Abstract
Dementia affects all domains of cognition. The relentless progression of the disease after diagnosis is associated with a 98% incidence of neuropsychiatric symptoms (NPS) at some point in the disease, including depression, psychosis, agitation, aggression, apathy, sleep disturbances, and disinhibition. These symptoms can be severe and lead to excess morbidity and mortality. The purpose of this article was to describe current literature on the medication management of NPS of dementia and highlight approaches to and concerns about the pharmacological treatment of NPS in the USA. Guidelines and expert opinion favor nonpharmacologic management of NPS as first-line management. Unfortunately, lack of adequate caregiver training and a high failure rate eventually result in the use of psychotropic agents in patients with dementia. Various psychotropic medications have been studied, although how they should be used in the management of NPS remains unclear. A systematic approach to evaluation, treatment, and monitoring, along with careful documentation and evidenced-based agent and dose selection, is likely to reduce risk and improve patient outcomes. Considerations should be given to the NPS presentation, including type, frequency, and severity, when weighing the risks and benefits of initiating, continuing, or discontinuing psychotropic management. Use of antidepressants, sedative/hypnotics, antipsychotics, and antiepileptic agents should include a clear and documented analysis of risk and benefit in a given patient with dementia.
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1 Introduction
Despite a declining age-specific incidence of dementia in high-income countries, the absolute numbers of patients with cognitive decline continues to rise as the population ages [1]. Treatment with cognition-enhancing/preserving medication, including cholinesterase inhibitors and memantine, is typically pursued in all but the least and most severely afflicted [2]. Noncognitive symptoms of dementia occur in 98% of individuals at some point in their disease and are often the most distressing to caregivers and patients themselves [3]. Neuropsychiatric symptoms (NPS), including apathy, depression, sleep disorders, hallucinations, delusions, psychosis, agitation, and aggression, are exceedingly prevalent [4, 5]. The presence of depression in dementia has been shown to accelerate the rate of cognitive decline, even beyond education level and sex [6]. Dementia symptoms will wax and wane as a natural course, according to both environmental factors and disease progression-related factors [7]. In their most severe manifestations, NPS can lead to worse patient outcomes, accelerated disease progression, institutionalization, morbidity and mortality, and significant caregiver stress and financial strain [4, 5, 8]. Studies have shown that determinants of nursing home placement in patients with dementia include difficult behaviors; patients scoring the highest on psychotic and behavioral symptoms are over two times more likely to be institutionalized [9, 10]. It is possible that caregivers may be willing to delay hospitalization or institutionalization if behaviors can be managed, though this theory has not yet been studied.
The presentations of NPS appear at different times during various types of dementia, and presentation frequencies may vary depending on setting. In early Alzheimer’s disease (AD), depression, disinhibition, apathy, and sleep disorders are prevalent, and disease progression leads to an increase in delusions, hallucinations, and aggression [11,12,13,14,15]. A naturalistic study of patients in a geriatric psychiatry unit in Germany found aggression, including both verbal and physical, was the most frequent symptom, occurring in approximately 57% of patients. However, the authors noted that symptoms such as depression and apathy might not warrant acute treatment or hospitalization, except in severe cases [16]. Apathy, arising from primary amotivation, appears to be the most common and lasting NPS of AD, affecting up to 76% of patients with AD [11, 17]. A recent systematic review by Theleritis et al. [18] focused on describing apathy and management approaches, so we refer readers to this review for more comprehensive discussion. Conversely, in Parkinson’s disease (PD), visual hallucinations appear earlier, and disease progression results in the gradual appearance of Parkinson’s disease dementia (PDD), intertwined commonly with depression, anxiety, and sleep disorders [19]. In vascular dementia, sleep disorders, agitation, depression, and anxiety are not associated with a specific stage of the disease [20]. Similar to PDD, dementia with Lewy bodies (DLB) is most often accompanied by nonthreatening visual hallucinations, sleep disorders, and anxiety [12, 13]. In a population-based study evaluating the frequency of symptoms in people with dementia, apathy was the most frequent symptom, followed by depression and agitation/aggression [21]. The majority of patients had AD, although people with vascular dementia, PDD, and others were also represented.
While it is clear that NPS can cause increased disease burden for both patients and caregivers, less clear guidelines regarding the appropriate management of NPS have been published. The American Association for Geriatric Psychiatry (AAGP), the Alzheimer’s Association, the American Geriatrics (AGS) Society, the National Institute for Health and Care Excellence (NICE), the American Psychiatric Association (APA) and the Detroit Expert Panel on the Assessment and Management of the NPS of Dementia agree and emphasize that nonpharmacologic treatment should be implemented as first-line management of NPS [3, 22,23,24,25,26]. Nonpharmacologic management is similar among guidelines, suggesting the use of techniques including but not limited to the removal or avoidance of triggers, environmental modifications, treatment of precipitating medical conditions, discontinuation of offending pharmacologic agents, aromatherapy, animal-assisted therapy, and exercise, music, art, and reminiscence therapies [3, 22,23,24,25, 27, 28].
However, even when nonpharmacologic approaches are effectively employed, a high percentage of patients with dementia are eventually treated with psychotropic medications, recently demonstrated to be 84% of nursing home and 29% of community-dwelling elders residing in the USA [29]. It is important to use all available evidence to select agents and doses of psychotropic medications to minimize risk and maximize the potential for benefit in these vulnerable patients.
Certain guidelines suggest that pharmacologic management may be considered first line after a thorough risk/benefit assessment in the following situations: significant risk of harm to patient or others due to psychosis or aggression, severely distressed patient or caregivers, and major depression with or without suicidal ideation [3, 22,23,24,25]. A noted difference among guidelines appears in those provided by the APA, in which only the patients are discussed in situations that may warrant pharmacologic treatment, and the feelings/distress of caregivers are omitted [25]. If nonpharmacologic interventions prove ineffective or if any of the aforementioned situations exist, recommendations from various groups, including the AAGP, AGS, and Alzheimer’s Association, as well as the APA and NICE, are that the use of pharmacologic therapy may be warranted [3, 22,23,24,25].
Recommendations regarding the choice of pharmacologic treatment vary greatly regarding the agents used for specific NPS, but a common theme does exist: pharmacologics should be used judiciously in the elderly [3, 22, 24,25,26]. Recommendations about the duration of treatment appear only in reference to the use of psychotropics and suggest that medications should be tapered and withdrawn if no clinically significant response to therapy occurs after a 4-week trial of adequate doses [25]. Furthermore, it is recommended that attempts to taper antipsychotics occur within 4 months of initiation [25]. In general, pharmacologic agents used for the management of NPS should be initiated at the lowest dose and titrated up to the minimum effective dose as tolerated. These agents should not be continued indefinitely, and their use should be continually reassessed [3, 22, 24,25,26]. The purpose of this article was to describe the current literature on medication management of NPS of dementia and highlight approaches to and concerns about the treatment of NPS to assist the practicing clinician. We sought to give perspectives as to why an individualized approach is imperative and to provide suggestions for why psychotropics may be perceived as having minimal and variable efficacy across patients with dementia-related NPS. If a clinician has a low threshold for starting a given psychotropic for any NPS, has expectations for nonspecific or global improvement of NPS, and has an unclear threshold for discontinuing the given psychotropic, the patient can ultimately be at risk for intolerabilities in addition to inefficacy. Thus, this review is a practical, yet detailed discussion with highlights from recently published randomized controlled trials aimed at any clinician who may care for patients with dementia and NPS. Selected common symptoms were identified for further discussion. We avoided elaboration where a specific symptom had recently been the subject of a comprehensive, systematic review, instead referring readers to that publication. Specific information regarding clinical trials designed to assess the use of pharmacologic agents for NPS in patients with dementia is included in Tables 1 and 2, which we revisit throughout this article.
2 Concerns Associated with the Use of Psychotropic Medication in Patients with Dementia
Justification for hesitation in using psychotropic medication in patients with dementia stems from the fact that all of the agents have significant toxicity and mostly weak evidence of efficacy in this population [30]. Antidepressants, sedatives/hypnotics, and antipsychotics are all associated with high rates of worsening of cognition, falls, and serious cardiovascular adverse effects [31]. In the case of antipsychotic use, large databases have revealed a significant association with increased mortality in patients with dementia, leading to a “black box warning” from the US FDA in 2005 [32]. Similar warnings have been issued to providers in other countries, including Canada, France, Germany, and other European countries. The excess mortality with antipsychotic use was approximately 1.5 times on average and attributed to cardiovascular events (stroke and myocardial events) and infection [32].
Medication toxicities include both short- and long-term adverse effects, some of which can cause complications affecting morbidity or mortality. One such example is dizziness or hypotension that leads to a fall, subsequently resulting in impaired functioning or reduced survival. Even interactions between multiple medications can lead to toxicities. Published lists of medications that are potentially inappropriate for older populations include many of the psychotropic medications used off-label for managing NPS of dementia [33, 34]. Medications considered “potentially inappropriate” may contribute to confusion and increased fall risk, such as anticholinergic effects, worsened cognitive impairment, extrapyramidal symptoms, orthostatic hypotension, sedation, or risk of delirium [33, 34]. A study of patients newly started on an acetylcholinesterase inhibitor for dementia showed that the anticholinergic drug burden increased with the number of physicians providing care [35]. Ruxton et al. [36] found that certain medications with anticholinergic effects and overall exposure increased not only the risk of cognitive impairment and falls in older adults but also all-cause mortality. Thus, providers should evaluate psychotropic utility in the context of the overall patient, with various symptoms, comorbidities, and concurrent medications. In patients with NPS receiving psychotropics who subsequently exhibit negative sequelae, providers should evaluate the severity and consider dose reduction or discontinuation of the offending agent. A switch to an alternative agent can be considered if pharmacotherapy is thought to provide symptomatic benefit. Only as a last resort, when the psychotropic has demonstrated clear benefit for NPS, should additional medications to target the side effects cautiously be added. Keep in mind that the additional agent will have its own side effects, will increase drug burden, and can put the patient at risk for more drug interactions.
Atypical antipsychotic medications are considered one of the most robustly studied classes in the management of NPS in patients with dementia [37]. These medications have been associated with several adverse effects, such as metabolic syndrome (which includes hyperlipidemia, weight gain, hyperglycemia, and increased diabetic risk), akathisia, drug-induced parkinsonism, and tardive dyskinesia/dystonia [38, 39]. In patients who have been treated with antipsychotic medications for several months or years, increases in the risk of death, pneumonia, cardiovascular events, parkinsonism, cognitive disturbance, gait problems including falls, and sedation have been observed [40, 41].
Although atypical antipsychotic medications have been found to help in decreasing agitation in patients with dementia, they have also been found to worsen cognitive symptoms, including confusion in this group of patients, even after the effect of sedation has been accounted for [42]. Aripiprazole and olanzapine were more likely to cause somnolence, whereas quetiapine accounted more for cognitive disturbance than did placebo [39, 40, 43]. Risperidone and olanzapine appeared to account more for the risk of cardiovascular adverse events, gait disturbance, and extrapyramidal side effects [39, 40, 44]. Among commonly used atypical antipsychotic medications, risperidone has been found to have more extrapyramidal side effects than the others, whereas olanzapine is more responsible for weight gain in the general population [45, 46]. In general, the use of antipsychotic medications has been associated with weight gain, but lower doses of these medications have not been associated with any weight gain in elderly patients with dementia [46, 47].
Some studies have found no increased diabetic risk in elderly patients with dementia who are being treated with antipsychotic medications even though the reverse is true in younger age groups [48]. Some atypical antipsychotic medications, such as risperidone, aripiprazole, and ziprasidone, as well high-potency typical antipsychotic medications such as haloperidol, appear to be associated with a decreased risk of hyperlipidemia, whereas other atypical antipsychotic medications such as olanzapine, quetiapine, and clozapine, as well as lower-potency typical antipsychotic medications such as chlorpromazine and thioridazine, appear to incur a higher risk of hyperlipidemia [49].
Based on a large meta-analysis, the odds ratio for the risk of death when using antipsychotic medications in patients with dementia was estimated to be 1.54, but no evidence was found for differential risk according to dementia severity, specific diagnoses, or individual drugs [32, 40]. Even though the risk of death was not associated with any particular group, it was more appreciated when all the atypical antipsychotic medications were considered together as a group [40]. Changing from one antipsychotic agent to the other while treating patients with dementia with NPS has also been associated with changes in mental status, a condition that has been identified as a crossover effect of antipsychotic medication [42].
3 General Approach to the Patient with Neuropsychiatric Symptoms (NPS)
Given the slim therapeutic index for psychotropic medication in patients with dementia, it is exceedingly important to carefully evaluate the symptoms and identify a compelling need for intervention. Kales et al. [3] recommended the DICE approach: Describe (context, environment, patient and caregiver perspective, degree of distress); Investigate (potential iatrogenic causes, pain, fear, boredom); Create (a plan for intervention with discrete follow-up time), and Evaluate (evaluate the intervention and plan continuation or withdrawal). In a busy neurology practice, the use of interview tools can be an efficient way to identify behaviors and symptoms to be addressed and quantify the degree of distress associated with each symptom. The Memory and Behavior Checklist, developed in 1992 by Teri et al. [50] and subsequently validated and circulated by the Alzheimer’s Association, is a 24-item list completed by the caregiver before the clinician’s examination, that allows rapid identification of severely problematic issues that should be addressed. Additional benefits of the checklist include allowing the caregiver to highlight problems that may be uncomfortable to verbalize in front of the patient and providing documentation of symptom severity if included in the medical record.
In our experience, patients presenting to a memory clinic are receiving, on average, eight medications, many of which have central nervous system adverse effects. Before any new medication is initiated, the prescribed and nonprescription agents should be optimized to reduce anticholinergic burden. Evidence also shows that switching cholinesterase inhibitors [51] can reduce NPS and the use of psychotropic medications. In the naturalistic study by Quante et al. [16], all patients admitted to the geriatric psychiatry unit for management of NPS showed improvement, regardless of whether pharmacotherapy treatment was prescribed.
Given the sheer number of publications related to NPS of dementia, we created Table 1 to highlight psychotropic medications that have been used in various studies. However, making definitive recommendations is difficult because of the heterogeneity of the studies in terms of patient population, type and severity of neuropsychiatric symptom, intervention, and outcome measures. We included studies published since 2004 in Table 1, because another publication reports on studies up to 2004 [52]. To align with selected criteria from the Sink et al. [52] review, we included only randomized controlled trials of agents available in the USA. The literature search was not limited to any particular type of dementia, though specific outcomes for NPS had to be reported. The following discussion highlights relevant secondary literature and selected key trials as it pertains to the medication management of specific symptoms. Selected symptoms were included in the following discussion if there was evidence or data to support changes to that specific symptom construct (e.g., agitation/aggression). We did not discuss symptoms for which comprehensive reviews existed highlighting the specific symptom (e.g., apathy).
4 Depression
Depression is one of the most common NPS, occurring in > 20% of individuals with dementia [29]. The symptoms can vary and include persistent sadness and anhedonia, accompanied by disturbed sleep/appetite, fatigue, and even suicidal ideation [53]. However, the relationship between depression and dementia is complicated. Not only has depression been shown to increase the risk of incident dementia, but uncontrolled depression can be associated with cognitive complaints and impairment (pseudodementia). In addition, antidepressants can worsen cognition, and depression can be a component of the dementing illness [31]. The evidence supporting the efficacy of antidepressants for managing depression in patients with dementia is mixed. Some clinical trials have shown no benefit, and most show significant adverse effects, including worsened cognition (Table 1) [54,55,56].
A 2011 meta-analysis reviewed seven placebo-controlled studies of antidepressants in patients with dementia and depression published between 1989 and 2010 [57]. The authors found inconclusive evidence of efficacy, as the included trials had variable designs and were underpowered. Of the seven studies, two found significantly beneficial effects of antidepressant versus placebo [57]. Of these two, the first studied clomipramine at a target dose of 100 mg/day for 6 weeks in 24 patients with probable AD. Patients receiving clomipramine showed significantly lower Hamilton Depressive Rating Scale (HDRS) scores over placebo in the first 6 weeks. The second evaluated sertraline at a mean dose of 95 mg/day in 44 patients for 12 weeks. Sertraline-treated patients showed greater improvements in scores on both the Cornell Scale for Depression in Dementia (CSDD) and the HDRS than did the placebo group. Five studies included in this meta-analysis did not demonstrate significant effects from an intervention with an antidepressant, including imipramine, sertraline, fluoxetine, and venlafaxine. The largest of the studies evaluated sertraline at a target dose of 100 mg/day in 131 patients for 12 weeks and found no demonstration of efficacy versus placebo [57].
It is clear that depression worsens the quality of life of patients with dementia, and the presence of major depression (with or without suicidal ideation) warrants pharmacologic treatment. However, most of the included randomized clinical trials were underpowered, and clinical judgment has led to the recommendation of a trial of a low-dose selective serotonin reuptake inhibitor (SSRI) (sertraline 25–50 mg, fluoxetine 10 mg, or citalopram 10 mg daily to start) in affected patients [58]. Tricyclic antidepressants and other agents with significant anticholinergic effects, such as paroxetine, should be avoided [31].
5 Sleep Disorders
Sleep disorders, consisting of disruption in sleep, is a common complaint of patients with dementia and their caregivers, with > 50% of patients affected at the more severe stages of the disease [59]. Implementation of improved sleep hygiene is often helpful in reducing the need for pharmacologic intervention. Reduction in caffeine-containing foods and beverages, reducing night-time fluid intake, increased daytime activity and exercise, and creation of an optimal environment for sleep (lighting, temperature), along with a more structured daily and evening routine, should be attempted [58]. If these tactics fail, pharmacologic intervention with the least offensive agents could be tried. First, cholinesterase inhibitors, usually already prescribed in patients with memory complaints, when given at bedtime, can improve sleep latency [60]. Second, trazodone 50 mg at bedtime has been shown to improve sleep metrics in individuals with dementia [61]. In a Cochrane review published in November 2016, authors analyzed four randomized controlled trials of melatonin with doses up to 10 mg and found no demonstration of efficacy over placebo in any sleep parameter, including efficiency of sleep and number of night-time awakenings. Results of this Cochrane review included one phase II trial of ramelteon 8 mg nightly in patients with mild to moderate AD. No significant differences from placebo were reported. The one positive study of trazodone, involving only 30 patients, was cited previously [61] and was considered low quality [62]. Benzodiazepines and benzodiazepine receptor agonists (zolpidem and zopiclone) should be avoided in elderly patients with dementia because they may induce falls and worsen cognition [31].
6 Psychosis
Psychotic episodes, which may consist of hallucinations or delusions are experienced by patients with dementia at much lower rates than that of depression and sleep disorders but can be a source of extreme distress for both the patient and their caregivers [63], which can lead to increased rates of nursing home placement [5, 64]. Though psychosis can persist and worsen over time, it may also fluctuate and resolve [5, 65]. It is estimated that between 16 and 75% of patients with PD and approximately 40% of patients with AD have psychosis at some point in their disease course [65, 66]. This rate is higher in patients with DLB as visual hallucinations are a key feature of this condition [64]. In multiple types of dementia, delirium may also present with psychotic symptoms, further clouding the clinical picture of NPS [67].
The presence of hallucinations does not automatically warrant the use of antipsychotic medication. In many cases, the hallucinations and/or delusions can be of minor consequence, and the caregiver can manage with only reassurance and redirection [58]. If possible, reducing the doses of or discontinuing concurrent medications that may contribute to NPS, such as sedatives or anticholinergics, may be considered [64]. In cases of DLB, donepezil can improve psychotic symptoms, including hallucinations and delusions [68]. However, if the patient, the caregiver, or both are severely affected by the symptoms, a low-dose antipsychotic agent can be trialed. The efficacy of antipsychotics for treating psychotic symptoms, specifically, in AD is unclear because many studies appear to group behavioral disturbances with psychotic symptoms in evaluating medication efficacy in patients with dementia [11, 69]. While most antipsychotics have been shown to be ineffective or intolerable secondary to worsened motor function, low-dose clozapine appears effective for PD psychosis [64]. Unfortunately, frequent blood monitoring (weekly evolving to bi-weekly) for agranulocytosis significantly limits the use of clozapine. In April 2016, pimavanserin was the first antipsychotic to receive approval for the treatment of hallucinations and delusions associated with PD psychosis [70, 71]. Pimavanserin is an inverse agonist at 5-HT2a (and less so at 5-HT2c) receptors in the brain and was not shown to worsen parkinsonism over 6 weeks in one study [71].
Documented adverse effects of atypical antipsychotics include increased risk of stroke, myocardial infarction and other cardiovascular events, pulmonary-related adverse effects, cognitive changes, sedation, drug-induced parkinsonism, tardive dyskinesia/dystonia, falls and hip fractures, and metabolic adverse effects [72]. Since all of the available antipsychotics carry the boxed warning for increased risk of death in patients with dementia-related psychosis, a documented discussion of the risks and benefits of the treatment should occur prior to the prescription [58]. A careful case-controlled analysis of the mortality risk of individual antipsychotic medication was performed on a large database of 46,008 veterans aged > 65 years with a diagnosis of dementia and a recent prescription for an antipsychotic, valproic acid, or an antidepressant [73]. The investigators reported increased mortality (from highest to lowest risk) with haloperidol, risperidone, olanzapine, and quetiapine, with numbers need to harm of 26, 27, 40, and 50, respectively. It was also noted that the mortality risk was dose dependent, reinforcing the need to use the lowest possible dose for the shortest possible duration in patients with dementia requiring these agents. Since the increased mortality is attributed to mostly cardiovascular events, patients with dementia with vascular risk factors may be particularly vulnerable. According to the APA practice guideline on using antipsychotics in the treatment of agitation or psychosis in patients with dementia, published in May 2016, antipsychotics should only be used when symptoms are severe, dangerous, or cause significant patient distress, and haloperidol should not be used as first-line treatment [25].
7 Agitation/Aggression
Agitation is used to describe a wide range of behaviors that include verbal outbursts, physical aggression, intense anxiety and crying, and persistent perambulation and wandering [3]. Agitation can happen at any stage of the disease and affects up to 20% of community-dwelling patients with AD [11]. It is exceedingly important to identify the triggers and context for the agitation and try to remove the cause. Possible causes of agitation include pain, infection, or other exacerbations of medical illness, loneliness, boredom, medication side effects, environmental changes, and fatigue [11]. Pharmacologic treatment should only be considered when measures to remove triggers are ineffective, the behavior is severe, and the agitation is persistent. Citalopram, an antidepressant, has been shown to be effective in combination with psychosocial intervention for reducing agitation in patients with dementia [54] but at the cost of impaired cognition and cardiac adverse effects (QTc prolongation). It was subsequently reported that patients with lower levels of cognitive impairment and only moderate agitation were most likely to benefit from citalopram and that restricting doses to ≤ 20 mg daily may reduce the chance of adverse effects [74].
Antipsychotic agents have modest benefits for agitation/aggression but are associated with increased mortality, as discussed in Sects. 2 and 6 [3]. They should only be employed when the patient demonstrates aggression with risk of harm to self or others and, even then, the intervention should be at the lowest possible dose (quetiapine 25 mg daily to start) and for a short duration (re-evaluate at 8 weeks). Quetiapine is recommended over risperidone or haloperidol because evidence exists of a lower mortality risk [73].
Some antiepileptic agents have been promoted as “mood stabilizers” and have been tried in patients with dementia and agitation [75]. In a recent review, valproic acid was not effective and caused significant side effects. Carbamazepine was effective in several small studies, but the medication must be titrated slowly over 6–8 weeks to avoid central nervous system side effects and has many drug interactions [75]. It is possible that some of the newer agents, such as levetiracetam and lamotrigine may have some benefits, but clinical trial evidence is lacking.
Benzodiazepines are used extensively in patients with dementia, particularly those in nursing homes, despite very little evidence of efficacy in managing NPS. A recent systematic review revealed usage data in up to 20% of patients and a clear association with accelerated cognitive decline and falls [76]. There is evidence that single doses of lorazepam can be effective for acute agitation, but little evidence supports chronic dosing for agitation or sleep disturbances [76, 77].
The development of additional, and safer, pharmacologic agents to manage agitation and aggression in patients with dementia is necessary. In a recent randomized clinical trial, patients with dementia and clinically significant agitation received either placebo or the combination of dextromethorphan and quinidine for 10 weeks. The treatment successfully reduced agitation, and the main adverse effects were falls and urinary tract infections [78]. This product is currently marketed for pseudobulbar affect and could be a safer alternative to antipsychotics for the management of agitation/aggression in dementia.
8 Medication Withdrawal
It has been suggested that discontinuing acetylcholinesterase inhibitors in patients with AD could be deleterious because of both worsened cognition and NPS [79]. Additionally, the effects of psychotropic withdrawal or discontinuation on adverse effects and symptom management are unclear. Table 2 summarizes the discontinuation studies. Even if the psychotropic is considered effective, providers may be wary of continuing them and quick to consider discontinuing treatment in light of adverse effects and federal regulations dictating discontinuation [80]. Devanand et al. [80] investigated patients with AD (both outpatients and residential) with psychosis and agitation–aggression who had responded to 16 weeks of risperidone treatment and the effects of discontinuation. At baseline, almost half of patients lived in an assisted-living facility or nursing home, 80% had psychosis, and 81% had agitation–aggression. Of the patients who responded to risperidone and were discontinued after the first 16 weeks, 60% relapsed compared with 33% of those randomized to continue risperidone. Another intervention arm included patients who continued risperidone for an additional 16 weeks (total of 32 weeks of treatment) and were discontinued. These patients were also more likely to relapse than those continuing risperidone treatment (48 vs. 15%, respectively; p = 0.02). Despite patients being at higher risk of relapse with discontinuation, the effect of risperidone on addressed psychosis and agitation was not robust. Furthermore, this study did not find that more severe symptoms were associated with a higher likelihood of relapse. Overall, it appears that, in patients who respond (characterized as ≥ 30% reduction on the neuropsychiatric inventory and 1 or 2 on the Clinical Global Impression of Change [CGI-C]) to risperidone, patients who discontinue medication should be closely monitored for relapse. Subsequently, Patel et al. [81] classified neuropsychiatric inventory symptoms in the previous study into absent, mild/moderate, and severe symptoms to identify that severe hallucinations were associated with relapse after 32 weeks. Auditory, but not visual, hallucinations were significantly predictive of relapse. Findings led authors to suggest that the initial severity of NPS, not just current or final presentation, should be included when considering appropriateness of antipsychotic discontinuation. Prior to this, the cognitive decline of patients with AD living in a nursing home or assisted-living facility and continuing or discontinuing risperidone, chlorpromazine, trifluoperazine, or haloperidol were evaluated [82]. Of note, 12% of patients had visual hallucinations and 33% of patients had delusions at baseline. There was no difference based on the Severe Impairment Battery over 6 months, nor were there any notable global differences based on loss of function and CGI scores, indicating that withdrawing antipsychotics does not lead to cognitive and functional decline. A longer-term follow-up to this study identified greater mortality with continued antipsychotic use, especially beyond the first year [83]. Another study found no differences between patients with AD who received antipsychotics for at least 3 months and then switched to memantine and those who continued on antipsychotics in terms of agitation, activities of daily living, or overall NPS [84]. A 2018 Cochrane review of long-term (≥ 3 months) antipsychotic withdrawal or discontinuation concluded that antipsychotics could be discontinued in patients with dementia, though the supportive evidence was low quality. Importantly, authors stated that antipsychotic continuation could be beneficial in patients with psychotic symptoms, agitation, or aggression, or who had demonstrated response [85].
In the 25-week DESEP study evaluating depressive symptoms in nursing home residents with AD and/or vascular dementia, patients who discontinued prespecified SSRIs (escitalopram, citalopram, sertraline, and paroxetine) experienced a significant increase in depressive symptoms compared with patients continuing their SSRI [86]. Of note, the authors sought to identify the effects of antidepressant discontinuation in patients where the medication yielded unclear or questionable benefits. Patients had been on the antidepressant for ≥ 3 months and those randomized to the discontinuation arm were prescribed a taper over 1 week. Though there were no differences between groups on the total neuropsychiatric inventory scores, there was a statistically significant difference on the affective subscore of the neuropsychiatric inventory. Though patients with a current documentation or history of depressive disorder were excluded, included patients could have had undiagnosed depression, as indicated by high scores on the depression rating scale. A further limitation was that patients could have been receiving other psychotropics [86]. Thus, it appears that, in patients who exhibit minimal benefit from SSRIs, discontinuation could lead to an increase in depressive symptoms.
Higher doses of psychotropic medications prior to withdrawal or discontinuation may be an indication of the severity of NPS, as these medications are generally started at low doses and slowly titrated to a balance of efficacy and tolerability, especially in the geriatric population. Overall, it might appear that patients with specific symptoms or more severe NPS (e.g., neuropsychiatric inventory scores of ≥ 14) may obtain greater benefit from psychotropic intervention than patients with milder symptoms [87, 88].
9 Additional Considerations for the Treating Clinician
Caregiver training, as one example of a nonpharmacologic technique, has been shown to significantly reduce the impact of NPS in patients with dementia [89]. Many patients respond positively to the use of nonpharmacological interventions, but it is important to note that some may find these interventions upsetting, further potentiating NPS [25]. Nonpharmacologic management techniques must be individualized and developed with input from healthcare providers and caregivers to increase their success [25]. When effective, nonpharmacologic strategies reduce the need for pharmacologic therapy, avoiding the use of potentially harmful medications [25].
Some studies allowed for inclusion of medications used for dementia, without specific attention to their possible effects on NPS. Alternatively, the clinical trial evidence supporting the efficacy or even the toxicity of psychotropic medication for patients with dementia usually excludes patients receiving multiple psychotropic medications or with important comorbid conditions. In practice, most patients do not meet these criteria and receive multiple medications with similar adverse effects and have age-induced impaired organ function (renal, hepatic), leading to additive risk in this vulnerable population. For example, it is common for a patient to receive trazodone for sleep and citalopram for agitation, both of which can increase risk of QTc prolongation. Opportunities to reduce pill burden and polypharmacy should be embraced whenever possible.
The mechanism by which various NPS present is unclear. For example, even within the realm of hallucinations, certain types may be more likely to present in one dementia than in another, and, subsequently, the response to medications directed towards visual versus auditory hallucinations among different dementias may also differ. Many presentations and nuances of symptoms may be characterized under categories such as “depressive symptoms” or “agitation and aggression.” To make it more difficult, some symptoms under each of these categories may respond readily to medication management, and others are fairly resistant. Improvements in specific symptoms may be significant during the study but then nonsignificant by study endpoint, further highlighting the variability in response over time. One evaluation of the CitAD study, highlighting individual items on the neuropsychiatric inventory, found that delusions, anxiety, and irritability/lability differed significantly between patients receiving citalopram and those receiving placebo [8]. In general, all patients had agitation/aggression, but the degrees of irritability/lability, anxiety, apathy/indifference, aberrant motor behavior, disinhibition, and depression/euphoria varied [8]. Given these findings, the application in clinical practice remains unclear. Questions may include whether patients in whom symptoms initially respond would most benefit from citalopram or whether citalopram would be efficacious in more severe psychosis. In addition, some studies look at the total score on a neuropsychiatric inventory, which may not yield any meaningful benefit until specific symptoms are analyzed. The identification of these individual symptom improvements helps identify the most appropriate candidate for medication therapy. The psychosocial or environmental context is not generally described in studies and may differ from a patient’s surroundings. It is also unclear how a co-occurring psychiatric illness, such as depression, may impact the overall treatment and response of a patient with dementia. How a patient, who has been carefully selected for medication management based on targeted symptoms with clearly defined goals, responds to the medication can also influence its continued use in NPS management. Thus, the management of NPS truly becomes individualized medicine as providers seek to understand the etiology and pathophysiology of specific symptoms, identify and apply relevant literature, observe the effects of medication management, and determine the appropriateness of continuation versus discontinuation according to response or remission and relapse risk in caring for their patients.
10 Conclusions
NPS occur in virtually all patients with dementia and can have dire consequences, including institutionalization and caregiver morbidity. Nonpharmacologic interventions can be quite effective but are difficult to implement and often fail to provide satisfactory resolution. Pharmacologic intervention should be pursued in only the most severely afflicted, with careful documentation of the indication and the risk and benefit discussion with the patient and caregiver. Careful consideration should be given to not only the initial presentation of the NPS but also the evidence of medication efficacy directed towards specific symptomatology and the overall risks of the “untreated” symptom compared with those of the medication. If a medication is initiated for NPS, the persistence of symptoms should be assessed thorough evaluation to ascertain which patients might be the best candidates for continued medication versus drug discontinuation while weighing the risks of symptomatic relapse and possible subsequent decline.
References
Satizabal CL, et al. Incidence of dementia over three decades in the framingham heart study. N Engl J Med. 2016;374(6):523–32.
Herrmann N, Lanctot KL, Hogan DB. Pharmacological recommendations for the symptomatic treatment of dementia: the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012. Alzheimers Res Ther. 2013;5(Suppl 1):S5.
Kales HC, Gitlin LN, Lyketsos CG. Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel. J Am Geriatr Soc. 2014;62(4):762–9.
O’Donnell BF, et al. Incontinence and troublesome behaviors predict institutionalization in dementia. J Geriatr Psychiatry Neurol. 1992;5(1):45–52.
Scarmeas N, et al. Delusions and hallucinations are associated with worse outcome in Alzheimer disease. Arch Neurol. 2005;62(10):1601–8.
Rapp MA, et al. Cognitive decline in patients with dementia as a function of depression. Am J Geriatr Psychiatry. 2011;19(4):357–63.
Macfarlane S, O’Connor D. Managing behavioural and psychological symptoms in dementia. Aust Prescr. 2016;39(4):123–5.
Leonpacher AK, et al. Effects of citalopram on neuropsychiatric symptoms in alzheimer’s dementia: evidence from the CitAD study. Am J Psychiatry. 2016;173(5):473–80.
Yaffe K, et al. Patient and caregiver characteristics and nursing home placement in patients with dementia. JAMA. 2002;287(16):2090–7.
Buhr GT, Kuchibhatla M, Clipp EC. Caregivers’ reasons for nursing home placement: clues for improving discussions with families prior to the transition. Gerontologist. 2006;46(1):52–61.
Lyketsos CG, et al. Neuropsychiatric symptoms in Alzheimer’s disease. Alzheimers Dement. 2011;7(5):532–9.
Lopez OL, et al. Psychiatric symptoms vary with the severity of dementia in probable Alzheimer’s disease. J Neuropsychiatry Clin Neurosci. 2003;15(3):346–53.
Hashimoto M, et al. Relationship between dementia severity and behavioral and psychological symptoms of dementia in dementia with Lewy bodies and Alzheimer’s disease patients. Dement Geriatr Cogn Dis Extra. 2015;5(2):244–52.
Gauthier S, et al. Management of behavioral problems in Alzheimer’s disease. Int Psychogeriatr. 2010;22(3):346–72.
Uchiyama M, et al. Pareidolias: complex visual illusions in dementia with Lewy bodies. Brain. 2012;135(Pt 8):2458–69.
Quante A, Sulejmani A. Prevalence and pharmacotherapy of behavioral and psychological symptoms of dementia in a geriatric psychiatry unit: a retrospective analysis. Prim Care Companion CNS Disord. 2017;. https://doi.org/10.4088/PCC.17m02137.
Tagariello P, Girardi P, Amore M. Depression and apathy in dementia: same syndrome or different constructs? A critical review. Arch Gerontol Geriatr. 2009;49(2):246–9.
Theleritis C, et al. Pharmacological and nonpharmacological treatment for apathy in alzheimer disease: a systematic review across modalities. J Geriatr Psychiatry Neurol. 2017;30(1):26–49.
Starkstein SE, et al. Neuropsychological and psychiatric differences between Alzheimer’s disease and Parkinson’s disease with dementia. J Neurol Neurosurg Psychiatry. 1996;61(4):381–7.
Sultzer DL, et al. A comparison of psychiatric symptoms in vascular dementia and Alzheimer’s disease. Am J Psychiatry. 1993;150(12):1806–12.
Lyketsos CG, et al. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA. 2002;288(12):1475–83.
Small GW et al. Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society. JAMA. 1997;278(16):1363–71.
National Institue for Health and Care Excellence. Dementia: assessment, management and support for people living with dementia and their carers. 2018. https://www.nice.org.uk/guidance/ng97/resources/dementia-assessment-management-and-support-forpeople-living-with-dementia-and-their-carers-pdf-1837760199109. Accessed 29 Apr 2019.
Lyketsos CG, et al. Position statement of the American Association for Geriatric Psychiatry regarding principles of care for patients with dementia resulting from Alzheimer disease. Am J Geriatr Psychiatry. 2006;14(7):561–72.
Reus VI, et al. The American Psychiatric Association Practice Guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. Am J Psychiatry. 2016;173(5):543–6.
The American Geriatrics Society. A guide to the management of psychotic disorders and neuropsychiatric symptoms of dementia in older adults. 2011. https://www.nhqualitycampaign.org/files/AGS_Guidelines_for_Telligen.pdf. Accessed 29 Apr 2019.
Cummings JL, et al. A practical algorithm for managing Alzheimer’s disease: what, when, and why? Ann Clin Transl Neurol. 2015;2(3):307–23.
Fung JK, Tsang HW, Chung RC. A systematic review of the use of aromatherapy in treatment of behavioral problems in dementia. Geriatr Gerontol Int. 2012;12(3):372–82.
Maust DT, et al. Psychotropic use and associated neuropsychiatric symptoms among patients with dementia in the USA. Int J Geriatr Psychiatry. 2017;32(2):164–74.
Salzman C, et al. Elderly patients with dementia-related symptoms of severe agitation and aggression: consensus statement on treatment options, clinical trials methodology, and policy. J Clin Psychiatry. 2008;69(6):889–98.
By the American Geriatrics Society Beers Criteria Update Expert, P., American Geriatrics Society 2015 Updated beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2015;63(11):2227–2246.
Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005;294(15):1934–43.
O’Mahony D, et al. STOPP/START criteria for potentially inappropriate prescribing in older people: version 2. Age Ageing. 2015;44(2):213–8.
By the 2019 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2019 Updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2019;67(4):674–94.
Reppas-Rindlisbacher CE, et al. Anticholinergic drug burden in persons with dementia taking a cholinesterase inhibitor: the effect of multiple physicians. J Am Geriatr Soc. 2016;64(3):492–500.
Ruxton K, Woodman RJ, Mangoni AA. Drugs with anticholinergic effects and cognitive impairment, falls and all-cause mortality in older adults: a systematic review and meta-analysis. Br J Clin Pharmacol. 2015;80(2):209–20.
Wang J, et al. Pharmacological treatment of neuropsychiatric symptoms in Alzheimer’s disease: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2015;86(1):101–9.
Atti AR, et al. A systematic review of metabolic side effects related to the use of antipsychotic drugs in dementia. Int Psychogeriatr. 2014;26(1):19–37.
Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry. 2006;14(3):191–210.
Tampi RR, et al. Antipsychotic use in dementia: a systematic review of benefits and risks from meta-analyses. Ther Adv Chronic Dis. 2016;7(5):229–45.
Ballard CG, et al. Management of agitation and aggression associated with Alzheimer disease. Nat Rev Neurol. 2009;5(5):245–55.
Devanand DP, Schultz SK. Consequences of antipsychotic medications for the dementia patient. Am J Psychiatry. 2011;168(8):767–9.
Ballard C, Waite J. The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer’s disease. Cochrane Database Syst Rev. 2006;1:CD003476.
Maher AR, et al. Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis. JAMA. 2011;306(12):1359–69.
Leucht S, et al. Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophr Res. 1999;35(1):51–68.
Gurevitz SL, Costakis T, Leiter J. Do atypical antipsychotics cause weight gain in nursing home dementia residents? Consult Pharm. 2004;19(9):809–12.
Goldberg RJ. Weight variance associated with atypical neuroleptics in nursing home dementia patients. J Am Med Dir Assoc. 2001;2(1):26–8.
Jalbert JJ, et al. Antipsychotic use and the risk of diabetes in nursing home residents with dementia. Am J Geriatr Pharmacother. 2011;9(3):153–63.
Meyer JM, Koro CE. The effects of antipsychotic therapy on serum lipids: a comprehensive review. Schizophr Res. 2004;70(1):1–17.
Teri L, et al. Assessment of behavioral problems in dementia: the revised memory and behavior problems checklist. Psychol Aging. 1992;7(4):622–31.
Kano O, et al. Clinically meaningful treatment responses after switching to galantamine and with addition of memantine in patients with Alzheimer’s disease receiving donepezil. Neuropsychiatr Dis Treat. 2013;9:259–65.
Sink KM, Holden KF, Yaffe K. Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. JAMA. 2005;293(5):596–608.
Lanctot KL, et al. Neuropsychiatric signs and symptoms of Alzheimer’s disease: new treatment paradigms. Alzheimers Dement (N Y). 2017;3(3):440–9.
Porsteinsson AP, et al. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014;311(7):682–91.
Weintraub D, et al. Sertraline for the treatment of depression in Alzheimer disease: week-24 outcomes. Am J Geriatr Psychiatry. 2010;18(4):332–40.
Finkel SI, et al. A randomized, placebo-controlled study of the efficacy and safety of sertraline in the treatment of the behavioral manifestations of Alzheimer’s disease in outpatients treated with donepezil. Int J Geriatr Psychiatry. 2004;19(1):9–18.
Nelson JC, Devanand DP. A systematic review and meta-analysis of placebo-controlled antidepressant studies in people with depression and dementia. J Am Geriatr Soc. 2011;59(4):577–85.
Sadowsky CH, Galvin JE. Guidelines for the management of cognitive and behavioral problems in dementia. J Am Board Fam Med. 2012;25(3):350–66.
Kazui H, et al. Differences of behavioral and psychological symptoms of dementia in disease severity in four major dementias. PLoS One. 2016;11(8):e0161092.
Scoralick FM, et al. Outpatient treatment of sleep disorders in Alzheimer patients. Einstein (Sao Paulo). 2015;13(3):430–4.
Camargos EF, et al. Trazodone improves sleep parameters in Alzheimer disease patients: a randomized, double-blind, and placebo-controlled study. Am J Geriatr Psychiatry. 2014;22(12):1565–74.
McCleery J, Cohen DA, Sharpley AL. Pharmacotherapies for sleep disturbances in dementia. Cochrane Database Syst Rev. 2016;11:CD009178.
Fauth EB, Gibbons A. Which behavioral and psychological symptoms of dementia are the most problematic? Variability by prevalence, intensity, distress ratings, and associations with caregiver depressive symptoms. Int J Geriatr Psychiatry. 2014;29(3):263–71.
Friedman JH. Parkinson disease psychosis: update. Behav Neurol. 2013;27(4):469–77.
Fenelon G, Alves G. Epidemiology of psychosis in Parkinson’s disease. J Neurol Sci. 2010;289(1–2):12–7.
Hasnain M, et al. Pharmacological management of psychosis in elderly patients with parkinsonism. Am J Med. 2009;122(7):614–22.
Morandi A, et al. The diagnosis of delirium superimposed on dementia: an emerging challenge. J Am Med Dir Assoc. 2017;18(1):12–8.
Cummings J, et al. Role of donepezil in the management of neuropsychiatric symptoms in Alzheimer’s disease and dementia with Lewy bodies. CNS Neurosci Ther. 2016;22(3):159–66.
Bassiony MM, et al. Delusions and hallucinations in Alzheimer’s disease: prevalence and clinical correlates. Int J Geriatr Psychiatry. 2000;15(2):99–107.
Acadia Pharmaceuticals. Nuplazid (pimvasanerin). 2016 [cited 2016 May 3]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207318lbl.pdf. Accessed 29 Apr 2019.
Cummings J, et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533–40.
APA and the Guideline Writing Group. The American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. [cited 2016 May 3]. http://psychiatryonline.org/doi/pdf/10.1176/appi.books.9780890426807.
Maust DT, et al. Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm. JAMA Psychiatry. 2015;72(5):438–45.
Schneider LS, et al. Heterogeneity of treatment response to citalopram for patients with Alzheimer's disease with aggression or agitation: the CitAD randomized clinical trial. Am J Psychiatry. 2016;173(5):465–72.
Gallagher D, Herrmann N. Antiepileptic drugs for the treatment of agitation and aggression in dementia: do they have a place in therapy? Drugs. 2014;74(15):1747–55.
Defrancesco M, et al. Use of benzodiazepines in Alzheimer’s disease: a systematic review of literature. Int J Neuropsychopharmacol. 2015;18(10):055.
Tampi RR, Tampi DJ. 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. 2014;29(7):565–74.
Cummings JL, et al. Effect of dextromethorphan-quinidine on agitation in patients with Alzheimer disease dementia: a randomized clinical trial. JAMA. 2015;314(12):1242–54.
O’Regan J, et al. Cholinesterase inhibitor discontinuation in patients with Alzheimer’s disease: a meta-analysis of randomized controlled trials. J Clin Psychiatry. 2015;76(11):e1424–31.
Devanand DP, et al. Relapse risk after discontinuation of risperidone in Alzheimer’s disease. N Engl J Med. 2012;367(16):1497–507.
Patel AN, et al. Prediction of relapse after discontinuation of antipsychotic treatment in Alzheimer’s disease: the role of hallucinations. Am J Psychiatry. 2017;174(4):362–9.
Ballard C, et al. A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial). PLoS Med. 2008;5(4):e76.
Ballard C, et al. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol. 2009;8(2):151–7.
Ballard C, et al. A double-blind randomized placebo-controlled withdrawal trial comparing memantine and antipsychotics for the long-term treatment of function and neuropsychiatric symptoms in people with Alzheimer’s disease (MAIN-AD). J Am Med Dir Assoc. 2015;16(4):316–22.
Van Leeuwen E, et al. Withdrawal versus continuation of long-term antipsychotic drug use for behavioural and psychological symptoms in older people with dementia. Cochrane Database Syst Rev. 2018;3:CD007726.
Bergh S, Selbaek G, Engedal K. Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): double blind, randomised, parallel group, placebo controlled trial. BMJ. 2012;344:e1566.
Ballard CG, et al. A 3-month, randomized, placebo-controlled, neuroleptic discontinuation study in 100 people with dementia: the neuropsychiatric inventory median cutoff is a predictor of clinical outcome. J Clin Psychiatry. 2004;65(1):114–9.
Ruths S, et al. Stopping antipsychotic drug therapy in demented nursing home patients: a randomized, placebo-controlled study—the Bergen District Nursing Home Study (BEDNURS). Int J Geriatr Psychiatry. 2008;23(9):889–95.
Haupt M, Karger A, Janner M. Improvement of agitation and anxiety in demented patients after psychoeducative group intervention with their caregivers. Int J Geriatr Psychiatry. 2000;15(12):1125–9.
Tariot PN, et al. Divalproex sodium in nursing home residents with possible or probable Alzheimer Disease complicated by agitation: a randomized, controlled trial. Am J Geriatr Psychiatry. 2005;13(11):942–9.
Herrmann N, et al. A placebo-controlled trial of valproate for agitation and aggression in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2007;23(2):116–9.
Sommer OH, et al. Effect of oxcarbazepine in the treatment of agitation and aggression in severe dementia. Dement Geriatr Cogn Disord. 2009;27(2):155–63.
Suh GH, et al. A randomized, double-blind, crossover comparison of risperidone and haloperidol in Korean dementia patients with behavioral disturbances. Am J Geriatr Psychiatry. 2004;12(5):509–16.
De Deyn P, et al. Aripiprazole for the treatment of psychosis in patients with Alzheimer’s disease. J Clin Psychopharmacol. 2005;25(5):463–7.
Deberdt WG, et al. Comparison of olanzapine and risperidone in the treatment of psychosis and associated behavioral disturbances in patients with dementia. Am J Geriatr Psychiatry. 2005;13(8):722–30.
Tariot PN, et al. Quetiapine treatment of psychosis associated with dementia: a double-blind, randomized, placebo-controlled clinical trial. Am J Geriatr Psychiatry. 2006;14(9):767–76.
Schneider LS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med. 2006;355(15):1525–38.
Verhey FR, et al. Olanzapine versus haloperidol in the treatment of agitation in elderly patients with dementia: results of a randomized controlled double-blind trial. Dement Geriatr Cogn Disord. 2006;21(1):1–8.
Kurlan R, et al. Quetiapine for agitation or psychosis in patients with dementia and parkinsonism. Neurology. 2007;68(17):1356–63.
Mintzer JE, et al. Aripiprazole for the treatment of psychoses in institutionalized patients with Alzheimer dementia: a multicenter, randomized, double-blind, placebo-controlled assessment of three fixed doses. Am J Geriatr Psychiatry. 2007;15(11):918–31.
Rainer M, et al. Quetiapine versus risperidone in elderly patients with behavioural and psychological symptoms of dementia: efficacy, safety and cognitive function. Eur Psychiatry. 2007;22(6):395–403.
Zhong KX, et al. Quetiapine to treat agitation in dementia: a randomized, double-blind, placebo-controlled study. Curr Alzheimer Res. 2007;4(1):81–93.
Paleacu D, et al. Quetiapine treatment for behavioural and psychological symptoms of dementia in Alzheimer’s disease patients: a 6-week, double-blind, placebo-controlled study. Int J Geriatr Psychiatry. 2008;23(4):393–400.
Streim JE, et al. A randomized, double-blind, placebo-controlled study of aripiprazole for the treatment of psychosis in nursing home patients with Alzheimer disease. Am J Geriatr Psychiatry. 2008;16(7):537–50.
De Deyn PP, et al. Tolerability of extended-release quetiapine fumarate compared with immediate-release quetiapine fumarate in older patients with Alzheimer’s disease with symptoms of psychosis and/or agitation: a randomised, double-blind, parallel-group study. Int J Geriatr Psychiatry. 2012;27(3):296–304.
Holmes C, et al. The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology. 2004;63(2):214–9.
Cummings JL, et al. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology. 2006;67(1):57–63.
Howard RJ, et al. Donepezil for the treatment of agitation in Alzheimer’s disease. N Engl J Med. 2007;357(14):1382–92.
Fox C, et al. Efficacy of memantine for agitation in Alzheimer’s dementia: a randomised double-blind placebo controlled trial. PLoS One. 2012;7(5):e35185.
Pollock BG, et al. A double-blind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia. Am J Geriatr Psychiatry. 2007;15(11):942–52.
Culo S, et al. Treating neuropsychiatric symptoms in dementia with Lewy bodies: a randomized controlled-trial. Alzheimer Dis Assoc Disord. 2010;24(4):360–4.
Freund-Levi Y, et al. Galantamine versus risperidone for agitation in people with dementia: a randomized, twelve-week, single-center study. Dement Geriatr Cogn Disord. 2014;38(3–4):234–44.
Peskind ER, et al. Propranolol for disruptive behaviors in nursing home residents with probable or possible Alzheimer disease: a placebo-controlled study. Alzheimer Dis Assoc Disord. 2005;19(1):23–8.
Wang LY, et al. Prazosin for the treatment of behavioral symptoms in patients with Alzheimer disease with agitation and aggression. Am J Geriatr Psychiatry. 2009;17(9):744–51.
Rosenberg PB, et al. Safety and efficacy of methylphenidate for apathy in Alzheimer’s disease: a randomized, placebo-controlled trial. J Clin Psychiatry. 2013;74(8):810–6.
van den Elsen GA, et al. Tetrahydrocannabinol for neuropsychiatric symptoms in dementia: a randomized controlled trial. Neurology. 2015;84(23):2338–46.
van den Elsen GA, et al. Tetrahydrocannabinol in behavioral disturbances in dementia: a crossover randomized controlled trial. Am J Geriatr Psychiatry. 2015;23(12):1214–24.
Ruths, S., et al., Effect of antipsychotic withdrawal on behavior and sleep/wake activity in nursing home residents with dementia: a randomized, placebo-controlled, double-blinded study. The Bergen District Nursing Home Study. J Am Geriatr Soc. 2004;52(10):1737–43.
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The authors acknowledge Yelena Lugin and Katherine Morgan for their contributions to this manuscript.
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Stephanie V. Phan is employed by the Health Services Advisory Group and is a consultant for Forward We Go, LLC. John C. Morgan is or has been a consultant for Abbvie, Acadia, Adamas, Impax, Neurocrine Biosciences, Parkinson’s Foundation, Sunovion, and Teva; a speaker for Acadia, Adamas, Impax, Parkinson’s Foundation, Neurocrine Biosciences, and Teva; a site principal investigator or sub-investigator for Abbvie, Acorda, Kyowa, Lilly, Lundbeck, Parkinson’s Foundation, Pharma2B, PSG, Sunovion, and US World Meds; and an expert witness in various legal cases, including some that involve parkinsonism. Sharmon Osae, Mfon Inyang, and Susan C. Fagan have no conflicts of interest that are directly relevant to the content of this article.
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At the time of writing and manuscript submission, Phan SV was affiliated with the University of Georgia College of Pharmacy.
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Phan, S.V., Osae, S., Morgan, J.C. et al. Neuropsychiatric Symptoms in Dementia: Considerations for Pharmacotherapy in the USA. Drugs R D 19, 93–115 (2019). https://doi.org/10.1007/s40268-019-0272-1
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DOI: https://doi.org/10.1007/s40268-019-0272-1