Management of Neuropsychiatric Symptoms in Neurocognitive Disorders
Abstract
Dementias, renamed neurocognitive disorders (NCDs) in the DSM-5, are defined by acquired decline in cognitive and functional abilities. DSM-5 now also includes mild NCD, which incorporates the previous diagnosis of mild cognitive impairment. DSM-5 recognizes the following etiologies for NCDs: NCD due to Alzheimer’s disease, vascular NCD, NCD with Lewy bodies, frontotemporal NCD, substance-/medication-induced NCD, NCD due to traumatic brain injury, NCD due to Huntington’s disease, NCD due to HIV infection, NCD due to prion disease, and NCD due to other medical conditions. In this review, the authors discuss a wide variety of interventions that have been studied for the treatment and management of neuropsychiatric symptoms of patients with NCDs. In addition to nonpharmacological interventions, several classes of medications—including antipsychotics, antidepressants, anticonvulsants, and cholinesterase inhibitors—have been studied for this indication.
General Overview of Neuropsychiatric Symptoms (NPSs) in Neurocognitive Disorders (NCDs)
Definition
The clinical symptoms of NCDs fall into two categories: cognitive and neuropsychiatric. Cognitive symptoms include impairments in memory, language, orientation, recognition, and executive functions. The other symptoms of NCDs are called “neuropsychiatric symptoms” (NPSs). Although NCD is defined by the presence of cognitive symptoms, NPSs are common, are distressing for patients and their caregivers (1–3), and predict shorter time to placement into long-term facilities (4, 5). In addition, NPSs are associated with, and may predict, more rapid functional decline and mortality risk (5, 6). Behavioral symptoms also significantly increase health care costs for patients with NCDs (7, 8). Therefore, prevention, diagnosis, and treatment of NPSs are crucial in the care of patients with NCDs.
The most common of the NPSs include apathy, agitation, psychosis (delusions and hallucinations), depression, and anxiety (9–11). Patients may also experience aggression, disinhibition, sleep disturbances, appetite changes, aberrant motor activity (fidgeting and pacing), repetitive vocalizations, wandering, restlessness, and refusal of care (3–5). Agitation may include irritability, aggressive behaviors, emotional distress, excessive psychomotor activity, wandering, pacing, disinhibition, vocally disruptive behaviors, and resistance to care (12). The relationship between apathy and depression in NCDs is complex. Apathy is defined as abnormality of motivation, manifesting with slowness of motor, thinking, and affective behaviors, without the presence of depressed mood or the neurovegetative symptoms or the negative cognition bias of depression.
DSM-5 codes for the presence of NPSs, among patients with NCDs, by using the general descriptor “with behavioral disturbances” (1). However, most psychiatrists specializing in geriatrics try to further dissect these NPSs to specific disorders—such as anxiety, depression, or psychosis—and plan treatment accordingly. Except for depression and psychosis in dementia, other diagnostic categories are not well elucidated. Other symptoms in NCDs—such as apathy, aberrant motor behaviors, and agitation—may not easily fit a diagnosis of mood, anxiety, or psychotic disorder. To date, there is no consensus on the appropriate treatment for NPSs among patients with NCDs. The goal of this review article is to summarize what is known to date about the assessment and management of NPSs in NCDs, with a focus on neurodegeneration and NCD due to vascular disease (vaNCD). In this review, we have chosen to highlight the evidence for use of the different medication classes in NPSs of NCDs rather than approaching the topic from treatment of the specific symptom.
Epidemiology
It is estimated that up to 90% of patients with NCDs experience NPSs at some point in the course of the illness (13, 14). The frequency of different clinical manifestations of NPSs appears to vary by the etiology of NCDs (Table 1).
| Symptom | mNCD (%)b | AD (%)c | LBD (%)d | vaNCD (%)d | bvFTD (%)e |
|---|---|---|---|---|---|
| Anxiety | 10.3–14.1 | 25.4–46.0 | 46.0–64.0 | 28.6–42.0 | 45.0–55.0 |
| Apathy | 18.1–18.5 | 41.6–57.0 | 60.0–73.0 | 55.0–66.0 | 75.0–95.0 |
| Depression | 20.0–29.0 | 36.7–46.7 | 38.0–40.3 | 35.7–43.5 | 40.0–42.0 |
| Delusions | 3.4–4.7 | 19.4–31.0 | 27.0–40.0 | 14.3–27.0 | 5.0–20.0 |
| Hallucinations | 0.6–2.5 | 9.1–24.0 | 18.0–55.0 | 3.6–14.0 | 0.0–5.0 |
| Agitation | 9.1–14.7 | 31.1–47.0 | 47.0–48.0 | 21.4–52.0 | 50.0–60.0 |
a
Studies of prevalence of neuropsychiatric disturbances in NCDs looked at different populations (community vs. referral centers), diagnostic criteria used, stage of the dementia, and length of observation. This table is meant to show rough estimates; actual reported estimates vary more widely. mNCD, mild NCD; AD, NCD due to Alzheimer’s disease; LBD, NCD due to Lewy body disease; vaNCD, NCD due to vascular disease; bvFTD, NCD due to behavioral variant frontotemporal degeneration.
Some NPSs of NCDs may fluctuate in frequency and severity or be persistent in course (20, 21). Some studies suggest that affective symptoms tend to decrease in severity but that apathy and agitation become more prevalent with progression of NCDs (20, 22). NPSs—such as delusions, hallucinations, agitation, anxiety, apathy, disinhibition, irritability, and aberrant motor behavior—tend to be more severe with disease progression (22, 23).
Pathogenesis
The correlation between the cognitive symptoms and NPSs of NCDs is complex. Mega et al. (24) compared these symptoms in a group of patients with Alzheimer’s disease (AD) and a healthy control group and found that having AD significantly increases the risk of having any of the aforementioned symptoms.
Some studies suggest that NPSs are universal consequences of NCDs, not specific to the etiology of NCDs (25, 26), whereas others have found correlations between particular symptoms and subtypes of NCDs (27, 28). For example, vaNCD and AD have similar NPS profiles, but patients with vaNCD are more likely to experience depression and anxiety (28), whereas those with AD may be more likely to exhibit agitation and psychotic symptoms (27).
The NPSs of NCDs overlap clinically with those of diseases classified primarily as psychiatric, although disease course, prognosis, treatment approach, and outcome often differ. There is growing evidence that not only the clinical manifestations but also the neuroanatomical bases of symptoms common to NPSs of NCDs and primary psychiatric disorders are shared. This finding has led some to propose that NPSs can be used as models to study the neuroanatomic changes of primary psychiatric disorders (29). For example, delusions in schizophrenia and NCDs both correlate with frontostriatal and temporal network dysfunction (30–32). Volumetric and functional studies of the brains of individuals with auditory and visual hallucinations, whether diagnosed as having schizophrenia or NCD, consistently associate these symptoms with alterations of function in relevant sensory and association regions (32–34). Apathy symptoms, seen in primary psychotic and mood disorders and in NCDs, have been shown to involve the anterior cingulate gyrus, basal ganglia, and other frontal regions regardless of the syndromal diagnosis (31). Anxiety and depressive symptoms in NCDs and primary psychiatric disorders also share similar neural substrates (31). Finally, failure of theory of mind (ability to understand other people’s desire, intention, emotional state, etc.), lack of empathy, and poor impulse control seen in behavioral variant frontotemporal degeneration shares similar neural networks with autistic spectrum disorders (35).
The neuropathological basis of depression appears to differ for various NCDs. For example, in a comparison between NPSs in vaNCD and AD, Ballard et al. (36) showed that depression and anxiety are more common in vaNCD than in AD. Moreover, the severity of depression and anxiety is highly correlated with the degree of cognitive decline in vaNCD, whereas such a correlation is not apparent in AD (36). As a possible explanation, they suggested that anxiety and depression may be more related to the location and extent of pathology in vaNCD, whereas in AD, psychosocial factors may be more important (4). Apart from psychosocial factors, a disruption in the serotonergic pathways, which occurs in AD, is implicated in pathogenesis of psychosis and depression in that patient population (37). Lyketsos et al. (16) suggested that a loss of noradrenergic cells in the locus ceruleus or a decrease in dorsal raphe serotonergic nuclei due to AD could also contribute to pathogenesis of depressive symptoms. More research is needed on the possible pathology and connection between NCDs and depression.
Diagnostic Considerations
When evaluating patients with possible NPSs of NCDs, it is important to consider broad differential diagnosis. Environmental changes—such as noise, a new caregiver, and interpersonal conflict—can lead to distress for patients with NCDs. Patients with NCDs are at increased risk of delirium, which can lead to changes in behavior and cognition. Hence, medications, infections, and toxic-metabolic causes of delirium need to be considered as causes of NPSs. In addition, pain, constipation, urinary retention, as well as visual and auditory impairment can contribute to behavioral changes of patients with NCDs. Although there are no widely accepted evidence-based guidelines, careful history and physical examination followed by laboratory testing and imaging as guided by the clinical examination should be pursued to rule out reversible causes of behavior changes. Dangerousness and risk of harm to self and others should be carefully assessed. The type, frequency, severity, pattern, and timing of symptoms should be noted.
Treatment of NPSs of NCDs
Nonpharmacological Treatment Approaches
Nonpharmacological treatment approaches can be effective because they address the underlying causes of the NPSs that are most problematic to the patient and caregiver (38). They also have little risk compared with pharmacological treatment (38). The goals of nonpharmacological treatments include preventing, managing, reducing, and even eliminating NPSs, therefore improving quality of life for the patient and caregivers (38). Nonpharmacological treatment includes psychoeducation—to identify the root cause(s) of specific behavior(s)—refocusing the patient with social interaction, initiating enjoyable activities, and eliminating conflict. Studies also show that caregiver support, education, training, and skill development—to effectively problem solve and communicate—can be beneficial (38, 39).
In addition, environmental adjustments—such as optimizing noise level and light, reducing clutter, and heightening orientation cues—can significantly reduce agitation of patients with NPSs (38). Other strategies include implementing structure and routines, engaging in physical exercise, and utilizing adult day services, all of which have alleviated patient symptoms and caregiver stress (38, 40). Many studies have investigated music therapy, aromatherapy, pet therapy, bright light therapy, reminiscence therapy, and cognitive-behavioral therapy to manage NPSs (41). Ballard et al. (41) recommend nonpharmacological therapies for agitation in AD. The authors suggested that pharmacological agents should only be sought after attempting nonpharmacological treatment (41).
Despite the studies pointing to possible efficacy of various nonpharmacologic interventions, clear and convincing evidence is still lacking (42, 43). Meta-analysis of studies looking at efficacy of nonpharmacologic interventions for NPSs in NCDs did not find convincing evidence to recommend routine use of these interventions (42, 43). Despite lack of evidence of efficacy, and given the low risk of these interventions, it is reasonable to try using the various strategies as initial management of NPSs in nonemergent situations.
Pharmacologic Treatment Approaches
Cognitive enhancers.
In addition to their cognitive and functional benefit, there is evidence to suggest that acetyl cholinesterase inhibitors have shown some efficacy for NPSs in NCDs (44). The benefit of cholinesterase inhibitors on the NPSs of dementia has been demonstrated among patients with AD, vaNCD, and Lewy body disease (44–47). Finkel (45) reported that rivastigmine may be a well-tolerated treatment option for improving or preventing psychotic and nonpsychotic symptoms (such as apathy and agitation) associated with AD. The results from other studies showed that beneficial effects tend to be modest at best and, at times, lacking (48). One study found no clear benefit from donepezil when compared with placebo on measures of NPSs in nursing home patients with AD (49). Two studies evaluating rivastigmine among patients with AD who were institutionalized found no benefit for rivastigmine when compared with placebo or the second-generation antipsychotics (SGAs) quetiapine (50) or risperidone in acute agitation (51).
Some studies also have suggested that memantine may decrease emergent agitation of patients with AD. Memantine may also be effective for agitation and psychosis, and it is generally well-tolerated. Wilcock et al. (52) conducted a pooled analysis of three large six-month randomized trials with patients who had moderate to severe AD. The study found that memantine is well-tolerated, is effective at managing NPSs, and improves general cognition and function (52).
In summary, cognitive enhancers may have the additional benefit of preventing and reducing NPSs of patients with NCDs. Careful monitoring for side effects—such as gastrointestinal, bradycardia, and syncope—with cholinesterase inhibitors is important.
Antidepressants.
A large body of recent literature has examined the use of antidepressants for managing NPSs in NCDs. Selective serotonin reuptake inhibitors (SSRIs) in particular have been studied for depression, apathy, agitation, and psychosis in dementia. In what follows, we first review the studies that found benefits in antidepressants for management of NPSs in NCDs. Afterward, we review the studies that did not find such benefits.
Many studies have found that antidepressants, in particular citalopram and sertraline, are effective in treating agitation, and perhaps psychosis, of patients with AD. A systemic review by Sink et al. (53) analyzed the double-blind, placebo-controlled trials (randomized controlled trials [RCTs]) published from 1966 to 2004, and it showed that among five studies examining antidepressants (sertraline, fluoxetine, citalopram, and trazodone), only citalopram was found to be effective in treating NPSs. Sertraline was also found to have significant benefit for treating depression in AD but not other symptoms (53). Thompson et al. (54) completed a meta-analysis of published, double-blind, placebo-controlled RTCs of antidepressants for treating depression in AD. They found a statistically significant effect in the proportion of patients who experienced a reduction and remission of depressive symptoms in favor of antidepressant therapy compared with placebo. The number needed to treat was five for both reduction in depressive symptoms and remission of depressive symptoms (53). A more recent literature review found that SSRIs and trazodone are beneficial NPSs in NCDs, and it suggested that antidepressants are a safer option than antipsychotics for treating NPSs in NCDs (37).
Seitz et al. (55) performed a review of RCTs of antidepressants (SSRIs, tricyclic antidepressants, trazodone, and other antidepressants), compared with either placebo or comparator medications, for efficacy for and safety of patients (total of 692 patients) with NCDs experiencing agitation and psychosis. The authors concluded that sertraline and citalopram were associated with a reduction in symptoms of agitation when compared with placebo in two studies. Both SSRIs and trazodone appear to be tolerated reasonably well when compared with placebo, first-generation antipsychotics and SGAs (55). The recent Citalopram for Agitation in Alzheimer Disease (CitAD) study was a randomized, placebo-controlled, double-blind study involving 186 patients with probable AD and clinically significant agitation from eight academic centers in the United States and Canada (56). The patients received psychosocial intervention—in addition to either 10 mg/day of citalopram (with titration to 30 mg/day over three weeks; N=94) or placebo (N=92)—for nine weeks. Participants who received citalopram showed significant improvement on the Cohen-Mansfield Agitation Inventory (57), total Neuropsychiatric Inventory (58), and caregiver distress scores but not on the Neuropsychiatric Inventory Agitation subscale, activities of daily living, or in less use of rescue lorazepam. Worsening of cognition and QT interval prolongation were seen in the group receiving citalopram, although the cognitive decline was mild and clinically nonsignificant (1 point on the Mini-Mental State Exam) (56, 59).
Despite these studies showing the benefits of using SSRIs in managing NPSs in NCDs, there are other studies that have questioned their efficacy for management of depression in dementia. A multicenter, placebo-controlled RCT of sertraline conducted with patients with AD and depression performed by Rosenberg et al. (60) found increased side effect but no statistically significant benefit in the patients treated with sertraline compared with the group receiving placebo. Sepehry et al. (61) focused specifically on comorbid depression of patients with AD in a meta-analysis of the efficacy of SSRIs, and they concluded that SSRIs do not seem to be efficacious in treating symptoms of depression in AD, and they also do not have any cognitive benefit. A multicenter, parallel-group, double-blind, placebo-controlled RCT of sertraline (target dose of 150 mg/day) and mirtazapine (target dose of 45 mg/day) for the treatment of depression in 326 patients with AD, with up to 39-week follow up, found that these antidepressants were ineffective at treating depression in AD; however, the study found increased adverse events in the patients treated with antidepressants compared with patients treated with placebos (62).
In summary, there is evidence to suggest that SSRIs can be of benefit in managing depression and agitation in NCDs. Specifically, sertraline and citalopram appear to be tolerated with few adverse events. More recent studies have raised the need to reexamine the benefit of antidepressants for NPSs in NCDs. For improved evidence-based practice, more research is needed to better understand the effects of antidepressants and other medications for NPSs of patients with NCDs, looking at short- and long-term efficacy as well as the role of antidepressants in other etiologies of NCDs besides AD.
Antiepileptic drugs.
Anticonvulsants, such as valproate and carbamazepine, have been studied for management of NPSs, especially agitation, in NCDs (53, 63, 64). A systemic review by Lonergan and Luxenberg (65) analyzed five placebo-controlled RCTs on the effect of valproate therapy on agitation of patients with NCDs. They concluded that valproate preparations are ineffective in treating agitation of patients with NCDs and that valproate therapy is associated with an unacceptable rate of adverse effects. Although small trials showed modest effect in management of agitation, there is currently insufficient evidence of benefit to recommend the use of carbamazepine for the treatment of NPSs, especially because of the black box warning for hematologic toxicity and the potential drug-drug interactions between carbamazepine and other drugs commonly prescribed to older adults (53, 66, 67). There is only limited published evidence to support routine use of gabapentin (68–71).
Antipsychotics.
The antipsychotic medications are not only the most widely prescribed class of drugs for the treatment of NPSs in NCDs but also the most controversial given issues of toxicity, increased mortality, cerebrovascular adverse effects, and cost. Until the mid-1990s, first-generation antipsychotics were the first-line pharmacological treatment for managing agitation and psychosis in dementia (72). However, these medications have limited efficacy, at best, and carry increased risk of causing significant extrapyramidal side effects (EPSs), including Parkinsonism, tardive dyskinesia, dystonia, and heart-corrected QT interval prolongation. Today, atypical or SGAs are the most widely prescribed medication because they have fewer side effects and greater tolerability in the older adult population (73). SGA side effects have prompted warnings from the Food and Drug Administration for increasing risk of mortality, stroke, and other cerebrovascular risks. Overall, SGAs are preferable to first-generation antipsychotics because of decreased risk of EPSs and possibly slightly lower mortality rate, but they are still not ideal in their risk-benefit ratio (74).
The recently published American Psychiatric Association practice guidelines on the use of antipsychotics to treat agitation and psychosis of patients with dementia summarizes the evidence base and puts forth recommendations for clinical use of antipsychotics for psychosis and agitation in dementia (75). The guidelines recommend against use of haloperidol as a first-line treatment for patients with dementia without evidence of delirium in nonemergency situations. The guidelines also suggest use of quantitative measures to develop a comprehensive treatment plan with individualized nonpharmacologic and pharmacologic interventions and to monitor a response to treatment (75).
Kales et al. (74) performed a retrospective cohort study on the safety of antipsychotics among 33,604 patients older than 65 years of age with NCDs with NPSs. The study revealed that although SGAs may improve some NPSs, their use is associated with significantly greater mortality, confirming the high level of risk with this treatment. Haloperidol was associated with the highest mortality risk, followed by the SGAs olanzapine and risperidone, valproic acid, and the SGA quetiapine (74).
Several placebo-controlled RCTs show that SGAs, particularly olanzapine and risperidone, have a modest but significant advantage over placebo in the short-term treatment of agitation and psychosis in dementia (about 6–12 weeks) (41, 76). The Clinical Antipsychotic Trials of Intervention Effectiveness—Alzheimer’s Disease study examined the safety and effectiveness of SGAs on associated psychosis and agitation in AD (77). In this large, double-blind RCT, 421 outpatients either received olanzapine, quetiapine, risperidone, or placebo for 36 weeks. Although the trial failed to demonstrate differences in the primary outcome of effectiveness as measured by the time to discontinuation for any reason (either because of lack of effectiveness or adverse effect) of either medication versus placebo, secondary analyses indicated that olanzapine and risperidone were modestly efficacious in reducing NPSs. However, the medications did not improve cognition, functioning, quality of life, or care needs. Overall, the study concluded that the adverse effects of SGAs outweigh the modest advantages of the medication, although certain individuals who tolerate the medications may benefit from symptom reduction (77).
Sink et al. (53) reviewed 29 double-blind, placebo-controlled RCTs in a meta-analysis. First-generation antipsychotics had little efficacy and many severe side effects (including EPSs and sedation), whereas studies on SGAs, especially risperidone and olanzapine, found modest efficacy. Doses of 5–10 mg/day of olanzapine or 1.0 mg/day of risperidone appear to be at least modestly effective for treating NPSs of patients with AD or vaNCD (53).
Several trials have focused specifically on the efficacy and safety of risperidone. De Deyn et al. (72) analyzed three randomized, placebo-controlled, double-blind trials of patients with dementia treated with risperidone (1.0 mg/day) in a nursing home. The study found that risperidone is effective in treating agitation, psychosis, and aggression independent of NCD etiology, severity, and presence of psychosis. The investigators concluded that although side effects caused some patients to stop the medication, the drug generally had a favorable risk-benefit profile (72). Similarly, Brodaty et al. (78) performed a double-blind, placebo-controlled RCT to investigate efficacy and safety of risperidone in 345 patients with AD, vaNCD, or mixed AD and vascular disease. A low dose of .95 mg/day, over the course of 12 weeks, showed significant improvement in agitation and psychotic symptoms associated with NCDs. The study also found that risperidone did not cause cognitive decline but did come with relatively high cerebrovascular risks (78).
Quetiapine treatment was effective in improving psychotic symptoms and agitation in several uncontrolled studies with patients who had NCDs (76). A double-blind RCT that included 333 participants with NCDs, using Positive and Negative Syndrome Scale—Excitement Component scores (79) as the primary outcome, found that 200 mg/day of quetiapine (but not 100 mg/day) was effective for treating agitation (80). Another RCT with haloperidol, quetiapine, and placebo arms enrolled patients with AD (N=284) and found improvement of psychosis in all three groups, without statistically significant difference (81). A smaller, double-blind RCT (N=46) of patients with AD did not find a statistically significant difference between placebo and quetiapine (median dose of 200 mg/day) (82).
Recent studies have also examined other SGAs. Mintzer et al. (83) conducted a placebo-controlled RCT of aripiprazole treatment of 487 patients with NCDs and psychosis. Aripiprazole, particularly at a 10 mg/day dose, was found to be effective especially for psychosis of patients with AD (83). Similar results were reported by others for aripiprazole treatment of patients with AD (84). However, a double-blind, flexible-dose RCT trial using patients with AD and psychotic symptoms who were institutionalized reported that aripiprazole did not confer specific benefits for the treatment of psychotic symptoms, but psychological and behavioral symptoms—including agitation, anxiety, and depression—were improved with aripiprazole and had a low risk of adverse effects (85). A small RCT (N=129) comparing intramuscular injection of placebo and aripiprazole found that 10 or 15 mg i.m. aripiprazole administered in divided doses was safe and well tolerated for treatment of agitation associated with AD, vascular disease, or mixed dementia in long-term care (86). Clozapine, the antipsychotic medication with the lowest risk of causing EPSs, has been studied among patients with NCDs complicated by Parkinsonian syndromes, including Lewy body dementia. In addition, clozapine can be effective for treatment-resistant agitation of patients with NCDs of multiple etiologies (87, 88). Finally, ziprasidone has demonstrated efficacy in treating four separate inpatient cases of agitation and psychosis in dementia (89).
Given that NPSs in NCDs fluctuate in severity, the optimal length of treatment with antipsychotics or other pharmacologic interventions is unknown (90). Devanand et al. (90) attempted to shed light on this important question by studying risk of relapse after discontinuation of risperidone treatment for patients with AD. In this study, 180 patients with AD and psychosis or agitation-aggression received open-label risperidone for 16 weeks, followed by randomization into three study arms: group 1 continued risperidone for 32 weeks; group 2 continued risperidone for 16 weeks and then switched to placebo for 16 weeks; group 3 switched to placebo for 32 weeks. Among patients with AD complicated by psychosis or agitation who had initially responded to risperidone therapy for 4–8 months, discontinuation of risperidone was associated with an increased risk of relapse (60% and 33% relapse comparing the first and the third groups, respectively, after 16 weeks) (90). This study suggested that discontinuing risperidone in a patient with AD, complicated by psychosis or agitation, who had a sustained response for a period of months must be weighed against the increased risk of relapse and side effects.
Overall, SGAs are widely used and studied medications to treat and manage agitation and psychosis in dementia. There are also differing conclusions and opinions surrounding the risk-benefit profile of SGAs, especially given their substantial side effects. Individualized treatment plans, obtaining informed consent from the patient or health-care-proxy, selecting target symptoms for the interventions, starting medications at low-dose and titrating doses gradually, as well as close monitoring for response and side effect are recommended.
Other Potential Interventions
Studies have shown that benzodiazepines continue to be widely prescribed for patients with NCDs despite limited evidence of efficacy and potential adverse cognitive and other side effects (91). The published evidence to support routine use of oxcarbazepine, topiramate, or lamotrigine is inadequate (92, 93). The use of lithium has limited published evidence (92). A retrospective study reported on the benefits of dronabinol for agitation in patients with NCDs who were acutely hospitalized (94). Hormonal treatments (estrogen, progesterone, antiandrogen treatments) have only limited evidence to recommend their use in routine practice for sexually inappropriate behaviors in NCDs (95). Electroconvulsive therapy has also been reported from some centers for selected patients with NCDs (96–98). Wide varieties of nutraceutical agents have been identified as potential treatments in NCDs, but the evidence to recommend routine use of these agents is far from adequate (99).
Summary
More studies are needed to establish an evidence-based treatment algorithm for the management of NPSs in NCDs. Studies should also further explore long-term efficacy, optimal length of treatment, dosing of pharmacological treatments, and integration of nonpharmacological management strategies.
Given lack of clear evidence and guidelines, we thought it would be helpful to share some of our clinical practice. What follows is meant as a general approach to enrich the discussion, incorporating the evidence presented earlier rather than a firm recommendation. We routinely institute individualized nonpharmacologic interventions as first-line treatment with or without pharmacotherapy for patients with NCDs experiencing NPSs. We initiate treatment with acetylcholinesterase inhibitors and memantine for the potential additional benefit of improving NPSs. For patients with NCDs and mild to moderate agitation, and in absence of immediate dangerousness, a trial of SSRI (e.g., citalopram, sertraline) or trazodone is our first-line treatment. For patients with severe agitation, dangerousness, or requiring hospitalization, we usually start with an antipsychotic medication. The antipsychotic choice depends on multiple factors, including whether Parkinson’s disease or Lewy body disease is suspected. In the absence of Parkinsonism, we tend to use risperidone or olanzapine as a first-line treatment with doses up to 2 mg and 10 mg, respectively, starting at a low dose, with slow dose titration. In general, we avoid using valproate or haloperidol as a first-line treatment for management of NPSs associated with NCDs.
References
1.
Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA, American Psychiatric Publishing, 2013
2.
Karttunen K, Karppi P, Hiltunen A, et al: Neuropsychiatric symptoms and quality of life in patients with very mild and mild Alzheimer’s disease. Int J Geriatr Psychiatry 2011; 26:473–482
3.
Schulz R, O’Brien AT, Bookwala J, et al: Psychiatric and physical morbidity effects of dementia caregiving: prevalence, correlates, and causes. Gerontologist 1995; 35:771–791
4.
Kales HC, Chen P, Blow FC, et al: Rates of clinical depression diagnosis, functional impairment, and nursing home placement in coexisting dementia and depression. Am J Geriatr Psychiatry 2005; 13:441–449
5.
Okura T, Plassman BL, Steffens DC, et al: Neuropsychiatric symptoms and the risk of institutionalization and death: the aging, demographics, and memory study. J Am Geriatr Soc 2011; 59:473–481
6.
Okura T, Plassman BL, Steffens DC, et al: Prevalence of neuropsychiatric symptoms and their association with functional limitations in older adults in the United States: the aging, demographics, and memory study. J Am Geriatr Soc 2010; 58:330–337
7.
Jönsson L, Eriksdotter Jönhagen M, Kilander L, et al: Determinants of costs of care for patients with Alzheimer’s disease. Int J Geriatr Psychiatry 2006; 21:449–459
8.
Beeri MS, Werner P, Davidson M, et al: The cost of behavioral and psychological symptoms of dementia (BPSD) in community dwelling Alzheimer’s disease patients. Int J Geriatr Psychiatry 2002; 17:403–408
9.
Fuh JL, Wang SJ, Cummings JL: Neuropsychiatric profiles in patients with Alzheimer’s disease and vascular dementia. J Neurol Neurosurg Psychiatry 2005; 76:1337–1341
10.
Fernández-Martínez M, Castro J, Molano A, et al: Prevalence of neuropsychiatric symptoms in Alzheimer’s disease and vascular dementia. Curr Alzheimer Res 2008; 5:61–69
11.
Johnson DK, Watts AS, Chapin BA, et al: Neuropsychiatric profiles in dementia. Alzheimer Dis Assoc Disord 2011; 25:326–332
12.
Aalten P, Verhey FR, Boziki M, et al: Neuropsychiatric syndromes in dementia. Results from the European Alzheimer Disease Consortium: part I. Dement Geriatr Cogn Disord 2007; 24:457–463
13.
Tariot PN, Mack JL, Patterson MB, et al: The Behavior Rating Scale for Dementia of the Consortium to Establish a Registry for Alzheimer’s Disease. The Behavioral Pathology Committee of the Consortium to Establish a Registry for Alzheimer’s Disease. Am J Psychiatry 1995; 152:1349–1357
14.
Chiu M-J, Chen TF, Yip PK, et al: Behavioral and psychologic symptoms in different types of dementia. J Formos Med Assoc 2006; 105:556–562
15.
Geda YE, Roberts RO, Knopman DS, et al: Prevalence of neuropsychiatric symptoms in mild cognitive impairment and normal cognitive aging: population-based study. Arch Gen Psychiatry 2008; 65:1193–1198
16.
Lyketsos CG, Lopez O, Jones B, et al: Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 2002; 288:1475–1483
17.
Caputo M, Monastero R, Mariani E, et al: Neuropsychiatric symptoms in 921 elderly subjects with dementia: a comparison between vascular and neurodegenerative types. Acta Psychiatr Scand 2008; 117:455–464
18.
Levy ML, Miller BL, Cummings JL, et al: Alzheimer disease and frontotemporal dementias. Behavioral distinctions. Arch Neurol 1996; 53:687–690
19.
Banks SJ, Weintraub S: Neuropsychiatric symptoms in behavioral variant frontotemporal dementia and primary progressive aphasia. J Geriatr Psychiatry Neurol 2008; 21:133–141
20.
Wetzels RB, Zuidema SU, de Jonghe JF, et al: Course of neuropsychiatric symptoms in residents with dementia in nursing homes over 2-year period. Am J Geriatr Psychiatry 2010; 18:1054–1065
21.
Garre-Olmo J, López-Pousa S, Vilalta-Franch J, et al: Grouping and trajectories of neuropsychiatric symptoms in patients with Alzheimer’s disease. Part II: two-year patient trajectories. J Alzheimers Dis 2010; 22:1169–1180
22.
Selbaek G, Engedal K, Benth JŠ, et al: The course of neuropsychiatric symptoms in nursing-home patients with dementia over a 53-month follow-up period. Int Psychogeriatr 2014; 26:81–91
23.
Brodaty H, Connors MH, Xu J, et al: The course of neuropsychiatric symptoms in dementia: a 3-year longitudinal study. J Am Med Dir Assoc 2015; 16:380–387
24.
Mega MS, Cummings JL, Fiorello T, et al: The spectrum of behavioral changes in Alzheimer’s disease. Neurology 1996; 46:130–135
25.
Echávarri C, Burgmans S, Uylings H, et al: Neuropsychiatric symptoms in Alzheimer’s disease and vascular dementia. J Alzheimers Dis 2013; 33:715–721
26.
Srikanth S, Nagaraja AV, Ratnavalli E: Neuropsychiatric symptoms in dementia-frequency, relationship to dementia severity and comparison in Alzheimer’s disease, vascular dementia and frontotemporal dementia. J Neurol Sci 2005; 236:43–48
27.
D’Onofrio G, Sancarlo D, Panza F, et al: Neuropsychiatric symptoms and functional status in Alzheimer’s disease and vascular dementia patients. Curr Alzheimer Res 2012; 9:759–771
28.
Hsieh CJ, Chang CC, Lin CC: Neuropsychiatric profiles of patients with Alzheimer’s disease and vascular dementia in Taiwan. Int J Geriatr Psychiatry 2009; 24:570–577
29.
Legesse B, Ducharme S, Forester B, et al: Neuropsychiatric symptoms of major neurocognitive disorders as a model for understanding neuroanatomic dysfunction in primary psychiatric disorders. JSM Alzheimer’s Disease and Related Dementia 2014; 2:1011
30.
Sultzer DL, Mahler ME, Mandelkern MA, et al: The relationship between psychiatric symptoms and regional cortical metabolism in Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 1995; 7:476–484
31.
Bruen PD, McGeown WJ, Shanks MF, et al: Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer’s disease. Brain 2008; 131:2455–2463
32.
Epstein J, Stern E, Silbersweig D: Mesolimbic activity associated with psychosis in schizophrenia. Symptom-specific PET studies. Ann N Y Acad Sci 1999; 877:562–574
33.
Imamura T, Ishii K, Hirono N, et al: Visual hallucinations and regional cerebral metabolism in dementia with Lewy bodies (DLB). Neuroreport 1999; 10:1903–1907
34.
Allen P, Modinos G, Hubl D, et al: Neuroimaging auditory hallucinations in schizophrenia: from neuroanatomy to neurochemistry and beyond. Schizophr Bull 2012; 38:695–703
35.
Gregory C, Lough S, Stone V, et al: Theory of mind in patients with frontal variant frontotemporal dementia and Alzheimer’s disease: theoretical and practical implications. Brain 2002; 125:752–764
36.
Ballard C, Neill D, O’Brien J, et al: Anxiety, depression and psychosis in vascular dementia: prevalence and associations. J Affect Disord 2000; 59:97–106
37.
Henry G, Williamson D, Tampi RR: Efficacy and tolerability of antidepressants in the treatment of behavioral and psychological symptoms of dementia, a literature review of evidence. Am J Alzheimers Dis Other Demen 2011; 26:169–183
38.
Gitlin LN, Kales HC, Lyketsos CG: Nonpharmacologic management of behavioral symptoms in dementia. JAMA 2012; 308:2020–2029
39.
Selwood A, Johnston K, Katona C, et al: Systematic review of the effect of psychological interventions on family caregivers of people with dementia. J Affect Disord 2007; 101:75–89
40.
Matura S, Carvalho AF, Alves GS, et al: Physical exercise for the treatment of neuropsychiatric disturbances in Alzheimer’s dementia: possible mechanisms, current evidence and future directions. Curr Alzheimer Res 2016; 13:1112–1123
41.
Ballard CG, Gauthier S, Cummings JL, et al: Management of agitation and aggression associated with Alzheimer disease. Nat Rev Neurol 2009; 5:245–255
42.
Brasure M, Jutkowitz E, Fuchs E, et al: Nonpharmacologic Interventions for Agitation and Aggression in Dementia. Rockville, MD, Agency for Healthcare Research and Quality, 2016
43.
Livingston G, Johnston K, Katona C, et al: Systematic review of psychological approaches to the management of neuropsychiatric symptoms of dementia. Am J Psychiatry 2005; 162:1996–2021
44.
Rodda J, Morgan S, Walker Z: Are cholinesterase inhibitors effective in the management of the behavioral and psychological symptoms of dementia in Alzheimer’s disease? A systematic review of randomized, placebo-controlled trials of donepezil, rivastigmine and galantamine. Int Psychogeriatr 2009; 21:813–824
45.
Finkel SI: Effects of rivastigmine on behavioral and psychological symptoms of dementia in Alzheimer’s disease. Clin Ther 2004; 26:980–990
46.
Birks J, Craig D: Galantamine for vascular cognitive impairment. Cochrane Database of Systematic Reviews 4:CD004746, 2006
47.
Wild R, Pettit T, Burns A: Cholinesterase inhibitors for dementia with Lewy bodies. Cochrane Database of Systematic Reviews 3:CD003672, 2003
48.
Birks J, McGuinness B, Craig D: Rivastigmine for vascular cognitive impairment. Cochrane Database of Systematic Reviews 5:CD004744, 2013
49.
Tariot PN, Cummings JL, Katz IR, et al: A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer’s disease in the nursing home setting. J Am Geriatr Soc 2001; 49:1590–1599
50.
Ballard C, Margallo-Lana M, Juszczak E, et al: Quetiapine and rivastigmine and cognitive decline in Alzheimer’s disease: randomised double blind placebo controlled trial. BMJ 2005; 330:874
51.
Holmes C, Wilkinson D, Dean C, et al: Risperidone and rivastigmine and agitated behaviour in severe Alzheimer’s disease: a randomised double blind placebo controlled study. Int J Geriatr Psychiatry 2007; 22:380–381
52.
Wilcock GK, Ballard CG, Cooper JA, et al: Memantine for agitation/aggression and psychosis in moderately severe to severe Alzheimer’s disease: a pooled analysis of 3 studies. J Clin Psychiatry 2008; 69:341–348
53.
Sink KM, Holden KF, Yaffe K: Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. JAMA 2005; 293:596–608
54.
Thompson S, Herrmann N, Rapoport MJ, et al: Efficacy and safety of antidepressants for treatment of depression in Alzheimer's disease: a meta-analysis. Can J Psychiatry 2007;52:248–255
55.
Seitz DP, Adunuri N, Gruneir A, et al: Antidepressants for agitation and psychosis in dementia. Cochrane Database Syst Rev 2011; 2:CD008191
56.
Porsteinsson AP, Drye LT, Pollock BG, et al: Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA 2014; 311:682–691
57.
Cohen-Mansfield J, Billig N: Agitated behaviors in the elderly: I. A Conceptual review. J Am Geriatr Soc 1986;34:711–721
58.
Cummings JL, Mega M, Gray K, et al: The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44:2308–2314
59.
Folstein MF, Folstein SE, McHugh PR: "Mini-Mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12(3):189–198
60.
Rosenberg PB, Drye LT, Martin BK, et al: Sertraline for the treatment of depression in Alzheimer disease. Am J Geriatr Psychiatry 2010; 18:136–145
61.
Sepehry AA, Lee PE, Hsiung GY, et al: Effect of selective serotonin reuptake inhibitors in Alzheimer’s disease with comorbid depression: a meta-analysis of depression and cognitive outcomes. Drugs Aging 2012; 29:793–806
62.
Banerjee S, Hellier J, Dewey M, et al: Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial. Lancet 2011; 378:403–411
63.
Ballard C: Agitation and psychosis in dementia. Am J Geriatr Psychiatry 2007; 15:913–917
64.
Seitz DP, Gill SS, Herrmann N, et al: Pharmacological treatments for neuropsychiatric symptoms of dementia in long-term care: a systematic review. Int Psychogeriatr 2013; 25:185–203
65.
Lonergan E, Luxenberg J: Valproate preparations for agitation in dementia. Cochrane Database of Systematic Reviews 3:CD003945, 2009
66.
Olin JT, Fox LS, Pawluczyk S, et al: A pilot randomized trial of carbamazepine for behavioral symptoms in treatment-resistant outpatients with Alzheimer disease. Am J Geriatr Psychiatry 2001; 9:400–405
67.
Tariot PN, Erb R, Podgorski CA, et al: Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J Psychiatry 1998; 155:54–61
68.
Kim Y, Wilkins KM, Tampi RR: Use of gabapentin in the treatment of behavioural and psychological symptoms of dementia: a review of the evidence. Drugs Aging 2008; 25:187–196
69.
Roane DM, Feinberg TE, Meckler L, et al: Treatment of dementia-associated agitation with gabapentin. J Neuropsychiatry Clin Neurosci 2000; 12:40–43
70.
Alkhalil C, Tanvir F, Alkhalil B, et al: Treatment of sexual disinhibition in dementia: case reports and review of the literature. Am J Ther 2004; 11:231–235
71.
Cooney C, Murphy S, Tessema H, et al: Use of low-dose gabapentin for aggressive behavior in vascular and mixed vascular/Alzheimer dementia. J Neuropsychiatry Clin Neurosci 2013; 25:120–125
72.
De Deyn PP, Katz IR, Brodaty H, et al: Management of agitation, aggression, and psychosis associated with dementia: a pooled analysis including three randomized, placebo-controlled double-blind trials in nursing home residents treated with risperidone. Clin Neurol Neurosurg 2005; 107:497–508
73.
Aupperle P: Management of aggression, agitation, and psychosis in dementia: focus on atypical antipsychotics. Am J Alzheimers Dis Other Demen 2006; 21:101–108
74.
Kales HC, Kim HM, Zivin K, et al: Risk of mortality among individual antipsychotics in patients with dementia. Am J Psychiatry 2012; 169:71–79
75.
Reus VI, Fochtmann LJ, Eyler AE, 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; 173:543–546
76.
Zaraa AS: Dementia update. Pharmacologic management of agitation and psychosis in older demented patients. Geriatrics 2003; 58:48–50, 52–53
77.
Schneider LS, Tariot PN, Dagerman KS, et al: Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med 2006; 355:1525–1538
78.
Brodaty H, Ames D, Snowdon J, et al: A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia. J Clin Psychiatry 2003; 64:134–143
79.
Kay SR, Fiszbein A, Opler LA: The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13:261–276. Doi 10.1093/schbul/13.2.261
80.
Zhong KX, Tariot PN, Mintzer J, et al: Quetiapine to treat agitation in dementia: a randomized, double-blind, placebo-controlled study. Curr Alzheimer Res 2007; 4:81–93
81.
Tariot PN, Schneider L, Katz IR, et al: Quetiapine treatment of psychosis associated with dementia: a double-blind, randomized, placebo-controlled clinical trial. Am J Geriatr Psychiatry 2006; 14:767–776
82.
Paleacu D, Barak Y, Mirecky I, 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; 23:393–400
83.
Mintzer JE, Tune LE, Breder CD, 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; 15:918–931
84.
De Deyn P, Jeste DV, Swanink R, et al: Aripiprazole for the treatment of psychosis in patients with Alzheimer’s disease: a randomized, placebo-controlled study. J Clin Psychopharmacol 2005; 25:463–467
85.
Streim JE, Porsteinsson AP, Breder CD, 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; 16:537–550
86.
Rappaport SA, Marcus RN, Manos G, et al: A randomized, double-blind, placebo-controlled tolerability study of intramuscular aripiprazole in acutely agitated patients with Alzheimer’s, vascular, or mixed dementia. J Am Med Dir Assoc 2009; 10:21–27
87.
Lee HB, Hanner JA, Yokley JL, et al: Clozapine for treatment-resistant agitation in dementia. J Geriatr Psychiatry Neurol 2007; 20:178–182
88.
Stinton C, McKeith I, Taylor JP, et al: Pharmacological management of Lewy body dementia: a systematic review and meta-analysis. Am J Psychiatry 2015; 172:731–742
89.
Cole SA, Saleem R, Shea WP, et al: Ziprasidone for agitation or psychosis in dementia: four cases. Int J Psychiatry Med 2005; 35:91–98
90.
Devanand DP, Mintzer J, Schultz SK, et al: Relapse risk after discontinuation of risperidone in Alzheimer’s disease. N Engl J Med 2012; 367:1497–1507
91.
Defrancesco M, Marksteiner J, Fleischhacker WW, et al: Use of benzodiazepines in Alzheimer’s disease: a systematic review of literature. Int J Neuropsychopharmacol 2015; 18:pyv055
92.
Yeh YC, Ouyang WC: Mood stabilizers for the treatment of behavioral and psychological symptoms of dementia: an update review. Kaohsiung J Med Sci 2012; 28:185–193
93.
Pinheiro D: Les antiépileptiques thymorégulateurs dans le traitement des symptômes comportementaux et psychologiques de la démence (SCPD)[Anticonvulsant mood stabilizers in the treatment of behavioral and psychological symptoms of dementia (BPSD)]. Encephale 2008; 34:409–415
94.
Woodward MR, Harper DG, Stolyar A, et al: Dronabinol for the treatment of agitation and aggressive behavior in acutely hospitalized severely demented patients with noncognitive behavioral symptoms. Am J Geriatr Psychiatry 2014; 22:415–419
95.
Guay DR: Inappropriate sexual behaviors in cognitively impaired older individuals. Am J Geriatr Pharmacother 2008; 6:269–288
96.
Wilkins KM, Ostroff R, Tampi RR: Efficacy of electroconvulsive therapy in the treatment of nondepressed psychiatric illness in elderly patients: a review of the literature. J Geriatr Psychiatry Neurol 2008; 21:3–11
97.
Ujkaj M, Davidoff DA, Seiner SJ, et al: Safety and efficacy of electroconvulsive therapy for the treatment of agitation and aggression in patients with dementia. Am J Geriatr Psychiatry 2012; 20:61–72
98.
Acharya D, Harper DG, Achtyes ED, et al: Safety and utility of acute electroconvulsive therapy for agitation and aggression in dementia. Int J Geriatr Psychiatry 2015; 30:265–273
99.
Perry E, Howes MJ: Medicinal plants and dementia therapy: herbal hopes for brain aging? CNS Neurosci Ther 2011; 17:683–698
Information & Authors
Information
Published In
History
Published in print: Winter 2017
Published online: 17 January 2017
Keywords
Authors
Competing Interests
Dr. Legesse has received research funding from Assurex Health, AstraZeneca, and Lundbeck. Dr. Forester has served as a consultant for Eli Lilly, INSYS Therapeutics and Sunovion and has received research funding from the Rogers Family Foundation, Assurex Health, Eli Lilly and Biogen. Dr. Babadi reports no financial relationships with commercial interests.
Metrics & Citations
Metrics
Citations
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
For more information or tips please see 'Downloading to a citation manager' in the Help menu.
View Options
View options
PDF/EPUB
View PDF/EPUBGet Access
Login options
Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.
Personal login Institutional Login Open Athens loginNot a subscriber?
PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.
Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).