JAMDA xxx (2015) 1e8
JAMDA journal homepage: www.jamda.com
Original Study
The Course of Neuropsychiatric Symptoms in Dementia: A 3-Year Longitudinal Study Henry Brodaty MD, BS, DSc a, b, *, Michael H. Connors PhD a, b, Jing Xu PhD a, b, Michael Woodward MD, BS c, David Ames MD, BS d, e on behalf of the PRIME study group a
Dementia Collaborative Research Center, School of Psychiatry, University of New South Wales, Sydney, Australia Center for Healthy Brain Aging, School of Psychiatry, University of New South Wales, Sydney, Australia c Austin Hospital, Heidelberg, Australia d National Aging Research Institute, Melbourne, Australia e University of Melbourne Academic Unit for Psychiatry of Old Age, Melbourne, Australia b
a b s t r a c t Keywords: Alzheimer’s disease behavioral and psychological symptoms of dementia dementia longitudinal study neuropsychiatric symptoms Neuropsychiatric Inventory
Objectives: Patients with dementia experience a wide range of neuropsychiatric symptoms. These symptoms often cause considerable distress to patients and caregivers, and often contribute to institutionalization. The current study examined the prevalence and course of neuropsychiatric symptoms in a large sample of patients with dementia attending memory clinics. Design: Three-year nonprescriptive, observational study examining relationships between predictors and outcome variables in patients with dementia. Setting: Nine memory clinics around Australia. Participants: Of 970 patients recruited, 779 patients had dementia at baseline. Measurements: Over 3 years, patients were rated on 6 occasions on the 12-item Neuropsychiatric Inventory and measures of cognition, dementia severity, function, and medication use. Analyses focused on the 514 patients with dementia who completed the Neuropsychiatric Inventory on 4 or more occasions. Results: Overall levels of neuropsychiatric symptoms increased over the 3 years. In particular, delusions, hallucinations, agitation, anxiety, apathy, disinhibition, irritability, and aberrant motor behavior increased over the 3 years. Depression, euphoria, night time behavior, and appetite did not significantly increase over this period. Severity of dementia, male sex, and frontotemporal dementia were associated with greater levels of neuropsychiatric symptoms at baseline. Dementia with Lewy bodies was associated with more hallucinations and less appetite disturbances, and Alzheimer’s disease was associated with lower levels of neuropsychiatric symptoms than other types of dementia at baseline. Conclusions: The findings confirm that different symptoms have different trajectories and that baseline characteristics of patients, including sex and dementia type, predict the subsequent course of symptoms. The findings also highlight the association between dementia severity and neuropsychiatric symptoms, indicating the need to control for this variable when examining their longitudinal trajectories. Ó 2015 AMDA e The Society for Post-Acute and Long-Term Care Medicine.
Data collection was funded by Janssen-Cilag Pty Limited. Janssen-Cilag had no input into data analysis or writing of the manuscript. H.B. and M.W. have worked on drug trials for patients with MCI and AD sponsored by major pharmaceutical companies including Eisai Pharmaceuticals, Eli Lilly and Company, GlaxoSmithKline, H Lundbeck A/S, Janssen-Cilag Pty Limited, Medivation Inc, Novartis Pharmaceuticals, Nutricia, Pfizer, Prana Biotechnology Limited, Sanofi-Aventis, Servier, Voyager Pharmaceutical Corporation, and Wyeth Limited. M.W. has also worked on trials sponsored by Servier, Forest, Merck Sharp and Dohme, Takeda, the Buck Institute, and Tau Rx. H.B. has been a consultant, advisory board member, and sponsored speaker for Baxter, H Lundbeck A/S, Janssen-Cilag Pty Limited, Medivation Inc, Novartis Pharmaceuticals, Pfizer, Prana Biotechnology Limited, Voyager http://dx.doi.org/10.1016/j.jamda.2014.12.018 1525-8610/Ó 2015 AMDA e The Society for Post-Acute and Long-Term Care Medicine.
Pharmaceutical Corporation, and Wyeth Limited. M.W. has been a consultant and speaker for these companies as well as bioCSL, Prana Biotechnology, Eli Lilly and Company, and Merck Sharp and Dohme. D.A. has served as a paid consultant to Janssen-Cilag and has also received payment for consultancies from Baxter, Eli Lilly, Lundbeck, Prana, Pfizer, and Novartis. M.C. and J.X. have no conflicts of interest to declare. * Address correspondence to Henry Brodaty, MD, BS, DSc, Dementia Collaborative Research Center, School of Psychiatry, University of New South Wales, Level 3, AGSM Bldg (G27), NSW 2052, Australia. E-mail address: [email protected] (H. Brodaty).
2
H. Brodaty et al. / JAMDA xxx (2015) 1e8
Most patients with dementia experience neuropsychiatric symptoms (also called behavioral and psychological symptoms of dementia) during their illness.1,2 Symptoms include depression, anxiety, disinhibition, irritability, delusions, and hallucinations. Such symptoms often cause considerable distress to both patients and their caregivers3,4 and are strong predictors of early nursing home admission.5,6 Accurate knowledge of the prevalence and course of neuropsychiatric symptoms is important for planning purposes and for providing information to patients and their families about prognosis. Knowledge of the course of symptoms is also important for management as treatment may be curtailed earlier and more confidently for symptoms that are likely to resolve spontaneously. Neuropsychiatric symptoms vary considerably in their prevalence and trajectory.1 Some neuropsychiatric symptoms may worsen with the progression of dementia. Apathy and disinhibition may become more severe and prevalent over time because of the progressive deterioration of brain regions responsible for motivation (eg, anterior cingulate) and inhibition (eg, frontal cortex) respectively.7 Other symptoms may not follow such a linear trajectory. Depression, for example, may become more pronounced in the middle stages of dementia because of both neural deterioration (eg, anterior cingulate, basal ganglia, limbic system) and psychological responses to dementia.7 Depression may become less apparent in later stages of dementia as cognitive abilities that are necessary to sustain depressive cognitions deteriorate and the ability to verbalize symptoms also declines. Finally, other symptoms may remain stable over the course of dementia. Hallucinations, euphoria, and irritability, for example, may appear with similar or only slightly increasing levels of frequency and severity across different stages of dementia because of their relatively specific neural underpinnings.7 Despite these broad predictions, there is considerable variation across studies in symptom trajectories. Whereas some studies report that apathy increases in prevalence and severity over time,8,9 other studies report that it remains stable10,11 or even decreases.12 Likewise, whereas some studies report that depression decreases in prevalence and severity over time,8,12,13 other studies report that it remains constant10,11 or fluctuates in prevalence.10,14 Part of this variation may be due to the different health care settings and locations in which the studies were conducted. Community samples typically have less frequent and severe neuropsychiatric symptoms than hospital or nursing home samples.1 Part of the variation may also be due to differences between samples, with more severe symptoms present in patients with more severe dementia.15 Previous research has been particularly limited by the fact that it has not controlled for the baseline severity of patients’ dementia and the impact of medications when examining the longitudinal course of neuropsychiatric symptoms. Given both these inconsistencies and limitations, the current study examined the course of neuropsychiatric symptoms in a large sample of patients with dementia living in the community over a 3-year period. The current study also examined whether baseline characteristics of patients, such as age, sex, dementia severity, type of dementia, and medication, predicted the subsequent trajectory of neuropsychiatric symptoms. These variables were selected on the basis of their clinical relevance and their ease of measurement in everyday practice. Patients and their carers completed the Neuropsychiatric Inventory (NPI) over a 3-year period. Patients also completed measures of cognition, dementia severity, and function, and listed their medications. We expected that different neuropsychiatric symptoms would have different trajectories and would vary according to diagnosis; specifically that patients with frontotemporal dementia would have more severe neuropsychiatric symptoms and those with dementia with Lewy bodies would have more severe hallucinations than patients with other dementias.1 We also expected that medications would be associated with the symptoms for which they are typically
prescribed (eg, anti-depressants for depression, benzodiazepines for anxiety, and antipsychotics for psychotic symptoms). Methods Design Participants were drawn from the Prospective Research In MEmory clinics (PRIME) study,16 a 3-year nonprescriptive, observational study examining relationships between predictors and outcome variables in 970 patients with either dementia or mild cognitive impairment (MCI) who were attending 1 of 9 memory clinics in Australia. These memory clinics were in 4 of the 8 states and territories of Australia and included both regional and capital centers. Patients were eligible for inclusion if they had been diagnosed with dementia by a clinician using the DSM-IV criteria17 or MCI using the Petersen criteria,18 were living in the community with less than 40 hours/wk nursing care, had a caregiver willing to provide consent for required components of the study, were fluent in English and could provide written informed consent directly, or through a legal guardian/proxy. The requirement that patients were living in the community with less than 40 hours/wk nursing care was implemented to ensure we excluded patients deemed equivalent to those with nursing home care. Patients were excluded if they were acutely ill or had any concomitant life-threatening illness considered likely to interfere with the patient’s ability to complete the study (as these patients are seen in emergency or other parts of the health care system), were diagnosed with MCI and prescribed a cholinesterase inhibitor or memantine (because of prescribing regulations), or were concurrently participating in a clinical trial of an investigational drug (phase I, II, or III). However, patients who commenced participation in a clinical trial after enrolment in PRIME were eligible to continue PRIME follow-up. Almost all patients were referred to these clinics by general practitioners. Ethics approvals were obtained from institutional ethics committees associated with individual referring centers (National Institute of Health clinical trials registry number: NCT00297271). Participants The current article focused on the 779 patients with dementia. All patients were assessed by specialist experienced clinicians and had received a diagnosis of dementia according to DSM-IV criteria.17 Patients were classed as having Alzheimer’s disease, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, mixed dementia, or other types of dementia by the specialist clinician according to clinical criteria.17,19e21 Measures and Procedure Patients were assessed annually with additional 3- and 6-month assessments in the first year. At baseline and at each subsequent visit (3, 6, 12, 24, and 36 months from baseline), a research nurse or specialist clinician administered measures of neuropsychiatric function, dementia severity, cognition, function, and caregiver burden and compiled a list of medications that participants were taking. Neuropsychiatric symptoms were assessed using the 12-item NPI; higher scores indicate greater levels of symptoms.22 Dementia severity was assessed using the Clinical Dementia Rating (CDR) scale23 and scored using the sum of boxes method; higher scores indicate greater severity (range 0e18).24 Cognition was assessed using the MiniMental State Examination; higher scores indicate better cognition (range 0e30).25 Functional ability was assessed using the Functional Autonomy Measurement System; higher scores indicate better
H. Brodaty et al. / JAMDA xxx (2015) 1e8
Table 1 Baseline Characteristics of Patients Included in the Analyses (n ¼ 514) Agew Sex Male Female Education Primary school or less High school Some postsecondary College/university Postgraduate Dementia type Alzheimer’s disease Vascular dementia Mixed dementia Dementia with Lewy bodies Frontotemporal dementia Other dementias Dementia severity CDR sum of boxesw CDR 0.5 CDR 1 CDR 2 CDR 3 MMSEw SMAFw Medication Cholinesterase inhibitors Memantine Antidepressants Typical antipsychotics Atypical antipsychotics Benzodiazepines
time points in the study (baseline, 3, 6, 12, 24, and 36 months). As LMMs assume normally distributed outcome variables, the NPI scores were adjusted by Blom transformation to remove skewness. 27 Following Bollen and Curran28 analyses adopted a stepped approach. Analysis first examined trajectory over time. To examine overall increases in symptoms over time, a LMM was fitted to the data. Baseline CDR was included as a covariate to control for baseline severity. To examine other possible trends over time, LMMs with quadratic and cubic time effects were also fitted to the data. In addition, the trajectory of symptoms over 1-year time intervals were analyzed in separate models to specifically assess whether trajectory changed across these different periods. Analysis next examined whether baseline variables predicted levels of neuropsychiatric symptoms and their rate of change over time. To do so, a LMM was fitted to the data with covariates of age, sex, type of dementia, and medications included in the model in addition to time and baseline CDR (as only 5 patients were receiving memantine without cholinesterase inhibitors, these 2 classes of Alzheimer medication were grouped together in analysis). Across all LMM analyses, a significant main effect of a covariate indicated that it was associated with the particular NPI symptom at baseline; positive values indicated that higher levels of the relevant covariate were associated with greater baseline levels of the symptom. Significant interactions between a covariate and time indicated that the covariate was associated with the rate of change in the NPI symptom over time; positive values indicated that higher levels of the covariate were associated with a faster increase in the symptom over time.
77.6 (7.6) 277 (53.9%) 237 (46.1%) 59 279 64 85 22
(11.5%) (54.3%) (12.5%) (16.5%) (4.3%)
344 33 76 10 24 27
(66.9%) (6.4%) (14.8%) (1.9%) (4.7%) (5.3%)
5.0 (3.3) 49.7% 35.7% 12.1% 1.9% 22.0 (5.0) 17.1 (10.7) 450 78 192 32 111 110
3
(90.4%) (15.7%) (37.4%) (6.2%) (21.6%) (21.4%)
Results
MMSE, Mini-Mental State Examination; SMAF, Functional Autonomy Measurement System. SD or percentages are shown in brackets. windicates mean (SD).
Patient Demographics Of the 779 patients with dementia at baseline, 514 (66.0%) patients had complete NPI data for 4 or more occasions and were included in the analyses. Their demographics and clinical information are summarized in Table 1. At baseline, the patients who completed NPI data for 4 or more occasions were younger, t(777) ¼ 2.09, P ¼ .04, and had lower NPI scores, t(660) ¼ 2.56, P ¼ .01, higher Mini-Mental State Examination scores, t(770) ¼ 3.82, P < .01, and lower CDR scores, t(770) ¼ 2.96, P < .01, than those who did not. Over the course of the study, 161 patients withdrew because they were institutionalized and 106 were known to have died.
function (range 87 to 0)26 Analyses considered 6 types of medication: cholinesterase inhibitors (ATC code N06DA), memantine (ATC code N06DX), antidepressants (ATC code N06A), benzodiazepines (ATC code N05BA), typical antipsychotics (ATC codes NO5AA, NO5AB, NO5AC, NO5AD), and atypical antipsychotics (ATC codes NO5AE, NO5AF, NO5AG, NO5AH, NO5AL, NO5AX). Statistical Analyses As analyses examined longitudinal trends, only patients with complete data for 4 or more time points were included in the analyses to ensure that symptoms reflected a consistent group of patients over time and to allow for both cubic and quadratic trends. Linear mixed models (LMMs) were used to estimate the trajectory of the total NPI score and the NPI scores for individual symptoms over the 6
Prevalence of Neuropsychiatric Symptoms The percentage of patients with neuropsychiatric symptoms is summarized in Table 2.
Table 2 Percentage of Participants With Neuropsychiatric Symptoms
Delusions Hallucinations Agitation Depression Anxiety Euphoria Apathy Disinhibition Irritability Aberrant motor Night Time Appetite
Baseline (n ¼ 511)*
3 Mo (n ¼ 504)
6 Mo (n ¼ 506)
1 Y (n ¼ 507)
2 Y (n ¼ 418)
3 Y (n ¼ 334)
16.0 10.6 51.7 49.3 50.3 11.0 50.9 20.7 49.7 19.0 33.5 27.2
17.1 10.3 53.0 46.0 46.8 10.9 54.6 24.6 49.0 21.8 30.6 25.2
16.2 9.5 54.7 43.5 53.0 14.8 55.1 25.9 53.0 25.9 34.4 25.1
19.5 13.4 54.6 46.4 52.9 14.0 58.4 28.0 54.0 27.4 37.9 29.4
20.1 12.7 59.1 43.8 53.3 11.7 63.4 27.5 52.6 29.7 35.4 31.8
21.0 12.0 59.6 41.0 54.8 13.8 65.6 30.5 50.3 32.9 34.4 29.6
(4.9) (2.9) (15.3) (12.7) (16.6) (3.1) (23.9) (3.9) (19.2) (8.8) (18.6) (15.7)
(5.2) (3.8) (14.1) (9.9) (16.9) (2.6) (25.6) (4.8) (15.3) (10.9) (13.7) (12.3)
(6.7) (3.6) (17.8) (9.9) (18.2) (3.4) (29.4) (7.7) (18.0) (13.8) (17.2) (12.3)
Number in brackets indicates the percentage of patients with clinically significant symptoms (NPI score 4). *Three patients did not have NPI data at baseline but had NPI data for four subsequent occasions.
(8.9) (5.9) (18.5) (14.4) (20.3) (4.3) (32.1) (9.9) (20.3) (16.2) (23.5) (15.8)
(8.4) (5.3) (20.6) (11.5) (21.1) (3.3) (37.8) (12.4) (22.5) (16.5) (20.1) (17.0)
(7.8) (6.3) (23.1) (10.2) (21.6) (3.9) (39.8) (12.0) (20.1) (18.9) (19.8) (17.1)
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H. Brodaty et al. / JAMDA xxx (2015) 1e8
Table 3 Number of Symptoms and Total NPI Score Over Time
Total NPI score Number of symptoms Any level of severity Clinically significantw Proportion (%) Affected Any level of severity 1 or more symptoms 2 or more symptoms 3 or more symptoms 4 or more symptoms 5 or more symptoms Clinically significantw 1 or more symptoms 2 or more symptoms 3 or more symptoms 4 or more symptoms 5 or more symptoms
Baseline (n ¼ 511)*
3 Mo (n ¼ 504)
6 Mo (n ¼ 506)
1 Y (n ¼ 507)
2 Y (n ¼ 418)
3 Y (n ¼ 334)
13.6 (14.8)
13.6 (16.0)
15.7 (18.8)
18.8 (21.7)
19.1 (20.5)
20.2 (22.4)
3.9 (2.6) 1.5 (1.8)
3.9 (2.6) 1.3 (1.8)
4.1 (2.7) 1.6 (2.1)
4.4 (2.8) 1.9 (2.3)
4.4 (2.7) 2.0 (2.2)
4.5 (2.7) 2.0 (2.3)
89.8 80.4 66.1 51.5 39.5
90.5 78.8 64.9 51.6 40.5
90.9 79.4 69.8 56.9 43.3
91.7 83.8 70.2 58.6 45.8
92.8 85.4 73.0 61.5 45.9
92.2 84.4 76.3 60.2 46.1
57.5 36.8 22.9 14.3 7.2
51.6 33.7 21.0 13.5 8.1
52.2 37.5 26.5 19.0 11.3
60.4 43.0 30.6 20.1 16.0
63.9 44.5 32.3 22.5 14.4
63.2 45.2 31.7 23.4 14.7
SD shown in brackets. wClinically significant ¼ individual NPI Item score 4. *Three patients did not have NPI data at baseline but had NPI data for four subsequent occasions.
Total NPI scores over time and the proportion of patients with multiple symptoms are summarized in Table 3. At each time point, approximately 90% of the sample had 1 or more neuropsychiatric symptoms and over 50% of the sample had 1 or more clinically significant symptoms. Most patientsdaround 80% of the sampledexperienced multiple symptoms, and over one-half the sample had 4 or more symptoms at each time point. As shown in Tables 2 and 3, the overall frequency of neuropsychiatric symptoms increased over the 3-year period. Trajectory of Neuropsychiatric Symptoms Over Time Changes in raw NPI scores over time are summarized in Figure 1. To examine increases over time, a LMM was fitted to the data over the study period. Baseline CDR was included as a covariate to control for baseline severity. As shown in Table 4, all symptomsdexcept depression, euphoria, and night time disturbancesdincreased significantly over time. Baseline CDR was associated with greater levels of all symptoms at baseline, with the exception of euphoria. Interactions between time and baseline severity (not shown in Table 4) were significant for total score, agitation, anxiety, and apathy, and in all cases the values were zero (bs ¼ 0.00, Ps < .05), indicating that while patients with greater dementia severity had worse symptoms, the rate of increase in these neuropsychiatric symptoms over time was the same for all levels of dementia severity. When quadratic and cubic time effect terms were introduced into the model, they were not significant for any of the symptoms (all Ps > .10). In order to examine the trajectory of symptoms over time, modeling thus examined changes in symptoms over 1-year intervals. As shown in Table 4, total NPI score showed significant increases over each 1-year interval. Other symptoms tended to increase over particular time periods: whereas delusions, disinhibition, and euphoria increased mainly over the first year, apathy and anxiety increased over both the first and second years. Predictors of Neuropsychiatric Symptoms and Trajectories We examined whether demographic characteristics, type of dementia, and medications were associated with the level of symptoms at baseline and their rate of change over time. In particular, age, sex, type of dementia, and medications were included in the LMM in addition to time and baseline CDR. Although baseline severity continued to be associated with greater levels of symptoms at baseline (except for euphoria and disinhibition), age was not statistically associated with
symptoms once other covariates were controlled for (all Ps > .09), with the exception of euphoria to a marginal degree (b ¼ 0.01, P ¼ .01). Sex, however, was associated with several neuropsychiatric symptoms. Males displayed greater neuropsychiatric symptoms overall (b ¼ 0.20, P ¼ .01), hallucinations (b ¼ 0.09, P ¼ .04), agitation (b ¼ 0.14, P ¼ .03), apathy (b ¼ 0.26, P < .01), disinhibition (b ¼ 0.12, P ¼ .02), irritability (b ¼ 0.21, P < .01), and night time disturbances (b ¼ 0.19, P < .01) at baseline than females. Females, by contrast, displayed greater depression at baseline (b ¼ 0.13, P ¼ .04). There were no interactions between either of these demographic variables and time (with the exception of age and disinhibition, b ¼ 0.00, P ¼ .02). In terms of dementia type, Alzheimer’s disease was associated with lower overall symptoms (b ¼ .24, P ¼ .02), hallucinations (b ¼ 0.18, P < .01), and disinhibition (b ¼ 0.12, P ¼ .02) at baseline than other types of dementia. There were no interactions with time (all Ps > .05). By contrast, vascular dementia was not associated with either baseline symptoms or their rate of change over time (all Ps > .05). Frontotemporal dementia was associated with greater symptoms overall (b ¼ 0.38, P ¼ .02), and greater levels of hallucinations (b ¼ 0.22, P ¼ .04), agitation (b ¼ 0.49, P < .01), anxiety (b ¼ 0.32, P ¼ .01), euphoria (b ¼ 0.75, P < .01), disinhibition (b ¼ 0.44, P < .01), and aberrant motor behavior (b ¼ 0.49, P < .01) at baseline, but not with their rates of change over time (Ps > .11). Dementia with Lewy bodies was associated with greater levels of hallucinations at baseline (b ¼ 0.82, P < .01), albeit with a lower rate of increase over time (b ¼ 0.04, P ¼ .04). Dementia with Lewy bodies was also associated with a lower level of appetite disturbances at baseline than other dementias (b ¼ 0.37, P ¼ .04). In terms of medications, medications specific to Alzheimer’s disease, namely cholinesterase inhibitors and memantine, were associated with less irritability (b ¼ 0.36, P ¼ .04) at baseline, and with a faster increase in overall symptoms (b ¼ 0.04, P ¼ .02), and irritability (b ¼ 0.04, P ¼.02) over time. Antidepressants were associated with both greater depression (b ¼ 0.24, P .05). By contrast, atypical antipsychotics were associated with greater overall symptoms (b ¼ .41, P < .01), delusions (b ¼ 0.25, P < .01), hallucinations (b ¼ 0.22, P < .01), agitation (b ¼ 0.28, P < .01), depression (b ¼ 0.32, P < .01), anxiety (b ¼ 0.37, P < .01), apathy (b ¼ 0.16, P ¼ .02), irritability, (b ¼ 0.22, P < .01), aberrant motor behavior (b ¼ 0.19, P
JAMDA journal homepage: www.jamda.com
Original Study
The Course of Neuropsychiatric Symptoms in Dementia: A 3-Year Longitudinal Study Henry Brodaty MD, BS, DSc a, b, *, Michael H. Connors PhD a, b, Jing Xu PhD a, b, Michael Woodward MD, BS c, David Ames MD, BS d, e on behalf of the PRIME study group a
Dementia Collaborative Research Center, School of Psychiatry, University of New South Wales, Sydney, Australia Center for Healthy Brain Aging, School of Psychiatry, University of New South Wales, Sydney, Australia c Austin Hospital, Heidelberg, Australia d National Aging Research Institute, Melbourne, Australia e University of Melbourne Academic Unit for Psychiatry of Old Age, Melbourne, Australia b
a b s t r a c t Keywords: Alzheimer’s disease behavioral and psychological symptoms of dementia dementia longitudinal study neuropsychiatric symptoms Neuropsychiatric Inventory
Objectives: Patients with dementia experience a wide range of neuropsychiatric symptoms. These symptoms often cause considerable distress to patients and caregivers, and often contribute to institutionalization. The current study examined the prevalence and course of neuropsychiatric symptoms in a large sample of patients with dementia attending memory clinics. Design: Three-year nonprescriptive, observational study examining relationships between predictors and outcome variables in patients with dementia. Setting: Nine memory clinics around Australia. Participants: Of 970 patients recruited, 779 patients had dementia at baseline. Measurements: Over 3 years, patients were rated on 6 occasions on the 12-item Neuropsychiatric Inventory and measures of cognition, dementia severity, function, and medication use. Analyses focused on the 514 patients with dementia who completed the Neuropsychiatric Inventory on 4 or more occasions. Results: Overall levels of neuropsychiatric symptoms increased over the 3 years. In particular, delusions, hallucinations, agitation, anxiety, apathy, disinhibition, irritability, and aberrant motor behavior increased over the 3 years. Depression, euphoria, night time behavior, and appetite did not significantly increase over this period. Severity of dementia, male sex, and frontotemporal dementia were associated with greater levels of neuropsychiatric symptoms at baseline. Dementia with Lewy bodies was associated with more hallucinations and less appetite disturbances, and Alzheimer’s disease was associated with lower levels of neuropsychiatric symptoms than other types of dementia at baseline. Conclusions: The findings confirm that different symptoms have different trajectories and that baseline characteristics of patients, including sex and dementia type, predict the subsequent course of symptoms. The findings also highlight the association between dementia severity and neuropsychiatric symptoms, indicating the need to control for this variable when examining their longitudinal trajectories. Ó 2015 AMDA e The Society for Post-Acute and Long-Term Care Medicine.
Data collection was funded by Janssen-Cilag Pty Limited. Janssen-Cilag had no input into data analysis or writing of the manuscript. H.B. and M.W. have worked on drug trials for patients with MCI and AD sponsored by major pharmaceutical companies including Eisai Pharmaceuticals, Eli Lilly and Company, GlaxoSmithKline, H Lundbeck A/S, Janssen-Cilag Pty Limited, Medivation Inc, Novartis Pharmaceuticals, Nutricia, Pfizer, Prana Biotechnology Limited, Sanofi-Aventis, Servier, Voyager Pharmaceutical Corporation, and Wyeth Limited. M.W. has also worked on trials sponsored by Servier, Forest, Merck Sharp and Dohme, Takeda, the Buck Institute, and Tau Rx. H.B. has been a consultant, advisory board member, and sponsored speaker for Baxter, H Lundbeck A/S, Janssen-Cilag Pty Limited, Medivation Inc, Novartis Pharmaceuticals, Pfizer, Prana Biotechnology Limited, Voyager http://dx.doi.org/10.1016/j.jamda.2014.12.018 1525-8610/Ó 2015 AMDA e The Society for Post-Acute and Long-Term Care Medicine.
Pharmaceutical Corporation, and Wyeth Limited. M.W. has been a consultant and speaker for these companies as well as bioCSL, Prana Biotechnology, Eli Lilly and Company, and Merck Sharp and Dohme. D.A. has served as a paid consultant to Janssen-Cilag and has also received payment for consultancies from Baxter, Eli Lilly, Lundbeck, Prana, Pfizer, and Novartis. M.C. and J.X. have no conflicts of interest to declare. * Address correspondence to Henry Brodaty, MD, BS, DSc, Dementia Collaborative Research Center, School of Psychiatry, University of New South Wales, Level 3, AGSM Bldg (G27), NSW 2052, Australia. E-mail address: [email protected] (H. Brodaty).
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H. Brodaty et al. / JAMDA xxx (2015) 1e8
Most patients with dementia experience neuropsychiatric symptoms (also called behavioral and psychological symptoms of dementia) during their illness.1,2 Symptoms include depression, anxiety, disinhibition, irritability, delusions, and hallucinations. Such symptoms often cause considerable distress to both patients and their caregivers3,4 and are strong predictors of early nursing home admission.5,6 Accurate knowledge of the prevalence and course of neuropsychiatric symptoms is important for planning purposes and for providing information to patients and their families about prognosis. Knowledge of the course of symptoms is also important for management as treatment may be curtailed earlier and more confidently for symptoms that are likely to resolve spontaneously. Neuropsychiatric symptoms vary considerably in their prevalence and trajectory.1 Some neuropsychiatric symptoms may worsen with the progression of dementia. Apathy and disinhibition may become more severe and prevalent over time because of the progressive deterioration of brain regions responsible for motivation (eg, anterior cingulate) and inhibition (eg, frontal cortex) respectively.7 Other symptoms may not follow such a linear trajectory. Depression, for example, may become more pronounced in the middle stages of dementia because of both neural deterioration (eg, anterior cingulate, basal ganglia, limbic system) and psychological responses to dementia.7 Depression may become less apparent in later stages of dementia as cognitive abilities that are necessary to sustain depressive cognitions deteriorate and the ability to verbalize symptoms also declines. Finally, other symptoms may remain stable over the course of dementia. Hallucinations, euphoria, and irritability, for example, may appear with similar or only slightly increasing levels of frequency and severity across different stages of dementia because of their relatively specific neural underpinnings.7 Despite these broad predictions, there is considerable variation across studies in symptom trajectories. Whereas some studies report that apathy increases in prevalence and severity over time,8,9 other studies report that it remains stable10,11 or even decreases.12 Likewise, whereas some studies report that depression decreases in prevalence and severity over time,8,12,13 other studies report that it remains constant10,11 or fluctuates in prevalence.10,14 Part of this variation may be due to the different health care settings and locations in which the studies were conducted. Community samples typically have less frequent and severe neuropsychiatric symptoms than hospital or nursing home samples.1 Part of the variation may also be due to differences between samples, with more severe symptoms present in patients with more severe dementia.15 Previous research has been particularly limited by the fact that it has not controlled for the baseline severity of patients’ dementia and the impact of medications when examining the longitudinal course of neuropsychiatric symptoms. Given both these inconsistencies and limitations, the current study examined the course of neuropsychiatric symptoms in a large sample of patients with dementia living in the community over a 3-year period. The current study also examined whether baseline characteristics of patients, such as age, sex, dementia severity, type of dementia, and medication, predicted the subsequent trajectory of neuropsychiatric symptoms. These variables were selected on the basis of their clinical relevance and their ease of measurement in everyday practice. Patients and their carers completed the Neuropsychiatric Inventory (NPI) over a 3-year period. Patients also completed measures of cognition, dementia severity, and function, and listed their medications. We expected that different neuropsychiatric symptoms would have different trajectories and would vary according to diagnosis; specifically that patients with frontotemporal dementia would have more severe neuropsychiatric symptoms and those with dementia with Lewy bodies would have more severe hallucinations than patients with other dementias.1 We also expected that medications would be associated with the symptoms for which they are typically
prescribed (eg, anti-depressants for depression, benzodiazepines for anxiety, and antipsychotics for psychotic symptoms). Methods Design Participants were drawn from the Prospective Research In MEmory clinics (PRIME) study,16 a 3-year nonprescriptive, observational study examining relationships between predictors and outcome variables in 970 patients with either dementia or mild cognitive impairment (MCI) who were attending 1 of 9 memory clinics in Australia. These memory clinics were in 4 of the 8 states and territories of Australia and included both regional and capital centers. Patients were eligible for inclusion if they had been diagnosed with dementia by a clinician using the DSM-IV criteria17 or MCI using the Petersen criteria,18 were living in the community with less than 40 hours/wk nursing care, had a caregiver willing to provide consent for required components of the study, were fluent in English and could provide written informed consent directly, or through a legal guardian/proxy. The requirement that patients were living in the community with less than 40 hours/wk nursing care was implemented to ensure we excluded patients deemed equivalent to those with nursing home care. Patients were excluded if they were acutely ill or had any concomitant life-threatening illness considered likely to interfere with the patient’s ability to complete the study (as these patients are seen in emergency or other parts of the health care system), were diagnosed with MCI and prescribed a cholinesterase inhibitor or memantine (because of prescribing regulations), or were concurrently participating in a clinical trial of an investigational drug (phase I, II, or III). However, patients who commenced participation in a clinical trial after enrolment in PRIME were eligible to continue PRIME follow-up. Almost all patients were referred to these clinics by general practitioners. Ethics approvals were obtained from institutional ethics committees associated with individual referring centers (National Institute of Health clinical trials registry number: NCT00297271). Participants The current article focused on the 779 patients with dementia. All patients were assessed by specialist experienced clinicians and had received a diagnosis of dementia according to DSM-IV criteria.17 Patients were classed as having Alzheimer’s disease, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, mixed dementia, or other types of dementia by the specialist clinician according to clinical criteria.17,19e21 Measures and Procedure Patients were assessed annually with additional 3- and 6-month assessments in the first year. At baseline and at each subsequent visit (3, 6, 12, 24, and 36 months from baseline), a research nurse or specialist clinician administered measures of neuropsychiatric function, dementia severity, cognition, function, and caregiver burden and compiled a list of medications that participants were taking. Neuropsychiatric symptoms were assessed using the 12-item NPI; higher scores indicate greater levels of symptoms.22 Dementia severity was assessed using the Clinical Dementia Rating (CDR) scale23 and scored using the sum of boxes method; higher scores indicate greater severity (range 0e18).24 Cognition was assessed using the MiniMental State Examination; higher scores indicate better cognition (range 0e30).25 Functional ability was assessed using the Functional Autonomy Measurement System; higher scores indicate better
H. Brodaty et al. / JAMDA xxx (2015) 1e8
Table 1 Baseline Characteristics of Patients Included in the Analyses (n ¼ 514) Agew Sex Male Female Education Primary school or less High school Some postsecondary College/university Postgraduate Dementia type Alzheimer’s disease Vascular dementia Mixed dementia Dementia with Lewy bodies Frontotemporal dementia Other dementias Dementia severity CDR sum of boxesw CDR 0.5 CDR 1 CDR 2 CDR 3 MMSEw SMAFw Medication Cholinesterase inhibitors Memantine Antidepressants Typical antipsychotics Atypical antipsychotics Benzodiazepines
time points in the study (baseline, 3, 6, 12, 24, and 36 months). As LMMs assume normally distributed outcome variables, the NPI scores were adjusted by Blom transformation to remove skewness. 27 Following Bollen and Curran28 analyses adopted a stepped approach. Analysis first examined trajectory over time. To examine overall increases in symptoms over time, a LMM was fitted to the data. Baseline CDR was included as a covariate to control for baseline severity. To examine other possible trends over time, LMMs with quadratic and cubic time effects were also fitted to the data. In addition, the trajectory of symptoms over 1-year time intervals were analyzed in separate models to specifically assess whether trajectory changed across these different periods. Analysis next examined whether baseline variables predicted levels of neuropsychiatric symptoms and their rate of change over time. To do so, a LMM was fitted to the data with covariates of age, sex, type of dementia, and medications included in the model in addition to time and baseline CDR (as only 5 patients were receiving memantine without cholinesterase inhibitors, these 2 classes of Alzheimer medication were grouped together in analysis). Across all LMM analyses, a significant main effect of a covariate indicated that it was associated with the particular NPI symptom at baseline; positive values indicated that higher levels of the relevant covariate were associated with greater baseline levels of the symptom. Significant interactions between a covariate and time indicated that the covariate was associated with the rate of change in the NPI symptom over time; positive values indicated that higher levels of the covariate were associated with a faster increase in the symptom over time.
77.6 (7.6) 277 (53.9%) 237 (46.1%) 59 279 64 85 22
(11.5%) (54.3%) (12.5%) (16.5%) (4.3%)
344 33 76 10 24 27
(66.9%) (6.4%) (14.8%) (1.9%) (4.7%) (5.3%)
5.0 (3.3) 49.7% 35.7% 12.1% 1.9% 22.0 (5.0) 17.1 (10.7) 450 78 192 32 111 110
3
(90.4%) (15.7%) (37.4%) (6.2%) (21.6%) (21.4%)
Results
MMSE, Mini-Mental State Examination; SMAF, Functional Autonomy Measurement System. SD or percentages are shown in brackets. windicates mean (SD).
Patient Demographics Of the 779 patients with dementia at baseline, 514 (66.0%) patients had complete NPI data for 4 or more occasions and were included in the analyses. Their demographics and clinical information are summarized in Table 1. At baseline, the patients who completed NPI data for 4 or more occasions were younger, t(777) ¼ 2.09, P ¼ .04, and had lower NPI scores, t(660) ¼ 2.56, P ¼ .01, higher Mini-Mental State Examination scores, t(770) ¼ 3.82, P < .01, and lower CDR scores, t(770) ¼ 2.96, P < .01, than those who did not. Over the course of the study, 161 patients withdrew because they were institutionalized and 106 were known to have died.
function (range 87 to 0)26 Analyses considered 6 types of medication: cholinesterase inhibitors (ATC code N06DA), memantine (ATC code N06DX), antidepressants (ATC code N06A), benzodiazepines (ATC code N05BA), typical antipsychotics (ATC codes NO5AA, NO5AB, NO5AC, NO5AD), and atypical antipsychotics (ATC codes NO5AE, NO5AF, NO5AG, NO5AH, NO5AL, NO5AX). Statistical Analyses As analyses examined longitudinal trends, only patients with complete data for 4 or more time points were included in the analyses to ensure that symptoms reflected a consistent group of patients over time and to allow for both cubic and quadratic trends. Linear mixed models (LMMs) were used to estimate the trajectory of the total NPI score and the NPI scores for individual symptoms over the 6
Prevalence of Neuropsychiatric Symptoms The percentage of patients with neuropsychiatric symptoms is summarized in Table 2.
Table 2 Percentage of Participants With Neuropsychiatric Symptoms
Delusions Hallucinations Agitation Depression Anxiety Euphoria Apathy Disinhibition Irritability Aberrant motor Night Time Appetite
Baseline (n ¼ 511)*
3 Mo (n ¼ 504)
6 Mo (n ¼ 506)
1 Y (n ¼ 507)
2 Y (n ¼ 418)
3 Y (n ¼ 334)
16.0 10.6 51.7 49.3 50.3 11.0 50.9 20.7 49.7 19.0 33.5 27.2
17.1 10.3 53.0 46.0 46.8 10.9 54.6 24.6 49.0 21.8 30.6 25.2
16.2 9.5 54.7 43.5 53.0 14.8 55.1 25.9 53.0 25.9 34.4 25.1
19.5 13.4 54.6 46.4 52.9 14.0 58.4 28.0 54.0 27.4 37.9 29.4
20.1 12.7 59.1 43.8 53.3 11.7 63.4 27.5 52.6 29.7 35.4 31.8
21.0 12.0 59.6 41.0 54.8 13.8 65.6 30.5 50.3 32.9 34.4 29.6
(4.9) (2.9) (15.3) (12.7) (16.6) (3.1) (23.9) (3.9) (19.2) (8.8) (18.6) (15.7)
(5.2) (3.8) (14.1) (9.9) (16.9) (2.6) (25.6) (4.8) (15.3) (10.9) (13.7) (12.3)
(6.7) (3.6) (17.8) (9.9) (18.2) (3.4) (29.4) (7.7) (18.0) (13.8) (17.2) (12.3)
Number in brackets indicates the percentage of patients with clinically significant symptoms (NPI score 4). *Three patients did not have NPI data at baseline but had NPI data for four subsequent occasions.
(8.9) (5.9) (18.5) (14.4) (20.3) (4.3) (32.1) (9.9) (20.3) (16.2) (23.5) (15.8)
(8.4) (5.3) (20.6) (11.5) (21.1) (3.3) (37.8) (12.4) (22.5) (16.5) (20.1) (17.0)
(7.8) (6.3) (23.1) (10.2) (21.6) (3.9) (39.8) (12.0) (20.1) (18.9) (19.8) (17.1)
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H. Brodaty et al. / JAMDA xxx (2015) 1e8
Table 3 Number of Symptoms and Total NPI Score Over Time
Total NPI score Number of symptoms Any level of severity Clinically significantw Proportion (%) Affected Any level of severity 1 or more symptoms 2 or more symptoms 3 or more symptoms 4 or more symptoms 5 or more symptoms Clinically significantw 1 or more symptoms 2 or more symptoms 3 or more symptoms 4 or more symptoms 5 or more symptoms
Baseline (n ¼ 511)*
3 Mo (n ¼ 504)
6 Mo (n ¼ 506)
1 Y (n ¼ 507)
2 Y (n ¼ 418)
3 Y (n ¼ 334)
13.6 (14.8)
13.6 (16.0)
15.7 (18.8)
18.8 (21.7)
19.1 (20.5)
20.2 (22.4)
3.9 (2.6) 1.5 (1.8)
3.9 (2.6) 1.3 (1.8)
4.1 (2.7) 1.6 (2.1)
4.4 (2.8) 1.9 (2.3)
4.4 (2.7) 2.0 (2.2)
4.5 (2.7) 2.0 (2.3)
89.8 80.4 66.1 51.5 39.5
90.5 78.8 64.9 51.6 40.5
90.9 79.4 69.8 56.9 43.3
91.7 83.8 70.2 58.6 45.8
92.8 85.4 73.0 61.5 45.9
92.2 84.4 76.3 60.2 46.1
57.5 36.8 22.9 14.3 7.2
51.6 33.7 21.0 13.5 8.1
52.2 37.5 26.5 19.0 11.3
60.4 43.0 30.6 20.1 16.0
63.9 44.5 32.3 22.5 14.4
63.2 45.2 31.7 23.4 14.7
SD shown in brackets. wClinically significant ¼ individual NPI Item score 4. *Three patients did not have NPI data at baseline but had NPI data for four subsequent occasions.
Total NPI scores over time and the proportion of patients with multiple symptoms are summarized in Table 3. At each time point, approximately 90% of the sample had 1 or more neuropsychiatric symptoms and over 50% of the sample had 1 or more clinically significant symptoms. Most patientsdaround 80% of the sampledexperienced multiple symptoms, and over one-half the sample had 4 or more symptoms at each time point. As shown in Tables 2 and 3, the overall frequency of neuropsychiatric symptoms increased over the 3-year period. Trajectory of Neuropsychiatric Symptoms Over Time Changes in raw NPI scores over time are summarized in Figure 1. To examine increases over time, a LMM was fitted to the data over the study period. Baseline CDR was included as a covariate to control for baseline severity. As shown in Table 4, all symptomsdexcept depression, euphoria, and night time disturbancesdincreased significantly over time. Baseline CDR was associated with greater levels of all symptoms at baseline, with the exception of euphoria. Interactions between time and baseline severity (not shown in Table 4) were significant for total score, agitation, anxiety, and apathy, and in all cases the values were zero (bs ¼ 0.00, Ps < .05), indicating that while patients with greater dementia severity had worse symptoms, the rate of increase in these neuropsychiatric symptoms over time was the same for all levels of dementia severity. When quadratic and cubic time effect terms were introduced into the model, they were not significant for any of the symptoms (all Ps > .10). In order to examine the trajectory of symptoms over time, modeling thus examined changes in symptoms over 1-year intervals. As shown in Table 4, total NPI score showed significant increases over each 1-year interval. Other symptoms tended to increase over particular time periods: whereas delusions, disinhibition, and euphoria increased mainly over the first year, apathy and anxiety increased over both the first and second years. Predictors of Neuropsychiatric Symptoms and Trajectories We examined whether demographic characteristics, type of dementia, and medications were associated with the level of symptoms at baseline and their rate of change over time. In particular, age, sex, type of dementia, and medications were included in the LMM in addition to time and baseline CDR. Although baseline severity continued to be associated with greater levels of symptoms at baseline (except for euphoria and disinhibition), age was not statistically associated with
symptoms once other covariates were controlled for (all Ps > .09), with the exception of euphoria to a marginal degree (b ¼ 0.01, P ¼ .01). Sex, however, was associated with several neuropsychiatric symptoms. Males displayed greater neuropsychiatric symptoms overall (b ¼ 0.20, P ¼ .01), hallucinations (b ¼ 0.09, P ¼ .04), agitation (b ¼ 0.14, P ¼ .03), apathy (b ¼ 0.26, P < .01), disinhibition (b ¼ 0.12, P ¼ .02), irritability (b ¼ 0.21, P < .01), and night time disturbances (b ¼ 0.19, P < .01) at baseline than females. Females, by contrast, displayed greater depression at baseline (b ¼ 0.13, P ¼ .04). There were no interactions between either of these demographic variables and time (with the exception of age and disinhibition, b ¼ 0.00, P ¼ .02). In terms of dementia type, Alzheimer’s disease was associated with lower overall symptoms (b ¼ .24, P ¼ .02), hallucinations (b ¼ 0.18, P < .01), and disinhibition (b ¼ 0.12, P ¼ .02) at baseline than other types of dementia. There were no interactions with time (all Ps > .05). By contrast, vascular dementia was not associated with either baseline symptoms or their rate of change over time (all Ps > .05). Frontotemporal dementia was associated with greater symptoms overall (b ¼ 0.38, P ¼ .02), and greater levels of hallucinations (b ¼ 0.22, P ¼ .04), agitation (b ¼ 0.49, P < .01), anxiety (b ¼ 0.32, P ¼ .01), euphoria (b ¼ 0.75, P < .01), disinhibition (b ¼ 0.44, P < .01), and aberrant motor behavior (b ¼ 0.49, P < .01) at baseline, but not with their rates of change over time (Ps > .11). Dementia with Lewy bodies was associated with greater levels of hallucinations at baseline (b ¼ 0.82, P < .01), albeit with a lower rate of increase over time (b ¼ 0.04, P ¼ .04). Dementia with Lewy bodies was also associated with a lower level of appetite disturbances at baseline than other dementias (b ¼ 0.37, P ¼ .04). In terms of medications, medications specific to Alzheimer’s disease, namely cholinesterase inhibitors and memantine, were associated with less irritability (b ¼ 0.36, P ¼ .04) at baseline, and with a faster increase in overall symptoms (b ¼ 0.04, P ¼ .02), and irritability (b ¼ 0.04, P ¼.02) over time. Antidepressants were associated with both greater depression (b ¼ 0.24, P .05). By contrast, atypical antipsychotics were associated with greater overall symptoms (b ¼ .41, P < .01), delusions (b ¼ 0.25, P < .01), hallucinations (b ¼ 0.22, P < .01), agitation (b ¼ 0.28, P < .01), depression (b ¼ 0.32, P < .01), anxiety (b ¼ 0.37, P < .01), apathy (b ¼ 0.16, P ¼ .02), irritability, (b ¼ 0.22, P < .01), aberrant motor behavior (b ¼ 0.19, P
