Continuing Education Activity

Dementia is a colloquial term to refer to what is formally called major neurocognitive disorder as defined by the Diagnostic and Statistical Manual 5th edition (DSM-5). In short, dementia is diagnosed by cognitive decline and a loss of function (decreased ability to perform daily tasks). Many possible etiologies lead to the syndrome of dementia, including Alzheimer dementia, vascular dementia, frontotemporal dementia, Lewy body dementia, and Parkinson disease, among others. Behavioral and psychological symptoms (BPSD) of dementia include a range of neuropsychiatric disturbances that could present in emergent, inpatient, or outpatient settings, leading to functional loss and diminished quality of life. Though no immediate solution exists, supportive, non-pharmacological, and pharmacological interventions improve the symptoms.

The activity addresses a spectrum of disturbances, including agitation, aggression, depression, and apathy, and provides knowledge for enhancing patient care in persons with dementia. In particular, the neurocognitive focus on history and physical examination is presented, with additional guidance on which deficits are considered manageable and which are considered emergencies. Participating clinicians will acquire valuable skills to navigate the complexities of BPSD, impacting prognosis, institutionalization, and caregiver well-being. The interprofessional team is equipped to improve outcomes for patients grappling with BPSD.

Objectives:

• Evaluate the environmental, psychosocial, and medical factors that may contribute to behavioral and psychological symptoms of dementia.

• Identify evidence-based treatment interventions for behavioral and psychological symptoms of dementia.

• Create a systematic strategy for evaluating and managing behavioral and psychological symptoms of dementia.

• Explain the importance of collaboration and communication among the interprofessional team in improving outcomes for patients affected by behavioral and psychological symptoms of dementia.

Introduction

Dementia is a colloquial term to refer to what is formally called Major Neurocognitive Disorder (MND) as defined by the Diagnostic and Statistical Manual 5th edition (DSM-5). In short, dementia is diagnosed by cognitive decline and a loss of function (decreased ability to perform daily tasks). Many possible etiologies lead to the syndrome of dementia, including Alzheimer dementia, vascular dementia, frontotemporal dementia, Lewy body dementia, and Parkinson disease, among others.[1]

Behavioral and psychological symptoms of dementia, or BPSD, are neuropsychiatric symptoms that accompany the syndrome of dementia, such as delusions, hallucinations, apathy, anxiety, depression, or disinhibition. BPSD symptoms are prevalent and can significantly impact the prognosis and management of dementia. BPSD includes emotional, perceptual, and behavioral disturbances that are similar to those seen in psychiatric disorders. It may be clinically useful to classify them into 5 domains: cognitive or perceptual (delusions, hallucinations), motor (pacing, wandering, repetitive movements, physical aggression), verbal (yelling, calling out, repetitive speech, verbal aggression), emotional (euphoria, depression, apathy, anxiety, irritability), and vegetative (disturbances in sleep and appetite).[2]

Etiology

No single etiology is evidenced for BPSD. Instead, a biopsychosocial model proposes that neuropsychiatric symptoms relate to interactions between an individual’s biology, prior experiences, and current environment. Dementia-related agitation, disinhibition, and psychosis are associated with volume reductions and decreased metabolism in the orbital and dorsolateral prefrontal cortex, anterior cingulate, insula, and temporal lobes, which are regions of the brain that mediate emotional regulation, self-awareness, and perception.[3] BPSD also correlates with cholinergic, noradrenergic, dopaminergic, serotonergic, and glutamatergic neurotransmission imbalances.[4] This evidence is preliminary and primarily relates to Alzheimer disease, supporting some of the pharmacotherapies currently used to treat BPSD. 

A review addressing non-biological determinants of BPSD identified pre-morbid neuroticism (a personality trait characterized by a tendency to respond to challenges with exaggerated negative emotions such as anxiety, depression, and anger), pre-morbid post-traumatic stress disorder, problematic caregiver communication styles, and environmental factors (sensory over or under stimulation, or surroundings that are too hot, cold, or loud) also contribute to BPSD. 

From a theoretical perspective, 3 main categories of environmental contributions have been described: unmet needs (for food, fluid, companionship), behavior or learning (when unwanted behavior is unwittingly reinforced, such as by providing attention when a patient calls out), and patient-environment mismatch (when a caregiver’s expectations exceed a patient’s capability).[5] 

Epidemiology

In 2016, the worldwide prevalence of dementia was approximately 43.8 million, representing a 117% increase from 1990 and 28.8 million disability-adjusted life years (DALY), and it was the world’s fifth leading cause of mortality.[6] Up to 97% of community-dwelling individuals with dementia will develop BPSD at some point, most commonly depression or apathy, although delusions, agitation, and aberrant motor behavior (eg, fidgeting, repetitive behaviors, wandering) occur in about a third of patients.[7] Symptom severity increases with time and correlates with institutional placement. While few studies have characterized BPSD symptoms according to dementia etiology, delusions are common in Alzheimer disease, depression and apathy in vascular dementia, and disinhibition and eating disturbances in frontotemporal dementia.[8]

History and Physical

The goal of history intake for patients with BPSD is to establish priorities regarding the nature and urgency of interventions, characterize the symptoms, and identify reversible exacerbating factors. These factors include environmental characteristics, medications, discomfort, substance use, and pre-morbid psychiatric disorders. The physical examination aims to confirm historical data and identify alternative or contributing psychiatric or medical conditions. 

Behavioral disturbances often occur in the evening, known as 'sundowning.' Some studies suggest that this phenomenon affects up to two-thirds of patients with dementia.[9] One of the most common psychiatric sequelae observed in this demographic is delusions. Often, the delusions consist of paranoid themes, as in Capgras syndrome and Othello syndrome. Hallucinations are not as prevalent as delusions, with estimates as low as 7% at baseline.[10] Furthermore, additional symptoms leading to subsequent hospital admissions include agitation, aggression, wandering, apathy, disinhibition, sleep disturbances, and depression. 

The physical examination may document the symptoms, although these are usually intermittent. The primary role of the physical exam is to identify factors that may contribute to worsening BPSD, such as superimposed delirium or discomfort. For example, the exam may reveal an altered level of consciousness (somnolence or hyper-alertness), features of delirium, or grimacing and guarding, suggesting pain. Physical findings such as fever, hypoxia, abdominal tenderness, fluid overload, inflammation, or localizing neurologic deficits may point to an acute medical condition that is causing delirium.

Evaluation

Unless evidence from the history or physical exam suggests alternative causes, evaluation with laboratory or imaging is not necessary for patients with dementia who present with gradually worsening BPSD. Acute or subacute onset of symptoms should prompt basic studies (typically, complete blood count, electrolytes, evaluation of liver and kidney function, urinalysis, thyroid function tests, toxicology screen, and head CT) to evaluate for causes of delirium.

Long-term staff members often attribute BPSD to urinary tract infections; however, the prevalence of bacteriuria is up to 50% in institutional settings, and routine testing may lead to over-diagnosis, unnecessary antimicrobial treatment, and the development of antibiotic resistance. According to the revised McGeer criteria, diagnostic evaluation and empiric therapy should be limited to patients with fever, dysuria, suprapubic pain, or new and increased urinary frequency, urgency, or incontinence. In other words, symptoms of a urinary tract infection, not just evidence of bacteria on urinalysis or culture. Other authors have suggested that culture and treatment could be initiated based on an acute mental status change with positive results on a urinalysis.[11]

Establish Priorities

The priority is characterizing the severity and nature of the symptoms; patients endangering themselves or others with aggressive behaviors or refusing basic care will warrant more intensive management, including hospitalization.

Therefore, the history should begin with an assessment of safety

1. Has the patient been aggressive toward others, and if so, has this caused injury?
2. Have they caused property damage?
3. Are they risking their health or safety by refusing basic hygiene, food, or fluids? 

Another priority is identifying delirium, which by definition is caused by a medical condition, medication, or non-prescribed CNS-active substance intoxication or withdrawal because this will require prompt medical evaluation and treatment. If delirium is identified, the patient will need a thorough medical evaluation, best accomplished in an inpatient setting.

Characterize Symptoms

Caregivers should be prompted to describe what they see rather than using generic terms such as “agitation” or “depression,” which can have different meanings to different observers. Other essential elements of the history include the onset (ie, acute, sub-acute, or chronic or progressive), frequency, timing, and trajectory of the disturbances and any relationship to environmental changes or medication changes. A temporal relationship may exist with events such as a change in environment (eg, moving from home to a nursing facility), or symptoms might worsen in the evenings, following family visits, or when providing personal care. 

Review Medications

Clinicians should ask caregivers about any medication changes in the weeks preceding the onset or worsening of BPSD. Patients with dementia are susceptible to the central nervous system (CNS) effects of medications, and not all culprit medications are easily recognized. In addition to the well-recognized adverse effects of bladder antispasmodics and histamine antagonists on cognition and behavior, antidepressants, benzodiazepines, digoxin, levetiracetam, and muscle relaxants can contribute to both agitation and apathy. Medication withdrawal, especially from antidepressants, benzodiazepines, or opioids, can also contribute to BPSD. Akathisia from antipsychotics, including second-generation antipsychotics, should be considered, especially in patients whose symptoms worsen despite increasing doses of these medications. 

Assess Comfort

The review of systems should address uncomfortable physical symptoms, including pain, constipation, and urinary retention. Because pain is present in 46% to 56% of patients with dementia, the presence of pain is associated with increased BPSD. The past medical history should have a review for painful conditions (eg, neuropathy, osteoarthritis, peripheral vascular disease), and caregivers should be asked about the patient’s self-reported pain and nonverbal signs of pain because patients with dementia may demonstrate nonverbal signs they do not express.[12] The Pain Assessment in Advanced Dementia (PAINAD) or Face, Legs, Activity, Cry, Consolability (FLACC) scales are reliable and valid tools for objectively evaluating and tracking pain. Most hospitals and some nursing homes use one of these instruments, and family caregivers can also be trained.

Review psychiatric history and substance use; caregivers should be questioned about the past medical history of psychiatric disorders, especially psychotic, mood, anxiety, and post-traumatic stress disorders, and whether the patient could be using alcohol, cannabis, non-prescribed medications, or illicit drugs.

Create a Baseline

Since BPSD can fluctuate and their assessment is subjective, establishing a clear baseline for assessing treatment effects is critically important. For overall BPSD, clinicians can use a standardized instrument such as the Neuropsychiatric Inventory (NPI) or the Behavioral Pathology in Alzheimer Disease Rating Scale (BEHAVE-AD). Both are based on structured interviews with caregivers and are extensively used in research, with similar performance in detecting global changes.

The NPI evaluates delusions, hallucinations, agitation, aggression, depression, dysphoria, anxiety, elation, euphoria, apathy, indifference, disinhibition, irritability, emotional lability, aberrant motor behavior, sleep disturbances, and disorders of appetite or eating. For each domain, caregivers are asked to rate the frequency, severity, and degree of distress over a period specified by the interviewer.

The BEHAVE-AD domains comprise delusions, hallucinations, activity disturbances, aggression, diurnal rhythm disturbances, tearfulness, depression, and anxiety; caregivers are asked to rate each symptom's severity over the past 2 weeks, provide a global rating of symptom severity, and identify the most troublesome symptom. The Cohen-Mansfield Agitation Inventory (CMAI) specifically evaluates agitated behaviors only, dividing them into 4 categories depending on whether they are physical, verbal, aggressive, or non-aggressive.

While the NPI, BEHAVE-AD, and CMAI are gold standards for evaluating BPSD, they are time-consuming, and a reasonable alternative in clinical practice is to ask caregivers to describe a problematic symptom, quantify its frequency, and assess the degree of distress it causes. For example, a symptom might be described as "pushing me away when I try to give her a shower" and then quantified by the percentage of showering time that this occurs (eg, 75% of the time) and the level of distress it causes for the caregiver (eg, 7 on a scale of 0 to 10). Having caregivers use a calendar or notebook to keep a daily prospective diary is the best way to get accurate information; ideally, this should occur before any intervention for at least 3 days and then be repeated after the intervention.

Treatment / Management

Management of BPSD involves choosing an appropriate setting, treating discomfort, implementing non-pharmacological interventions, and conducting systematic trials of evidence-based pharmacological therapies if needed. Unless patients endanger themselves or others, interventions should begin only after establishing a baseline by identifying and quantifying target symptoms.

Choose an Appropriate Setting

The first step in management is to decide on the proper setting for treatment and address safety issues. Patients with delirium are best managed in a hospital to facilitate medical evaluation because parenteral medications may be required. Referral to a geropsychiatry unit is appropriate for medically stable patients who are endangering themselves or others (aggression with injury or capacity to cause injury, refusing fluids or basic hygiene, suicidal behavior), especially if pharmacotherapy is refused or is ineffective. Pending transfer, patients who are dangerous to themselves or others require monitoring with one-on-one observation, and treatment with antipsychotic medications will usually be necessary, following a risk or benefit discussion with their surrogates or guardians. 

Treat Discomfort

Before any BPSD-specific interventions, all patients should be assessed and treated for causes of discomfort (eg, pain, constipation, urinary retention, room temperature), as described above and treated appropriately.  

Non-Pharmacological Interventions for BPSD

The next step in management is implementing non-pharmacological interventions, which may be sufficient for mild BPSD and should always accompany pharmacotherapy. Geriatrics organizations and experts advocate the use of non-pharmacological interventions for BPSD. However, a meta-analysis of 10 randomized controlled trials in patients with moderate to severe dementia found no benefit, except for music therapy in reducing overall BPSD and massage therapy in reducing depression.[13]

Caregiver training: This meta-analysis excluded interventions focused on caregiver training, effectively reducing a range of BPSD and improving caregiver well-being.[14] Caregiver training focuses on understanding behavioral disturbances as responses to discomfort, unmet needs, or attempts to communicate, creating soothing environments with optimal levels of stimulation, and responding to patients in ways that de-escalate problematic behaviors (eg, distraction, giving patients clear instructions and simple choices, not rewarding the behaviors).

The Alzheimer Association offers online educational modules and in-person training classes, providing professional and peer support for caregivers. For patients whose BPSD occurs primarily during personal care, a randomized, multi-site crossover study showed that training caregivers to deliver a protocol called Bathing without a Battle (available online) reduced agitation, bathing time, and antipsychotic use.[15]

Other non-pharmacological approaches: While non-pharmacological interventions other than caregiver training and music therapy have not been consistently effective for BPSD in randomized, controlled trials, they may benefit individual patients and, unlike medications, rarely have adverse effects. These include aromatherapy, bright light therapy to reduce circadian disturbances, massage, multisensory stimulation, and reminiscence therapy, in which patients review their past via conversation, photographs, or music.[16] Some interventions with anecdotal effectiveness for agitation include giving patients simple tasks to perform, such as folding laundry or using busy quilts (lap quilts with exciting objects such as zippers, Velcro, beads, ties, etc) and weighted blankets (similar to those used to calm children with pervasive developmental disorders). A clinical trial (ClinicalTrials.gov ID NCT03643991) is currently underway to evaluate the latter. In general, non-pharmacological approaches are well-tolerated, but rare cases of worsening agitation have occurred with music therapy.

Pharmacologic Interventions for Agitation and Aggression

Psychotropic medications are frequently used to treat BPSD, although the side effect burden is high, and the benefits are modest. Wandering and repetitive vocalizations rarely respond to pharmacotherapy and are best addressed with non-pharmacological measures. Pharmacological approaches will differ based on the nature and severity of the symptoms. The primary focus of clinical trials has been on symptoms of agitation, aggression, and psychosis since these are typically the most problematic and distressing manifestations. 

Empiric treatment of pain: Painful conditions are present in at least 49% of patients with dementia, but only 20% to 40% of patients with dementia receive analgesics, compared to 60% to 80% of similar patients without dementia. This relates to both under-reporting by patients and under-recognition by clinicians.[12] Since untreated pain has a strong relationship with BPSD, an 8-week multicenter cluster randomized controlled trial examined the effect of a stepwise protocol for empiric treatment of pain in patients with dementia-related agitation. Patients were started on routine acetaminophen (3 g daily) if they were not receiving analgesics. If this was insufficient, they were stepped up to low-dose morphine (up to 20 mg daily), buprenorphine transdermal patch (up to 10 mcg hourly), or pregabalin (up to 300 mg daily). The primary outcome measure was a change in scores on the Cohen-Mansfield Agitation Inventory; cognitive and physical functioning changes were also assessed. After 8 weeks, agitation was reduced by 17% in the intervention group (an effect comparable to that seen with risperidone, the antipsychotic most commonly used for BPSD), without any adverse effects on cognition or physical functioning, suggesting that pain relief did not achieve benefit for BPSD simply by sedating patients.[17] 

This study supports the empiric treatment of known or potential pain as a first step in addressing BPSD. An excellent first step is initiating routine acetaminophen, with a maximum recommended dose of 3 g/day in the elderly. Topical therapies such as transdermal lidocaine, diclofenac gel, or methyl salicylate cream are safe. They can be effective if a localized source of pain is suspected. Duloxetine, Gabapentin, or Pregabalin can be helpful if there is a concern for neuropathic pain, although they are associated with an increase in falls. Clinicians should generally avoid using muscle relaxants, chronic NSAIDs, and tricyclic antidepressants. Although opioids can also contribute to falls and fractures, Tramadol has a stronger association than most other opioids. Transdermal Buprenorphine may be the safest alternative and does not worsen renal insufficiency, which is common in older adults.[18] 

Antipsychotics: Second-generation antipsychotics (primarily risperidone, olanzapine, quetiapine, and aripiprazole) are the mainstay of treatment for agitation and aggression, although, in a systematic review of 16 meta-analyses of randomized, controlled trials, the effect sizes (differences between treatment and placebo) were typically quite small for Risperidone, Olanzapine, and Aripiprazole, ranging between 0.15 to 0.30 in most studies, and Quetiapine generally did not differ from placebo. Adverse effects, including extrapyramidal symptoms, cerebrovascular events, somnolence, urinary tract symptoms, and death, were higher in the antipsychotic group, and worsening confusion was common with Quetiapine and Olanzapine.[19] In the United States, the Food and Drug Administration (FDA) has issued a black box warning about the increased risk for death among elderly patients with dementia who receive treatment with antipsychotics for BPSD (3.5% vs. 2.3%, mainly due to cerebrovascular disease and infections). For this reason, antipsychotic medications should only be an option when non-pharmacological interventions and pharmacological interventions, such as pain control and selective serotonin reuptake inhibitors (SSRIs), have been ineffective or if the patient is a harm to themselves or others. 

Starting maximum doses of antipsychotics for BPSD are as follows: Aripiprazole 2 mg daily and 15 mg daily, respectively; Olanzapine 2.5 mg daily and 10 mg daily; Quetiapine 12.5 mg twice daily and 100 mg twice daily; and Risperidone 0.25 mg twice daily and 1 mg twice daily. Doses can be increased in small increments every 2 weeks after insufficient improvement, based on prospective ratings from caregivers. Due to their potential to worsen motor symptoms, clinicians should avoid using antipsychotics other than Quetiapine, Pimavanserin, and Clozapine in Lewy body dementia and dementia associated with Parkinson disease. Clozapine requires special monitoring and reporting when prescribed. In the United States, Pimavanserin is approved by the Food and Drug Association for the treatment of psychosis related to Parkinson disease. However, it carries the same black box warning as other antipsychotics.[20] The starting and target dose of pimvanserine is the same (34 mg). Like other antipsychotics, it prolongs the QT interval and carries a black box warning about the increased risk of death in geriatric patients with dementia.

Patients receiving antipsychotic medications require monitoring for adverse motor effects, and periodic (every 3 to 6 months) attempts to taper and discontinue the medication are necessary. Although the quality of evidence is low, antipsychotic discontinuation does not result in the worsening of BPSD, as evidenced by one longitudinal study in which about 80% of patients on long-term antipsychotics were successfully discontinued without increased BPSD or use of as-needed medication.[21] Discontinuation may be less successful for patients who have had severe symptoms. 

Selective serotonin reuptake inhibitors (SSRIs): Due to the adverse effects associated with antipsychotics, other medications have undergone research for the treatment of agitation and aggression. A 2011 meta-analysis demonstrated that the SSRI antidepressants Citalopram and Sertraline were associated with improvement in these symptoms, with a rate of adverse effects similar to placebo, although Trazodone was ineffective.[22] A subsequent multicenter randomized controlled trial of Citalopram 30 mg daily versus placebo showed a number needed to treat for moderate to marked overall benefit in BPSD of 7. Still, no difference in agitation scores was seen, and patients had an average increase in corrected QT interval of 18 ms.[23] Antidepressant dosing strategies used in the studies were the same as for depression, and researchers observed common SSRI adverse effects such as nausea and hyponatremia. It is wise to heed the geropsychiatry maxim "start low, go slow, but go as high as you need to go" when treating mild to moderate BPSD with SSRIs because too-rapid titration can worsen agitation. Citalopram should be started at 10 mg daily and Sertraline at 25 mg daily. Target symptoms and their baseline frequency or severity should undergo an assessment before starting the medication, and patients should be followed for 2 to 3 weeks for response and tolerability. If no benefit exists but also no adverse effects, Citalopram dosing should increase to 20 mg and Sertraline to 50 mg. Sertraline may be further increased to a maximum dose of 200 mg daily. The maximum recommended dose of Citalopram is 20 mg daily due to QTc prolongation at higher doses. 

Other pharmacotherapies: The combination of Dextromethorphan and Quinidine, which has approval in the U.S. and Europe for the pseudobulbar effect, was studied in a single randomized trial, with modest benefit for agitation but significant adverse effects, especially falls.[24] Prazosin (average dose of about 6 mg daily) was beneficial for BPSD without adverse effects on blood pressure in a study with 22 participants.[25] Medications that have no clinically meaningful efficacy for agitation or aggression include Cholinesterase inhibitors, Memantine, Valproate, and benzodiazepines.[26][27][28][29][30] An exception to the negative findings regarding cholinesterase inhibitors in the dementia population as a whole is the possible benefit for patients with Lewy body dementia and dementia associated with Parkinson disease, in which a small effect size of 0.2 was found, albeit at the cost of an increase in motor symptoms.[31] Both Valproate and benzodiazepines have correlated with accelerating cognitive decline in patients with dementia.[29][32] Haloperidol is ineffective for BPSD in general but can be useful for aggression.[33] Cannabinoids (Dronabinol, purified delta-9-tetrahydrocannabinol, and Nabilone) have been evaluated in a systematic review, in which the best randomized controlled trial did not support benefit for a reduction in either symptoms or caregiver burden. However, differences in adverse events were minimal.[34] Among other complementary and alternative therapies, only ginkgo at a dose of 240 mg/d has shown consistent benefit for BPSD in randomized, controlled trials, and these studies were of low to moderate quality.[35]

Pharmacologic Interventions for Depression and Apathy

While depression and apathy are the most common BPSD, fewer studies have examined the outcomes of pharmacotherapy. 

Depression: A meta-analysis of 10 studies conducted on the effectiveness of various antidepressants for treating depression in dementia patients showed no significant difference between the group of antidepressants and the placebo on the primary outcome measure, which was the scores on depression rating scales. However, some evidence showed that SSRI antidepressants were more effective than other antidepressants in terms of the number of responders and remitters. The quality of this evidence was lower. Patients receiving antidepressants had higher rates of adverse events and study dropouts.[36] In elderly patients without dementia, a greater response rate to a combination of Citalopram (average dose 34 mg daily) and Methylphenidate (average dose 16 mg daily) was evidenced than to either medication alone, without an increase in adverse effects, but whether the combination would be effective in patients with dementia is unknown. The benefits of Citalopram doses below the currently recommended maximum of 20 mg daily cannot be determined from this study.[37][37] SSRIs are the antidepressant treatment of choice, with Citalopram and Sertraline favored due to fewer drug-drug interactions than Paroxetine or Fluoxetine, which inhibit cytochrome p450 enzymes.

Apathy: Methylphenidate may improve apathy, cognition, and function, with minimal risk for adverse effects, but studies of cholinesterase inhibitors, Memantine, and antidepressants have not demonstrated a benefit for apathy.[38] In the ADMET trial of Methylphenidate, patients did not meet exclusion criteria if they had cardiovascular conditions but were excluded if they had agitation at baseline. No differences from placebo are evident on any cardiac outcomes, but patients receiving methylphenidate did have greater weight loss. Two methylphenidate patients developed hallucinations or delusions versus none on placebo (not statistically significant).[39] The response to methylphenidate usually occurs within several days. Hence, a good dosing strategy is to begin the immediate-release formulation at 2.5 mg or 5 mg twice daily (morning and early afternoon) and titrate up by 2.5 mg or 5 mg weekly.

General Approach to Pharmacotherapy for BPSD

Given the limited overall benefits of pharmacotherapy, a systematic approach to implementing and evaluating BPSD is critical. Except for urgent safety situations, an established, clear baseline is necessary regarding the frequency and severity of target behaviors. Medications should be given an adequate trial of at least 4 weeks at the maximum recommended dose before concluding they are ineffective. To avoid prematurely abandoning an effective strategy, educating and supporting caregivers is a vital component of this process. Caregivers should understand that change is often so gradual that it may not be noticeable until comparing recent behavior diaries to those from 3 to 4 weeks prior. If an intervention (especially a medication) is ineffective after an adequate trial, it should be discontinued, and the lack of benefit should be documented.

For agitated behaviors, when uncomfortable symptoms have been treated, environmental triggers removed, and non-pharmacological interventions implemented, pharmacotherapy should start with Citalopram or Sertraline. If this is ineffective, the next step would be adding Risperidone or Aripiprazole unless the patient has Lewy body dementia or Parkinson disease. For these cases, the clinician can add an acetylcholinesterase inhibitor if the patient is not already receiving one. Suppose they are already prescribed an acetylcholinesterase inhibitor; Pimavanserin or Quetiapine are options.

Despite the lack of high-quality evidence for effectiveness, many clinicians will trial Quetiapine in patients with Lewy body dementia or Parkinson disease. A standard error with Quetiapine is inadequate dosing; doses up to 200 mg/d are useful in patients with Parkinson disease without any adverse motor effects. Trials of antipsychotic tapering should take place every 3 to 6 months (sooner if adverse effects emerge). If an antipsychotic is insufficient, an alternative antipsychotic can be tried using a cross-titration, but Olanzapine should generally be avoided due to its anticholinergic effects and lower benefit overall.

Finally, Prazosin or Dextromethorphan-Quinidine are potential therapies. At each step, re-evaluation and attention to environmental factors and non-pharmacological interventions are necessary. Severe agitation or aggressive symptoms usually require immediate initiation of antipsychotic therapy, but this should not obviate the need to implement additional interventions or attempt discontinuation when the patient stabilizes. For depression, pharmacotherapy should begin with Citalopram or Sertraline, with consideration of adding Methylphenidate if there is a limited response after an adequate trial of the antidepressant. If symptoms do not respond, discontinuation of the medication is recommended. 

Treatment-Refractory Patients 

Neurostimulation therapies may have a role in refractory patients. While randomized, controlled trials have not found any benefit from transcranial direct current stimulation, repetitive transcranial magnetic stimulation was beneficial in most studies, with minimal adverse effects.[40] Electroconvulsive therapy is highly effective for both depression and aggression in patients with dementia.[41] The availability of these therapies is a limiting factor.

Differential Diagnosis

The differential diagnosis for BPSD includes:

• Delirium
• Schizophrenia
• Bipolar disorder
• Major depressive disorder
• Post-traumatic stress disorder
• Central nervous system (CNS) neoplasms

Delirium demonstrates acute onset, fluctuating course, and the presence of an underlying medical condition, medication or psychoactive substance, or medication withdrawal. A change in attention characterizes delirium, often involving changes in behavior and orientation. Patients with BPSD can also have superimposed delirium as a cause for an abrupt worsening of their usual symptoms. History is the key to differentiating BPSD from delirium. In delirium, the onset of symptoms occurs over days to 1 to 2 weeks, while in BPSD, symptoms gradually worsen over several weeks to months. Patients with delirium frequently have changes in the level of consciousness, such as periods of somnolence or extended periods of wakefulness, which are typically less prominent in BPSD.

Visual hallucinations may be prominent in delirium, whereas delusions are more common in patients with BPSD. It can be challenging to distinguish Lewy body dementia from delirium since patients with Lewy body may have visual hallucinations and fluctuations in the level of consciousness. Still, these symptoms have a more gradual onset than in patients with delirium. Patients with suspected delirium should have a thorough medical evaluation, beginning with a history and physical and followed by targeted laboratory testing and imaging based on these findings; typically, a comprehensive metabolic panel, CBC, urinalysis, cardiac enzymes, chest X-ray, and toxicology screens are performed routinely, with neuroimaging, lumbar puncture, blood gases, and EEG reserved for select cases. Unlike BPSD, delirium-related symptoms will resolve, albeit sometimes gradually, once the underlying cause is corrected. Patients who have pain, urinary retention, constipation, or other causes of discomfort cannot communicate their experience and may become agitated. When the cause is corrected, the behavioral disturbances improve. 

Presentations of psychiatric conditions, such as schizophrenia, bipolar disorder, major depressive disorder, and post-traumatic stress disorder, may be quite similar to BPSD. Patients will have a history of these disorders before the onset of their dementia. In the case of psychotic or mood disorders, the presentation is generally episodic rather than continuous. 

Patients with primary CNS neoplasms have a high frequency of behavioral and psychological disturbance, most commonly apathy, anger, and disinhibition. Compared to BPSD, the emotional and behavioral symptoms that occur with CNS neoplasms are more prominent than the cognitive deficits that also occur in patients with brain tumors, and usually, other neurological findings are present. All patients with new BPSD should have a thorough neurological evaluation. Neuroimaging may be necessary, especially in patients with frontotemporal dementia, who present with behavioral disturbances rather than memory impairment.

Prognosis

Dementia is associated with significant decreases in life expectancy compared to age-matched controls, with a median survival from diagnosis ranging from 4.5 years for men with Lewy body or Parkinsonian dementia to 12 years for women with Alzheimer disease. BPSD correlates with more rapid progression of dementia and earlier mortality; whether the treatment has any impact on these variables is unknown.[42]

Complications

BPSD substantially contributes to the overall burden of dementia on patients, caregivers, and society. They predict more rapid cognitive decline and earlier mortality. They are associated with increased hospital length of stay, hospital complications, earlier nursing home placement, and increased rates of psychiatric and cardiovascular disorders in family caregivers.[43] Studies have not explicitly reported injuries to patients and caregivers as a result of BPSD, but agitation and aggression would presumably increase the risk. Whether the treatment has any impact on these variables is unknown; interventions that involve training and supporting family caregivers have been found to reduce or delay nursing home placement in patients with dementia.

Deterrence and Patient Education

No studies specifically examine the prevention of BPSD, although some strategies have been shown to reduce the risk of cognitive decline and the development of dementia. Both a dietary intervention combining a Mediterranean diet with the Dietary Approach to Systolic Hypertension (DASH) and pharmacological treatment of hypertension results in a decreased risk for incident dementia, and physical exercise improves cognitive function in patients with existing dementia. Although depression is associated with an increased risk of developing dementia, no consistent evidence indicates that treating it reduces this risk, nor is there any evidence to support cognitive training exercises as a strategy for prevention.[44]

Enhancing Healthcare Team Outcomes

Effective management of BPSD requires a coordinated interprofessional healthcare team that partners with the patient's home caregiver.[43] 

• Nurses and nursing assistants are on the front lines of identifying, quantifying, and monitoring BPSD in hospitals and long-term care facilities. They are usually the first to notice changes in the environment, medications, and physical symptoms. In addition to delivering direct nursing care, home health nurses provide education and guidance to family caregivers. 
• Physical, occupational, and recreational therapists can aid in identifying and removing sources of danger, assist with family caregiver education, and provide non-pharmacological interventions such as busy quilts (or other distracting activities) and weighted blankets. 
• Social workers can support family caregivers and connect them with resources such as caregiver education, respite, and permanent placement. 
• Clinical psychologists can create behavioral plans integrating non-pharmacological interventions with measures to avoid inadvertently reinforcing undesirable behaviors.
• Pharmacists can assist in identifying medications or drug interactions that may contribute to BPSD, as well as checking for drug interactions and verifying dosing regimens.
• Physicians, nurse practitioners, and physician assistants perform medical evaluations, initiate and monitor pharmacotherapy, and oversee the interprofessional treatment plan.

All team members are responsible for maintaining clear communication with other team members, informing everyone regarding any concerns or new developments, and addressing safety risks. For in-home settings, a log that contains caregiver ratings of symptoms, medications, medication schedules, and instructions given by each discipline is beneficial. Open collaboration and communication among interprofessional healthcare team members will improve the effectiveness of BPSD management and result in better patient outcomes.