CB, RMS, RJ, and EJ designed the experiments/the study. MML, MT, SD, and KK collected data or did experiments for the study. RMS, LY, and EJ analyzed the data. MML, MT, SD, and RJ enrolled patients. CB and EJ wrote the first draft of the paper. SD, RMS, RJ, and EJ contributed to the writing of the paper. MT collected all the data for the Oxfordshire patients over the first two years. SD managed the trial in Newcastle for the majority of its running time, collecting data and also setting up the trial in London. SD also entered data and helped to track down missing data prior to analysis, proof read the manuscript and offered suggestions for changes. RJ contributed to the writing of the grant application and was one of the holders of the grant from the Alzheimer's Research Trust. RJ was also a principal investigator for the study and supervised the collection of the clinical data in the Oxford (UK) patients. KK identified patients, collected data, and wrote the follow-up protocol for the study. LY critically reviewed the manuscript. EJ was the trial statistician and part of the trial management group which met every 2 months. EJ presented regular interim analyses to the Data Monitoring Committee, and co-authored the annual report to the funder. EJ co-wrote the statistical analysis plan and was senior reviewer of the final statistical report.
CB has received honoraria from Novartis, Pfizer, Shire, Lundbeck, Myriad, Janssen, Astra Zeneca, and Servier pharmaceutical companies and research grants from Novartis, Lundbeck, Astra-Zeneca, and Janssen pharmaceuticals. The remaining authors have declared that they have no competing interests.
There have been increasing concerns regarding the safety and efficacy of neuroleptics in people with dementia, but there are very few long-term trials to inform clinical practice. The aim of this study was to determine the impact of long-term treatment with neuroleptic agents upon global cognitive decline and neuropsychiatric symptoms in patients with Alzheimer disease.
Design: Randomised, blinded, placebo-controlled parallel two-group treatment discontinuation trial.
Setting: Oxfordshire, Newcastle and Gateshead, London and Edinburgh, United Kingdom.
Participants: Patients currently prescribed the neuroleptics thioridazine, chlorpromazine, haloperidol trifluoperazine or risperidone for behavioural or psychiatric disturbance in dementia for at least 3 mo.
Interventions: Continue neuroleptic treatment for 12 mo or switch to an identical placebo.
Outcome measures: Primary outcome was total Severe Impairment Battery (SIB) score. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory (NPI).
Results: 165 patients were randomised (83 to continue treatment and 82 to placebo,
i.e., discontinue treatment), of whom 128 (78%) commenced treatment (64
continue/64 placebo). Of those, 26 were lost to follow-up (13 per arm), resulting in 51
patients per arm analysed for the primary outcome. There was no significant difference
between the continue treatment and placebo groups in the estimated mean change in SIB
scores between baseline and 6 mo; estimated mean difference in deterioration (favouring
placebo) −0.4 (95% confidence interval [CI]
−6.4 to 5.5), adjusted for baseline value (
For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this benefit must be weighed against the side effects of therapy.
In a randomized trial of patients with dementia, Clive Ballard and colleagues show that withdrawal of neuroleptics had no overall detrimental effect, and by some measures improved, functional and cognitive status.
The number of people with dementia (currently 25 million worldwide) is expected to increase by 5 million each year. The risk of dementia, including Alzheimer disease, increases sharply with age: Alzheimer's Disease International estimates that 1.4% of people 65–69 have dementia, whereas almost a full quarter of those over the age of 85 years are affected. Almost all older dementia patients will experience, along with the cognitive and functional decline typical of the illness, some neuropsychiatric symptoms. These symptoms can include agitation, aggression, and psychosis, and are often devastating for the older patient and his or her family and caregiver. Managing these symptoms is often a prime concern for health-care providers and families. Neuroleptics (sometimes called antipsychotics) are the class of drugs often used to manage or control neuropsychiatric problems, but there have been questions about their safety and appropriateness. Safety concerns involve risk of stroke, parkinsonism, sedation, edema, and chest infections but also include a worsening of cognitive decline with prolonged use of neuroleptics.
Previous studies on the effectiveness and safety of neuroleptics in older people have been short term. Ballard and colleagues wanted to study over a longer period of time the impact of neuroleptic drugs on elderly patients with dementia. Specifically, they wanted to know if being on a neuroleptic was associated with more cognitive decline than coming off the drug. They also wanted to investigate whether discontinuing the drug exacerbated any neuropsychiatric symptoms, Parkinson disease-like symptoms, or other functional, language, and cognition difficulties frequently associated with dementia.
The researchers recruited older patients with Alzheimer disease from across England who had been on neuroleptics for at least three months. They randomised patients to one of two groups: the first group continued taking the same neuroleptic at the same dosage level while the second group was switched to an identical-looking placebo. The researchers assessed the patients' cognitive status and neuropsychiatric symptoms upon their entry into the study. Six and 12 months later the researchers assessed any cognitive decline and the level of neuropsychiatric and other problems that patients were experiencing.
At both 6 and 12 months, the researchers found that there were no differences between the two groups (continued treatment and placebo) in terms of cognitive decline. The placebo group may have had less cognitive decline, but this was not statistically significant. They also found no overall differences between the two groups in the change in the number of neuropsychiatric symptoms over these time periods. Patients with severe neuropsychiatric problems at the outset of the trial did better on continued neuroleptic therapy, but this advantage was not statistically significant. There was a significant decline on the verbal fluency language tests among the patients who continued on their neuroleptic.
The researchers report perhaps the first trial of this duration on continued versus withdrawn neuroleptic treatment among older dementia patients. The findings do not indicate any benefit of continuing neuroleptic therapies in older patients on either cognitive or neuropsychiatric outcomes. The researchers conclude that neuroleptics, with their known safety issues, should not be used as first-line treatment to manage problems such as agitation or aggression. For older dementia patients whose neuropsychiatric symptoms are not remedied by nonpharmaceutical treatments, the researchers advise caution. More studies are urgently needed to find better solutions to help older patients with dementia who have agitation, aggression, and psychosis.
Please access these Web sites via the online version of this summary at
The
The US National Institutes of Aging has information on Alzheimer Disease in
Two governmental regulatory agencies—the
Worldwide, there are 25 million people with dementia [
Neuroleptics are widely used as the first-line pharmacological approach to treat these
neuropsychiatric symptoms. Efficacy has been examined in eight randomized,
placebo-controlled trials with typical neuroleptics [
Any beneficial effects of neuroleptics in people with AD must be weighed against the short-
and long-term adverse effects which, according to meta-analyses, include parkinsonism,
sedation, oedema, chest infections, stroke (odds ratio 2.5–3) and mortality (odds
ratio 1.5–1.7) [
In the US the Food and Drug Administration [
The main aim of the trial was to determine whether ongoing treatment with neuroleptics accelerates cognitive decline in people with AD. We additionally sought to determine whether ongoing treatment with neuroleptics confers any benefit for the long-term maintenance treatment of neuropsychiatric symptoms in people with AD.
Participants were patients in Oxfordshire, South Birmingham, Newcastle and Gateshead, London and Edinburgh prescribed the neuroleptics thioridazine, chlorpromazine, haloperidol, trifluoperazine or risperidone for behavioural or psychiatric disturbance in dementia for at least 3 months.
Participants had to meet all inclusion criteria. The inclusion criteria were (a) patient
lived in a nursing or residential home; (b) patient fulfilled the NINCDS/ADRDA criteria
for possible or probable AD [
The exclusion criteria were (a) patient was unable to complete primary outcome measures
at baseline assessment; (b) clinician responsible for care or study clinician considered
that the patient suffered from any physical condition—including marked
extrapyramidal disorder—that would have made participation in the trial
distressing or likely to increase suffering; (c) patient was currently taking thioridazine
and showing a prolonged QTc on electrocardiogram [
Two caregivers of people with Alzheimer's disease were closely involved in the
development of the protocol, which was peer reviewed through the auspices of the
Alzheimer's Research Trust (Cambridge, UK). As this was a multicentre trial, the study was
in the first instance reviewed and approved by a properly constituted Multi-Centre
Research Ethics Committee (the North of England MREC). Subsequent site-specific approval
was then granted by properly constituted Local Research Ethics Committees at each of the
participating centres. All Ethics Committees were conducted under the auspices of the
Central Organization of Research Ethics Committees (COREC, now the National Research
Ethics Service UK,
Potentially suitable individuals residing in care facilities, their next of kin, and staff within the care facilities were provided with comprehensive information about the study. Those wishing to take part were invited to participate. If the potential participant had adequate capacity, the individual him- or herself was asked to complete the written study consent procedures. In these circumstances, the next of kin (or if no family members were in contact, an appropriate guardian, usually the manager of the care facility) was also asked to provide written assent to participation. If participants did not have adequate capacity, then written assent from the next of kin and agreement as far as could be ascertained from the potential participant were obtained and considered appropriate to enable participation. This procedure was fully approved by the MREC, and was standard procedure in clinical trials involving vulnerable adults in the UK, until subsequent legislative changes (Mental Capacity Act 2005), introduced after the current study, enabled consent to be provided by a caregiver.
Participants were randomised in equal numbers either to continue neuroleptic treatment
for 12 mo or to switch to placebo. Three fixed dosages, named respectively (a) very low;
(b) low; and (c) high, were chosen for each of the permitted neuroleptic drugs to
correspond as near as possible to the dose the patient was being prescribed prior to trial
entry (
Fixed Dosage Regimens for the Respective Neuroleptics
Each of the neuroleptics was overencapsulated to conceal the identity of the contents. Placebo capsules were identical to the overencapsulated neuroleptics, but contained only inert filler. The respective treatments were maintained at the same fixed dose throughout the 12 mo treatment period of the trial.
The primary aim of this study was to determine whether treatment with neuroleptic agents
is associated with an accelerated rate of cognitive decline in dementia. Secondary
objectives were: (a) to examine the impact of neuroleptics on function and other cognitive
outcomes; (b) to determine whether discontinuing neuroleptics was associated with an
exacerbation of neuropsychiatric symptoms, both overall and in people with NPI scores
above and below 14 [
The primary outcome was the total SIB score [
1. Standardised Mini Mental State Examination (SMMSE) [
2. FAS test of Verbal Fluency [
3. Bristol Activities of Daily Living Scale (BADLS) [
4. Sheffield Test for Acquired Language Disorders (STALD) [
5. NPI [
6. Functional Assessment Staging (FAST) [
7. Modified Unified Parkinson's Disease Rating Scale (M-UPDRS): A modification of the
full UPDRS, to focus only the items that were independent of cognitive function
[
8. Clinician's Global Impression of Change (CGIC): A widely used and validated rating
scale [
For scales requiring an informant, the information was provided by a nurse or
professional caregiver who had regular contact with the individual, usually the key
worker. As far as possible, the same informant provided information for subsequent
assessments. The outcome assessment schedule is summarised in
Outcome Assessment Schedule
Although the study was of 12 mo treatment (or discontinuation), our primary focus was the progression of cognitive impairment at the 6 mo assessment. This schedule was predetermined in view of the frailty and predicted high mortality of this patient population.
The planned sample size of this trial was 110 patients per treatment group. In the
absence of data from randomized clinical trials to inform power calculations at the time
the protocol was developed, this calculation was undertaken using two different
approaches. First, based upon the occurrence of clinically significant cognitive decline
(defined as decline greater than the mean expected cognitive decline of four points per
year on the MMSE), in 50% of patients continuing on neuroleptics versus
30% on placebo, allowing for a dropout rate of
15%–20%. Second, using a generic approach [
Randomisation was performed centrally at the Centre for Statistics in Medicine in Oxford
(CSMO), using dedicated computer software (MINIM). The clinician responsible for
randomisation of a patient faxed a randomisation form to the CSMO (or sent e-mail in
exceptional circumstances) and provided details appropriate and sufficient for
establishing eligibility. If a patient was eligible and informed consent/assent had been
obtained and baseline assessments had been completed, the patient was randomised by the
statistician either to continue taking medication or to discontinue (placebo group). The
statistician directly communicated the allocation to the relevant trial pharmacy, ensuring
concealment. The randomisation programme included a minimisation algorithm to ensure
balanced allocation of participants across the intervention groups for the following
important prognostic factors: presence or absence of extrapyramidal signs (EPS); visual
hallucinations and delusions; use of cholinesterase inhibitors (y/n); SMMSE score
(<6/≥6); and current neuroleptic medication (atypical/typical). The first 22
patients (10% of the target sample size) were allocated randomly to avoid
predictability at the outset. These allocations were computer generated using block
randomisation (block sizes of two and four) using Stata version 7 software (ralloc.ado
v3.2.3 subroutine) [
The clinicians, those administering the trial medication, the caregivers, the relatives, the patients themselves, and those assessing the outcomes were all blinded to treatment allocation.
We used SPSS (release 12.0.1) to enter and manage data, and Stata (release 9.2) for
analysis. Demographic factors and clinical characteristics were summarised with counts
(percentages) for categorical variables, mean (standard deviation [SD])
for normally distributed continuous variables, or median (interquartile
[IQR] or entire range) for other continuous variables. We restricted
comparative analysis to those patients who started allocated treatment and had at least
one assessment after randomisation, and participants were analysed in the groups to which
they were allocated. Primary analysis was performed on patients with complete data at both
baseline and week 26, including those who did not adhere to the protocol (e.g., those who
never started treatment but for whom we had complete data). As the trial was conducted
with masking of treatments, knowledge of allocation could not have contributed to
drop-outs before or after treatment, so that exclusion of such patients did not impart
bias. For the primary analysis, we summarised the change in the severe impairment battery
(i.e., SIB at 6 mo − SIB at baseline) score from baseline to 6 mo using the mean
and SD. To establish the magnitude and direction of the treatment effect, we used analysis
of covariance (ANCOVA) to compare the two groups, giving the mean difference (in change in
SIB from baseline to 6 mo) between groups (plus 95% CIs and
For non-normally distributed continuous outcomes, we performed nonparametric Wilcoxon rank-sum tests to investigate differences between the treatment groups.
Prespecified sensitivity analyses were carried out to examine the robustness of conclusions to different assumptions about departures from randomised policies, dependent on the availability of data and the particular set of circumstances, namely:
1. Imputation is a method of “filling in” missing data with plausible
values to give a completed dataset. Multiple imputation replaces each missing value with a
set of plausible values that represent the uncertainty about the right value to impute.
The procedure involves filling in missing data
2. In order to test the robustness of the SIB result, we limited a sensitivity analysis
to those patients for whom the risk of possible floor and ceiling effects was smallest,
i.e., SIB baseline cut-off values ≥ 40 but ≤ 90. Prespecified subgroup
analyses were carried out on change in SIB and change in NPI. We performed the test of
interaction, i.e., examined whether the treatment effects were consistent across
subgroups. The subgroups investigated were (a) type of neuroleptic (atypical versus
typical)—it made clinical sense to examine whether the type of neuroleptic
(atypical versus typical) at baseline made a difference since, if one type was more
harmful than the other, then discontinuation would benefit those patients more; (b)
baseline NPI (≤ 14 versus ≥ 15)—we intended to look at consistency
of treatment effect in relation to baseline NPI (≤ 14 versus 15 or more) in an
attempt to replicate Ballard et al. 2004 [
A three-person independent data-monitoring committee (DMC) was charged with overseeing patient safety. Its remit included prompt review of serious adverse events and a comprehensive review of all adverse events based upon interim data reports. The remit also required advice regarding any new or emerging information on the safety of the study treatments. If required, the DMC would make recommendations to the trial steering group and the sponsor about the safe continuation of the trial and any issues of concern. These decisions relied upon the independence and expertise of the DMC members and did not follow any strict “stopping rules.”
The first patient was randomised in October 2001 and the last in December 2004. 165
patients were randomised (83 to continue treatment and 82 to placebo, i.e., discontinue
treatment), of whom 128 (78%) commenced treatment (64 continue/64 placebo)
(
Demographic and Clinical Characteristics and Assessments at Baseline (All Patients Randomized)
Demographic and Clinical Characteristics and Assessments at Baseline (Analysis Population)
Details of Type and Dose of Treatment before Randomisation by Allocated Treatment Group
There was no significant difference between the continue treatment and placebo groups
(
Summary of Change from Baseline to 6 Months for Main Outcomes plus Comparative Statistics
For the NPI, there was no significant difference between the continue treatment and
placebo groups (
For the SMMSE, there was no significant difference between the continue treatment and
placebo groups (
For the STALD (receptive skills), once again there was no significant difference
between the continue treatment and placebo groups (
However, for the FAS, there was strong evidence, i.e., a highly significant difference
between the continue treatment and placebo groups (
For the M-UPDRS, there was a slight but nonsignificant difference between the continue
treatment and placebo groups (
For the change in FAST and CGIC, there was no evidence whatsoever of any differences
between the continue treatment and placebo groups (Wilcoxon rank-sum test
Imputed values were included for 12 participants, six in each treatment arm. These
individuals had similar characteristics to the overall trial population, but as would be
expected for participants unable to complete the trial, at baseline they were more
cognitively impaired (SIB ± SD, 68.1 ± 22.3 versus 74.4 ±
21.9) and had higher levels of neuropsychiatric symptoms (NPI ± SD, 22.2
± 14.8 versus 16.0 ± 13.9) than patients who subsequently completed
the 6 month assessments. The results for SIB (mean difference −2.1,
95% CI −8.8 to 4.6,
There was no evidence of any interaction between treatment group and the various
subgroups (
Given that a substantial proportion of patients did not actually start allocated treatment (∼22%), we decided to examine the robustness of results by performing an analysis with all data available. In addition, according to the protocol, all patients with SMMSE < 6 at pretrial screening were not required to complete SMMSE and FAS at any subsequent assessments; however, some measures were collected during the follow-up. Therefore, additional sensitivity analysis was performed on SMMSE and FAS to assess if results remained consistent when these measures were included. Once again, there were no substantive differences between the primary and sensitivity analyses, i.e., the results are very robust.
Although not specified in the original analysis plan, to avoid omitting potentially important clinical differences, additional descriptive data were also obtained regarding emergent delusions and agitation in participants who did not have these symptoms at baseline. The pattern of emergent symptoms appeared similar in the two treatment arms at 1, 3, and 6 mo assessments, respectively, for both delusions (neuroleptics 14%, 16%, 5% versus placebo 5%, 8%, 13%) and agitation (neuroleptics 17%, 23%, 32% versus placebo 23%, 26%, 34%).
Analysis at 12 mo was limited to the two main outcomes, cognitive function and
neuropsychiatric features, given the large amount of missing data. There was no
significant difference between the continue treatment and placebo groups
(
For the NPI, there was, however, a significant difference between the continue treatment
and placebo groups (
Because of difficulties in identifying people with Alzheimer disease in nursing homes who were taking neuroleptics and were able to complete the rigorous cognitive assessments, the recruitment target sample size based on the power calculation was not attained. However, despite this drawback, we report the largest and longest-duration randomized placebo controlled trial of neuroleptic discontinuation. To our knowledge this is the first study of this type to evaluate outcome over 6 mo and beyond.
Treatment with neuroleptics was not associated with significantly greater decline in global
cognitive function than placebo, although there were numerical advantages for the
placebo-treated group on the SIB and the SMMSE (1 point decrease on SMMSE, 0.4 point
decrease on SIB overall, ∼3 point decrease on SIB in people with NPI scores ≤
14) at 6 mo, which became more pronounced by month 12, at which point there was an 8 point
advantage on the SIB for the placebo-treated group, equivalent to approximately 6 mo of
average expected cognitive decline. The failure of these differences to attain statistical
significance may be because of limited statistical power (a type II error), as the magnitude
of difference in change in global cognition between neuroleptics and placebo at 6 mo was
consistent with the effect size identified in a recent meta-analysis [
On secondary cognitive outcomes, there was a significant deterioration in verbal fluency for patients taking neuroleptics compared to people receiving placebo, and there was a nonsignificant numerical advantage for the placebo-treated group on the BADLS. There were nonsignificant numerical advantages for the placebo group with respect to the severity of parkinsonism.
There was a marginal nonsignificant 2.4 point advantage on the total NPI score for
continuing neuroleptic treatment over the first 6 mo of treatment. Using a baseline NPI
threshold ≤14, previously reported to be predictive of outcome in a 3 mo neuroleptic
withdrawal trial [
In the post-hoc analysis there was no indication of a difference between people taking typical or atypical neuroleptics. The majority of individuals were taking risperidone or haloperidol, and the number of people taking other drugs was too small to enable any meaningful comparison. In particular, it will be important in further work to determine whether neuroleptics with more prominent antimuscarinic properties have a more potent impact on cognition in patients with dementia.
Several studies have demonstrated that psychological management approaches can replace
neuroleptic therapy without any significant worsening of neuropsychiatric symptoms
[
The magnitude of the impact of neuroleptics upon cognition, although consistent with a
recent meta-analysis, was considerably less marked than reported in a recent 6 mo
placebo-controlled trial of quetiapine [
The results of the current study must be interpreted within the context of a number of limitations. In particular, the sample size was much smaller than intended, conferring limited statistical power, and the number of deaths and withdrawals precluded meaningful analysis of data beyond the 6 mo follow-up. In addition a sizeable proportion of patients did not start their allocated treatment for a variety of reasons, mainly related to frailty and concurrent illnesses. The sample size achieved was short of the 220 target due mainly to problems identifying eligible patients, which in turn led to slow recruitment, bringing on more centres, and ultimately curtailing recruitment due to a lack of resources. Given the vulnerability of the study population, a substantial number of deaths and withdrawals are an almost inevitable problem to contend with. Probably the only solution would be to exclude people with profound dementia or with a certain degree of physical frailty, but this would then diminish the validity of drawing more general conclusions from the results. Although it is difficult, therefore, to see how this problem could have been avoided, the high number of drop-outs must be considered when interpreting the results.
In addition, the reason for the initial prescription of neuroleptic drugs was unclear in the majority of instances. Most prescriptions had been instigated by primary care physicians and, as a number of the individuals had changed their primary care physician, or been admitted to a care facility, or changed care facility since neuroleptics were first prescribed, the clinical indication for the original prescription was often lost. Although in many ways this lack of information is unsatisfactory, it does reflect real clinical practice, so that the population studied and the information available were representative of what faces clinicians in their routine practice. As few individuals were under specialist care, it is unlikely that treatment-refractory symptoms were a reason for neuroleptic use in most of the participants. The data regarding outcome and the baseline severity of symptoms do, however, provide a useful basis for clinical decisions. It is possible that the profile of the original symptoms for which the neuroleptics were prescribed may have influenced outcome, but this possibility could practically be investigated only in people with neuroleptic prescriptions of shorter duration, for which the presenting symptoms would be easier to ascertain.
For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status and by some measures improved functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this possibility must be weighed against the unwanted effects of therapy. The current study helps to inform a clinical management strategy for current practice, but the considerable risks of maintenance therapy highlight the urgency of further work to find, develop, and implement safer and more effective treatment approaches for neuropsychiatric symptoms in people with AD.
(44 KB PDF)
Other DART AD investigators: Timothy Smith, Ruth Elvish, Claire Maddison, Carol Bannister.
Data Monitoring and Ethics Committee: Clive Holmes (Chair), John Geddes and Robert Clarke.
DART-AD Pharmacists: (North East) Vranda Barbieri, Kay Carson, Gavin Mankin; (Oxfordshire) Michael Marven, Kim Gray; (London) Charlotte Gibbs.
Alzheimer disease
analysis of covariance
Bristol Activities of Daily Living Scale
Clinician's Global Impression of Change
confidence interval
data-monitoring committee
extrapyramidal signs and symptoms
Verbal Fluency Task
Functional Assessment Staging
interquartile range
Neuropsychiatric Inventory
standard deviation
Severe Impairment Battery
(Standardised) Mini Mental State Examination
Sheffield Test for Acquired Language Disorders
Unified Parkinson's Disease Rating Scale