Management of Neuropsychiatric Symptoms in Neurocognitive Disorders

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).

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.