 1: 11–18. Brown CA, Berry R, Tan MC et al. (2013). A critique of the evidence base for non-pharmacological sleep interventions for persons with dementia. Dementia (London) 12: 210–237. Byers AL, Yaffe K (2011). Depression and risk of developing dementia. Nat Rev Neurol 7: 323–331. Camargos EF, Louzada LL, Quintas JL et al. (2014). Trazodone improves sleep parameters in Alzheimer disease patients: a randomized, double-blind, and placebocontrolled study. Am J Geriatr Psychiatry 22: 1565–1574. Canevelli M, Lucchini F, Garofalo C et al. (2017). Inappropriate sexual behaviors among community-dwelling patients with dementia. Am J Geriatr Psychiatry 25: 365–371. Chand S, Grossberg G (2013). How to adapt cognitive-behavioral therapy for older adults. Curr Psychiatr 12: 10–15. Chen N, Yang M, Guo J et al. (2013). Cerebrolysin for vascular dementia. Cochrane Database Syst Rev 14: CD008900. Chen RC, Liu CL, Lin MH et al. (2014). Non-pharmacological treatment reducing not only behavioral symptoms, but also psychotic symptoms of older adults with dementia: a prospective cohort study in Taiwan. Geriatr Gerontol Int 14: 440–446. Chenoweth L, King MT, Jeon YH et al. (2009). Caring for aged dementia care resident study (CADRES) of person-centred care, dementia-care mapping, and usual care in dementia: a cluster-randomised trial. Lancet Neurol 8: 317–325. Cherbuin N, Kim S, Anstey KJ (2015). Dementia risk estimates associated with measures of depression: a systematic review and meta-analysis. BMJ Open 5: e008853. Cipriani G, Ulivi M, Danti S et al. (2016). Sexual disinhibition and dementia. Psychogeriatrics 16: 145–153. Clerici F, Vanacore N, Elia A et al. (2012). Memantine effects on behaviour in moderately severe to severe Alzheimer’s disease: a post-marketing surveillance study. Neurol Sci 33: 23–31.

Clyburn LD, Stones MJ, Hadjistavropoulos T et al. (2000). Predicting caregiver burden and depression in Alzheimer’s disease. J Gerontol B Psychol Sci Soc Sci 55: S2–13. Cohen-Mansfield J (1996). Conceptualization of agitation: results based on the Cohen-Mansfield agitation inventory and the agitation behavior mapping instrument. Int Psychogeriatr 8 (Suppl. 3): 309–315. discussion 351–304. Cohen-Mansfield J (2003). Nonpharmacologic interventions for psychotic symptoms in dementia. J Geriatr Psychiatry Neurol 16: 219–224. Cohen-Mansfield J, Golander H (2011). The measurement of psychosis in dementia: a comparison of assessment tools. Alzheimer Dis Assoc Disord 25: 101–108. Cohen-Mansfield J, Golander H, Arnheim G et al. (2014). Reactions and interventions for delusions in nursing home residents with dementia. Am J Alzheimers Dis Other Demen 29: 386–394. Cohen-Mansfield J, Cohen R, Golander H et al. (2016). The impact of psychotic symptoms on the persons with dementia experiencing them. Am J Geriatr Psychiatry 24: 213–220. Cohen-Mansfield J, Golander H, Cohen R (2017). Rethinking psychosis in dementia: an analysis of antecedents and explanations. Am J Alzheimers Dis Other Demen32: 265–271. https://doi.org/10.1177/1533317517703478. Cooke JR, Loredo JS, Liu L et al. (2006). Acetylcholinesterase inhibitors and sleep architecture in patients with Alzheimer’s disease. Drugs Aging 23: 503–511. Coupland C, Dhiman P, Morriss R et al. (2011). Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ 343: d4551. Cumbo E, Ligori LD (2014). Differential effects of current specific treatments on behavioral and psychological symptoms in patients with Alzheimer’s disease: a 12-month, randomized, open-label trial. J Alzheimers Dis 39: 477–485. Cummings JL, Schneider L, Tariot PN et al. (2004). Reduction of behavioral disturbances and caregiver distress by galantamine in patients with Alzheimer’s disease. Am J Psychiatry 161: 532–538. Cummings JL, Koumaras B, Chen M et al. (2005). Effects of rivastigmine treatment on the neuropsychiatric and behavioral disturbances of nursing home residents with moderate to severe probable Alzheimer’s disease: a 26-week, multicenter, open-label study. Am J Geriatr Pharmacother 3: 137–148. Cummings J, Friedman JH, Garibaldi G et al. (2015a). Apathy in neurodegenerative diseases: recommendations on the design of clinical trials. J Geriatr Psychiatry Neurol 28: 159–173. 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. Cummings JL, Lyketsos CG, Peskind ER et al. (2015c). Effect of dextromethorphan-quinidine on agitation in patients with Alzheimer disease dementia: a randomized clinical trial. JAMA 314: 1242–1254.

BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS de Jonghe A, Korevaar JC, van Munster BC et al. (2010). Effectiveness of melatonin treatment on circadian rhythm disturbances in dementia. Are there implications for delirium? A systematic review. Int J Geriatr Psychiatry 25: 1201–1208. de Medeiros K, Robert P, Gauthier S et al. (2010). The neuropsychiatric inventory-clinician rating scale (NPI-C): reliability and validity of a revised assessment of neuropsychiatric symptoms in dementia. Int Psychogeriatr 22: 984–994. Declercq T, Petrovic M, Azermai M et al. (2013). Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia. Cochrane Database Syst Rev 25: CD007726. Devanand DP, Mintzer J, Schultz SK et al. (2012). Relapse risk after discontinuation of risperidone in Alzheimer’s disease. N Engl J Med 367: 1497–1507. Drye LT, Scherer RW, Lanctot KL et al. (2013). Designing a trial to evaluate potential treatments for apathy in dementia: the apathy in dementia methylphenidate trial (ADMET). Am J Geriatr Psychiatry 21: 549–559. Echavarri C, Burgmans S, Uylings H et al. (2013). Neuropsychiatric symptoms in Alzheimer’s disease and vascular dementia. J Alzheimers Dis 33: 715–721. Erkinjuntti T, Kurz A, Gauthier S et al. (2002). Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomised trial. Lancet 359: 1283–1290. 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. Farlow MR, Shamliyan TA (2017). Benefits and harms of atypical antipsychotics for agitation in adults with dementia. Eur Neuropsychopharmacol 27: 217–231. Ferro JM, Caeiro L, Figueira ML (2016). Neuropsychiatric sequelae of stroke. Nat Rev Neurol 12: 269–280. Fischer C, Bozanovic R, Atkins JH et al. (2006). Treatment of delusions in Alzheimer’s disease—response to pharmacotherapy. Dement Geriatr Cogn Disord 22: 260–266. Folstein MF, Folstein SE, McHugh PR (1975). "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12: 189–198. Forbes D, Blake CM, Thiessen EJ et al. (2014). Light therapy for improving cognition, activities of daily living, sleep, challenging behaviour, and psychiatric disturbances in dementia. Cochrane Database Syst Rev 7: CD003946. Fox C, Crugel M, Maidment I et al. (2012). Efficacy of memantine for agitation in Alzheimer’s dementia: a randomised double-blind placebo controlled trial. PLoS One 7e35185. Frakey LL, Salloway S, Buelow M et al. (2012). A randomized, double-blind, placebo-controlled trial of modafinil for the treatment of apathy in individuals with mild-tomoderate Alzheimer’s disease. J Clin Psychiatry 73: 796–801. Gallagher D, Herrmann N (2014). Antiepileptic drugs for the treatment of agitation and aggression in dementia: do they have a place in therapy? Drugs 74: 1747–1755.

27

Garay RP, Citrome L, Grossberg GT et al. (2016). Investigational drugs for treating agitation in persons with dementia. Expert Opin Investig Drugs 25: 973–983. Gauthier S, Schlaefke S (2014). Efficacy and tolerability of Ginkgo biloba extract EGb 761(R) in dementia: a systematic review and meta-analysis of randomized placebocontrolled trials. Clin Interv Aging 9: 2065–2077. Gauthier S, Feldman H, Hecker J et al. (2002). Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer’s disease. Int Psychogeriatr 14: 389–404. Gauthier S, Loft H, Cummings J (2008). Improvement in behavioural symptoms in patients with moderate to severe Alzheimer’s disease by memantine: a pooled data analysis. Int J Geriatr Psychiatry 23: 537–545. Gauthier S, Juby A, Dalziel W et al. (2010). Effects of rivastigmine on common symptomatology of Alzheimer’s disease (EXPLORE). Curr Med Res Opin 26: 1149–1160. Gebara MA, Lipsey KL, Karp JF et al. (2015). Cause or effect? selective serotonin reuptake inhibitors and falls in older adults: a systematic review. Am J Geriatr Psychiatry 23: 1016–1028. Geda YE, Schneider LS, Gitlin LN et al. (2013). Neuropsychiatric symptoms in Alzheimer’s disease: past progress and anticipation of the future. Alzheimers Dement 9: 602–608. Gehrman PR, Connor DJ, Martin JL et al. (2009). Melatonin fails to improve sleep or agitation in double-blind randomized placebo-controlled trial of institutionalized patients with Alzheimer disease. Am J Geriatr Psychiatry 17: 166–169. Gentile S (2010). Second-generation antipsychotics in dementia: beyond safety concerns. A clinical, systematic review of efficacy data from randomised controlled trials. Psychopharmacology (Berl) 212: 119–129. Greenan C, Murphy L, Yu LM et al. (2016). A randomised controlled trial of calcium channel blockade (CCB) with Amlodipine For the treatment oF subcortical ischaEmic vasCular demenTia (AFFECT): study protocol. Trials 17: 324. Grupe DW, Nitschke JB (2013). Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective. Nat Rev Neurosci 14: 488–501. Guay DR (2008). Inappropriate sexual behaviors in cognitively impaired older individuals. Am J Geriatr Pharmacother 6: 269–288. Hackett ML, Anderson CS, House A et al. (2008). Interventions for treating depression after stroke. Cochrane Database Syst Rev 18: CD003437. Harrison F, Aerts L, Brodaty H (2016). Apathy in dementia: systematic review of recent evidence on pharmacological treatments. Curr Psychiatry Rep 18: 103. Herrmann N, Rothenburg LS, Black SE et al. (2008). Methylphenidate for the treatment of apathy in Alzheimer disease: prediction of response using dextroamphetamine challenge. J Clin Psychopharmacol 28: 296–301.

28

W.J. DEARDORFF AND G.T. GROSSBERG

Herrmann N, Cappell J, Eryavec GM et al. (2011). Changes in nursing burden following memantine for agitation and aggression in long-term care residents with moderate to severe Alzheimer’s disease: an open-label pilot study. CNS Drugs 25: 425–433. Herrmann N, Gauthier S, Boneva N et al. (2013). A randomized, double-blind, placebo-controlled trial of memantine in a behaviorally enriched sample of patients with moderate-to-severe Alzheimer’s disease. Int Psychogeriatr 25: 919–927. Herrschaft H, Nacu A, Likhachev S et al. (2012). Ginkgo biloba extract EGb 761(R) in dementia with neuropsychiatric features: a randomised, placebo-controlled trial to confirm the efficacy and safety of a daily dose of 240 mg. J Psychiatr Res 46: 716–723. Hirono N, Mega MS, Dinov ID et al. (2000). Left frontotemporal hypoperfusion is associated with aggression in patients with dementia. Arch Neurol 57: 861–866. Holmes C, Wilkinson D, Dean C et al. (2004). The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology 63: 214–219. Holth J, Patel T, Holtzman DM (2017). Sleep in Alzheimer’s disease—beyond amyloid. Neurobiol Sleep Circadian Rhythms 2: 4–14. Howard RJ (2016). Disentangling the treatment of agitation in Alzheimer’s disease. Am J Psychiatry 173: 441–443. Howard RJ, Juszczak E, Ballard CG et al. (2007). Donepezil for the treatment of agitation in Alzheimer’s disease. N Engl J Med 357: 1382–1392. Huang AX, Delucchi K, Dunn LB et al. (2015). A systematic review and meta-analysis of psychotherapy for late-life depression. Am J Geriatr Psychiatry 23: 261–273. Ihl R, Bachinskaya N, Korczyn AD et al. (2011). Efficacy and safety of a once-daily formulation of Ginkgo biloba extract EGb 761 in dementia with neuropsychiatric features: a randomized controlled trial. Int J Geriatr Psychiatry 26: 1186–1194. Ishii S, Weintraub N, Mervis JR (2009). Apathy: a common psychiatric syndrome in the elderly. J Am Med Dir Assoc 10: 381–393. Jennings L, Grossberg GT (2013). Antipsychotics continue to have a place in the management of difficult behavior problems in patients with dementia. J Am Med Dir Assoc 14: 447–449. Jeste DV, Finkel SI (2000). Psychosis of Alzheimer’s disease and related dementias. Diagnostic criteria for a distinct syndrome. Am J Geriatr Psychiatry 8: 29–34. Ju YE, Lucey BP, Holtzman DM (2014). Sleep and Alzheimer disease pathology—a bidirectional relationship. Nat Rev Neurol 10: 115–119. 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. Katz I, de Deyn PP, Mintzer J et al. (2007). The efficacy and safety of risperidone in the treatment of psychosis of Alzheimer’s disease and mixed dementia: a meta-analysis of 4 placebo-controlled clinical trials. Int J Geriatr Psychiatry 22: 475–484.

Kaufer DI, Cummings JL, Ketchel P et al. (2000). Validation of the NPI-Q, a brief clinical form of the neuropsychiatric inventory. J Neuropsychiatry Clin Neurosci 12: 233–239. Kavirajan H, Schneider LS (2007). Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials. Lancet Neurol 6: 782–792. Kazui H, Yoshiyama K, Kanemoto H et al. (2016). Differences of behavioral and psychological symptoms of dementia in disease severity in four major dementias. PLoS One 11e0161092. Kiosses DN, Teri L, Velligan DI et al. (2011). A homedelivered intervention for depressed, cognitively impaired, disabled elders. Int J Geriatr Psychiatry 26: 256–262. Kiosses DN, Ravdin LD, Gross JJ et al. (2015). Problem adaptation therapy for older adults with major depression and cognitive impairment: a randomized clinical trial. JAMA Psychiatry 72: 22–30. Korner A, Lauritzen L, Abelskov K et al. (2006). The Geriatric Depression Scale and the Cornell Scale for Depression in Dementia. A validity study. Nord J Psychiatry 60: 360–364. Kwak YT, Yang Y, Kwak SG et al. (2013). Delusions of Korean patients with Alzheimer’s disease: study of drugnaive patients. Geriatr Gerontol Int 13: 307–313. Lam LC, Lui VW, Luk DN et al. (2010). Effectiveness of an individualized functional training program on affective disturbances and functional skills in mild and moderate dementia—a randomized control trial. Int J Geriatr Psychiatry 25: 133–141. Lanctot KL, Herrmann N, Black SE et al. (2008). Apathy associated with Alzheimer disease: use of dextroamphetamine challenge. Am J Geriatr Psychiatry 16: 551–557. Lee D, Morgan K, Lindesay J (2007). Effect of institutional respite care on the sleep of people with dementia and their primary caregivers. J Am Geriatr Soc 55: 252–258. Lenze EJ (2011). Treating depression in older adults with dementia. J Am Geriatr Soc 59: 754–755. Leong C (2014). Antidepressants for depression in patients with dementia: a review of the literature. Consult Pharm 29: 254–263. Leontjevas R, Teerenstra S, Smalbrugge M et al. (2013). More insight into the concept of apathy: a multidisciplinary depression management program has different effects on depressive symptoms and apathy in nursing homes. Int Psychogeriatr 25: 1941–1952. Lim MM, Gerstner JR, Holtzman DM (2014). The sleep-wake cycle and Alzheimer’s disease: what do we know? Neurodegener Dis Manag 4: 351–362. Livingston G, Kelly L, Lewis-Holmes E et al. (2014). Nonpharmacological interventions for agitation in dementia: systematic review of randomised controlled trials. Br J Psychiatry 205: 436–442. Lonergan E, Luxenberg J (2009). Valproate preparations for agitation in dementia. Cochrane Database Syst Rev 1: CD003945. Lopez-Arrieta JM, Birks J (2002). Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst Rev 9: CD000147.

BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS Magni E, Binetti G, Bianchetti A et al. (1996). Risk of mortality and institutionalization in demented patients with delusions. J Geriatr Psychiatry Neurol 9: 123–126. Maher AR, Maglione M, Bagley S et al. (2011). Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis. JAMA 306: 1359–1369. Malouf R, Birks J (2004). Donepezil for vascular cognitive impairment. Cochrane Database Syst Rev 64: CD004395. Marshall GA, Monserratt L, Harwood D et al. (2007). Positron emission tomography metabolic correlates of apathy in Alzheimer disease. Arch Neurol 64: 1015–1020. 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 Psychiatry 72: 438–445. Mayo NE, Fellows LK, Scott SC et al. (2009). A longitudinal view of apathy and its impact after stroke. Stroke 40: 3299–3307. McCleery J, Cohen DA, Sharpley AL (2016). Pharmacotherapies for sleep disturbances in dementia. Cochrane Database Syst Rev 11: CD009178. McKhann GM, Knopman DS, Chertkow H et al. (2011). The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on AgingAlzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7: 263–269. Mead GE, Hsieh CF, Lee R et al. (2012). Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery. Cochrane Database Syst Rev 11CD009286. Mega MS, Lee L, Dinov ID et al. (2000). Cerebral correlates of psychotic symptoms in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 69: 167–171. Mikami K, Jorge RE, Moser DJ et al. (2013). Prevention of poststroke apathy using escitalopram or problem-solving therapy. Am J Geriatr Psychiatry 21: 855–862. Millan-Calenti JC, Lorenzo-Lopez L, Alonso-Bua B et al. (2016). Optimal nonpharmacological management of agitation in Alzheimer’s disease: challenges and solutions. Clin Interv Aging 11: 175–184. Miller MD, Reynolds 3rd CF (2007). Expanding the usefulness of interpersonal psychotherapy (IPT) for depressed elders with co-morbid cognitive impairment. Int J Geriatr Psychiatry 22: 101–105. Mitchell PH, Veith RC, Becker KJ et al. (2009). Brief psychosocial-behavioral intervention with antidepressant reduces poststroke depression significantly more than usual care with antidepressant: living well with stroke: randomized, controlled trial. Stroke 40: 3073–3078. Montgomery P, Dennis J (2003). Cognitive behavioural interventions for sleep problems in adults aged 60 +. Cochrane Database Syst Rev 29: CD003161. Moraes Wdos S, Poyares DR, Guilleminault C et al. (2006). The effect of donepezil on sleep and REM sleep EEG in patients with Alzheimer disease: a double-blind placebocontrolled study. Sleep 29: 199–205.

29

Moran M, Lynch CA, Walsh C et al. (2005). Sleep disturbance in mild to moderate Alzheimer’s disease. Sleep Med 6: 347–352. Mourao RJ, Mansur G, Malloy-Diniz LF et al. (2016). Depressive symptoms increase the risk of progression to dementia in subjects with mild cognitive impairment: systematic review and meta-analysis. Int J Geriatr Psychiatry 31: 905–911. Murakami T, Hama S, Yamashita H et al. (2013). Neuroanatomic pathways associated with poststroke affective and apathetic depression. Am J Geriatr Psychiatry 21: 840–847. Naharci MI, Ozturk A, Yasar H et al. (2015). Galantamine improves sleep quality in patients with dementia. Acta Neurol Belg 115: 563–568. Napryeyenko O, Borzenko I, GINDEM-NP Study Group (2007). Ginkgo biloba special extract in dementia with neuropsychiatric features. A randomised, placebo-controlled, double-blind clinical trial. Arzneimittelforschung 57: 4–11. Napryeyenko O, Sonnik G, Tartakovsky I (2009). Efficacy and tolerability of Ginkgo biloba extract EGb 761 by type of dementia: analyses of a randomised controlled trial. J Neurol Sci 283: 224–229. Nasreddine ZS, Phillips NA, Bedirian V et al. (2005). The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 53: 695–699. Nelson JC, Devanand DP (2011). A systematic review and meta-analysis of placebo-controlled antidepressant studies in people with depression and dementia. J Am Geriatr Soc 59: 577–585. Okura T, Plassman BL, Steffens DC et al. (2011). Neuropsychiatric symptoms and the risk of institutionalization and death: the aging, demographics, and memory study. J Am Geriatr Soc 59: 473–481. Olin JT, Fox LS, Pawluczyk S et al. (2001). A pilot randomized trial of carbamazepine for behavioral symptoms in treatment-resistant outpatients with Alzheimer disease. Am J Geriatr Psychiatry 9: 400–405. Olin JT, Schneider LS, Katz IR et al. (2002). Provisional diagnostic criteria for depression of Alzheimer disease. Am J Geriatr Psychiatry 10: 125–128. Orgeta V, Qazi A, Spector AE et al. (2014). Psychological treatments for depression and anxiety in dementia and mild cognitive impairment. Cochrane Database Syst Rev 33: CD009125. Orgogozo JM, Rigaud AS, Stoffler A et al. (2002). Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke 33: 1834–1839. Ouslander JG, Connell BR, Bliwise DL et al. (2006). A nonpharmacological intervention to improve sleep in nursing home patients: results of a controlled clinical trial. J Am Geriatr Soc 54: 38–47. Ozkan B, Wilkins K, Muralee S et al. (2008). Pharmacotherapy for inappropriate sexual behaviors in dementia: a systematic review of literature. Am J Alzheimers Dis Other Demen 23: 344–354.

30

W.J. DEARDORFF AND G.T. GROSSBERG

Padala PR, Burke WJ, Shostrom VK et al. (2010). Methylphenidate for apathy and functional status in dementia of the Alzheimer type. Am J Geriatr Psychiatry 18: 371–374. Patel AN, Lee S, Andrews HF et al. (2017). Prediction of relapse after discontinuation of antipsychotic treatment in Alzheimer’s disease: the role of hallucinations. Am J Psychiatry 174: 362–369. Perry E, Ziabreva I, Perry R et al. (2005). Absence of cholinergic deficits in "pure" vascular dementia. Neurology 64: 132–133. Peters ME, Schwartz S, Han D et al. (2015). Neuropsychiatric symptoms as predictors of progression to severe Alzheimer’s dementia and death: the Cache County dementia progression study. Am J Psychiatry 172: 460–465. Petrovic M, Hurt C, Collins D et al. (2007). Clustering of behavioural and psychological symptoms in dementia (BPSD): a European Alzheimer’s disease consortium (EADC) study. Acta Clin Belg 62: 426–432. Porsteinsson AP, Drye LT, Pollock BG et al. (2014). Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA 311: 682–691. Rafii MS, Taylor CS, Kim HT et al. (2014). Neuropsychiatric symptoms and regional neocortical atrophy in mild cognitive impairment and Alzheimer’s disease. Am J Alzheimers Dis Other Demen 29: 159–165. Rapoport MJ, van Reekum R, Freedman M et al. (2001). Relationship of psychosis to aggression, apathy and function in dementia. Int J Geriatr Psychiatry 16: 123–130. 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. Robert PH, Berr C, Volteau M et al. (2008). Importance of lack of interest in patients with mild cognitive impairment. Am J Geriatr Psychiatry 16: 770–776. Robert P, Onyike CU, Leentjens AF et al. (2009). Proposed diagnostic criteria for apathy in Alzheimer’s disease and other neuropsychiatric disorders. Eur Psychiatry 24: 98–104. Rosen WG, Mohs RC, Davis KL (1984). A new rating scale for Alzheimer’s disease. Am J Psychiatry 141: 1356–1364. Rosenberg PB, Drye LT, Martin BK et al. (2010). Sertraline for the treatment of depression in Alzheimer disease. Am J Geriatr Psychiatry 18: 136–145. Rosenberg PB, Lanctot KL, Drye LT et al. (2013). Safety and efficacy of methylphenidate for apathy in Alzheimer’s disease: a randomized, placebo-controlled trial. J Clin Psychiatry 74: 810–816. Rosenberg PB, Nowrangi MA, Lyketsos CG (2015). Neuropsychiatric symptoms in Alzheimer’s disease: what might be associated brain circuits? Mol Aspects Med 4344: 25–37.

Rowe MA, Feinglass NG, Wiss ME (2004). Persons with dementia who become lost in the community: a case study, current research, and recommendations. Mayo Clin Proc 79: 1417–1422. Ruthirakuhan M, Herrmann N, Abraham E et al. (2018). Pharmacological interventions for apathy in Alzheimer’s disease. Cochrane Database Syst Rev5: CDO12197. https://doi.org/10.1002/14651858.CD012197.pub2. Sachdev PS (2017). Inappropriate sexual behaviors in dementia. Am J Geriatr Psychiatry 25: 372–373. Saxton J, Swihart AA (1989). Neuropsychological assessment of the severely impaired elderly patient. Clin Geriatr Med 5: 531–543. Schneider LS, Dagerman KS, Insel P (2005). Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 294: 1934–1943. Schneider LS, Dagerman K, Insel PS (2006a). Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry 14: 191–210. Schneider LS, Tariot PN, Dagerman KS et al. (2006b). Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med 355: 1525–1538. Schneider LS, Frangakis C, Drye LT et al. (2016). Heterogeneity of treatment response to citalopram for patients with Alzheimer’s disease with aggression or agitation: the CitAD randomized clinical trial. Am J Psychiatry 173: 465–472. 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. Scripnikov A, Khomenko A, Napryeyenko O et al. (2007). Effects of Ginkgo biloba extract EGb 761 on neuropsychiatric symptoms of dementia: findings from a randomised controlled trial. Wien Med Wochenschr 157: 295–300. Seitz DP, Adunuri N, Gill SS et al. (2011). Antidepressants for agitation and psychosis in dementia. Cochrane Database Syst Rev 29: CD008191. Sepehry AA, Lee PE, Hsiung GY et al. (2012). Effect of selective serotonin reuptake inhibitors in Alzheimer’s disease with comorbid depression: a meta-analysis of depression and cognitive outcomes. Drugs Aging 29: 793–806. Sepehry AA, Sarai M, Hsiung GR (2017). Pharmacological therapy for apathy in Alzheimer’s disease: a systematic review and meta-analysis. Can J Neurol Sci 44: 267–275. Shin HY, Han HJ, Shin DJ et al. (2014). Sleep problems associated with behavioral and psychological symptoms as well as cognitive functions in Alzheimer’s disease. J Clin Neurol 10: 203–209. Singer C, Tractenberg RE, Kaye J et al. (2003). A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer’s disease. Sleep 26: 893–901. Singh-Manoux A, Dugravot A, Fournier A et al. (2017). Trajectories of depressive symptoms before diagnosis of dementia: a 28-year follow-up study. JAMA Psychiatry .

BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS Skrobot OA, O’Brien J, Black S et al. (2016). The vascular impairment of cognition classification consensus study. Alzheimers Dement 13: 624–633. Song HR, Woo YS, Wang HR et al. (2013). Effect of the timing of acetylcholinesterase inhibitor ingestion on sleep. Int Clin Psychopharmacol 28: 346–348. Stanton BR, Leigh PN, Howard RJ et al. (2013). Behavioural and emotional symptoms of apathy are associated with distinct patterns of brain atrophy in neurodegenerative disorders. J Neurol 260: 2481–2490. Starkstein SE, Brockman S, Hatch KK et al. (2016). A randomized, placebo-controlled, double-blind efficacy study of nefiracetam to treat poststroke apathy. J Stroke Cerebrovasc Dis 25: 1119–1127. Steinberg M, Shao H, Zandi P et al. (2008). Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study. Int J Geriatr Psychiatry 23: 170–177. 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. Tampi RR, Tampi DJ, Balachandran S et al. (2016). Antipsychotic use in dementia: a systematic review of benefits and risks from meta-analyses. Ther Adv Chronic Dis 7: 229–245. Tariot PN, Schneider LS, Cummings J et al. (2011). Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Arch Gen Psychiatry 68: 853–861. Taylor WD, Aizenstein HJ, Alexopoulos GS (2013). The vascular depression hypothesis: mechanisms linking vascular disease with depression. Mol Psychiatry 18: 963–974. Taylor CP, Traynelis SF, Siffert J et al. (2016). Pharmacology of dextromethorphan: relevance to dextromethorphan/ quinidine (Nuedexta(R)) clinical use. Pharmacol Ther 164: 170–182. Theleritis C, Politis A, Siarkos K et al. (2014). A review of neuroimaging findings of apathy in Alzheimer’s disease. Int Psychogeriatr 26: 195–207. Theleritis C, Siarkos K, Katirtzoglou E et al. (2017). Pharmacological and nonpharmacological treatment for apathy in Alzheimer disease: a systematic review across modalities. J Geriatr Psychiatry Neurol 30: 26–49. Thompson S, Herrmann N, Rapoport MJ et al. (2007). Efficacy and safety of antidepressants for treatment of depression in Alzheimer’s disease: a metaanalysis. Can J Psychiatry 52: 248–255. Towfighi A, Ovbiagele B, El Husseini N et al. (2017). Poststroke depression: a scientific statement for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke 48: e30–e43. Treusch Y, Majic T, Page J et al. (2015). Apathy in nursing home residents with dementia: results from a clusterrandomized controlled trial. Eur Psychiatry 30: 251–257. Urrestarazu E, Iriarte J (2016). Clinical management of sleep disturbances in Alzheimer’s disease: current and emerging strategies. Nat Sci Sleep 8: 21–33.

31

van Dalen JW, Moll van Charante EP, Nederkoorn PJ et al. (2013). Poststroke apathy. Stroke 44: 851–860. van der Linde RM, Dening T, Stephan BC et al. (2016). Longitudinal course of behavioural and psychological symptoms of dementia: systematic review. Br J Psychiatry 209: 366–377. van der Steen JT, Smaling J, van der Wouden JC et al. (2018). Music-based therapeutic interventions for people with dementia. Cochrane Database Syst Rev 5CD003477. Vetter PH, Krauss S, Steiner O et al. (1999). Vascular dementia versus dementia of Alzheimer’s type: do they have differential effects on caregivers’ burden? J Gerontol B Psychol Sci Soc Sci 54: S93–S98. 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. Volicer L (2018). Behavioral problems and dementia. Clin Geriatr Med 34(4): 637–651. von Gunten A, Schlaefke S, Uberla K (2016). Efficacy of Ginkgo biloba extract EGb 761(R) in dementia with behavioural and psychological symptoms: a systematic review. World J Biol Psychiatry 17: 622–633. Waldemar G, Gauthier S, Jones R et al. (2011). Effect of donepezil on emergence of apathy in mild to moderate Alzheimer’s disease. Int J Geriatr Psychiatry 26: 150–157. Weamer EA, DeMichele-Sweet MA, Cloonan YK et al. (2016). Incident psychosis in subjects with mild cognitive impairment or Alzheimer’s disease. J Clin Psychiatry 77: e1564–e1569. Weldemichael DA, Grossberg GT (2010). Circadian rhythm disturbances in patients with Alzheimer’s disease: a review. Int J Alzheimers Dis 2010: 1–9. Wilcock G, Mobius HJ, Stoffler A et al. (2002). A doubleblind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol 17: 297–305. Wilcock GK, Ballard CG, Cooper JA et al. (2008). Memantine for agitation/aggression and psychosis in moderately severe to severe Alzheimer’s disease: a pooled analysis of 3 studies. J Clin Psychiatry 69: 341–348. Wilkins VM, Kiosses D, Ravdin LD (2010). Late-life depression with comorbid cognitive impairment and disability: nonpharmacological interventions. Clin Interv Aging 5: 323–331. Wilson RS, Gilley DW, Bennett DA et al. (2000). Hallucinations, delusions, and cognitive decline in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 69: 172–177. Withall A, Brodaty H, Altendorf A et al. (2011). A longitudinal study examining the independence of apathy and depression after stroke: the Sydney Stroke study. Int Psychogeriatr 23: 264–273. Wong A, Lau AY, Yang J et al. (2016). Neuropsychiatric symptom clusters in stroke and transient ischemic attack by cognitive status and stroke subtype: frequency and relationships with vascular lesions, brain atrophy and amyloid. PLoS One 11e0162846.

32

W.J. DEARDORFF AND G.T. GROSSBERG

Yaffe K, Fox P, Newcomer R et al. (2002). Patient and caregiver characteristics and nursing home placement in patients with dementia. JAMA 287: 2090–2097. Yang G, Wang Y, Sun J et al. (2016). Ginkgo biloba for mild cognitive impairment and Alzheimer’s disease: a systematic review and meta-analysis of randomized controlled trials. Curr Top Med Chem 16: 520–528. Yesavage JA, Friedman L, Ancoli-Israel S et al. (2003). Development of diagnostic criteria for defining sleep disturbance in Alzheimer’s disease. J Geriatr Psychiatry Neurol 16: 131–139.

You SC, Walsh CM, Chiodo LA et al. (2015). Neuropsychiatric symptoms predict functional status in Alzheimer’s disease. J Alzheimers Dis 48: 863–869. Zawacki TM, Grace J, Paul R et al. (2002). Behavioral problems as predictors of functional abilities of vascular dementia patients. J Neuropsychiatry Clin Neurosci 14: 296–302. Zhao QF, Tan L, Wang HF et al. (2016). The prevalence of neuropsychiatric symptoms in Alzheimer’s disease: systematic review and meta-analysis. J Affect Disord 190: 264–271.