Introduction Worldwide, there are 25 million people with dementia [1], the majority of whom have Alzheimer disease (AD). It is a devastating illness that results in a progressive decline in cognitive ability and functional capacity, causes immense distress to patients, their carers, and families, and has an enormous societal impact. Currently the most frequent treatment issue for people with AD presenting to clinical services remains the management of neuropsychiatric symptoms, such as aggression, agitation, and psychosis. Over 90% of people with dementia develop these symptoms at some point during their illness [2]. The symptoms are frequently distressing for the patients who experience them [3] and problematic for their caregivers [4], in whom they are associated with clinically significant depression [5]. In addition, they are often the precipitant for institutional care [6]. 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 [7,8] and 18 placebo-controlled trials with atypical neuroleptics [9–11]. The strongest evidence of efficacy is for risperidone, for which there are five published trials indicating a modest but significant diminution in aggression compared to placebo, but limited evidence of benefit for other neuropsychiatric symptoms [9–11]. However, given that in the US and Europe, up to 60% of people with dementia residing in care facilities are prescribed neuroleptics (e.g., [12,13]) for median periods of greater than a year [14,15], the pivotal question is whether longer-term therapy with atypical neuroleptics confers any treatment benefit. There are only two placebo-controlled trials of a neuroleptic for more than 14 wk, and neither showed significant efficacy of neuroleptic treatment for neuropsychiatric symptoms [16,17]. Similarly, longitudinal cohort studies [18] and placebo-controlled neuroleptic withdrawal studies [14,15,19] do not indicate benefit from neuroleptic therapy. However, all of the withdrawal studies continued for 3 mo or less, leaving some uncertainty regarding long-term symptom outcome. In addition, the largest study did suggest a benefit for treatment with atypical neuroleptics in people with scores greater than 14 on the Neuropsychiatric Inventory (NPI) [15]. 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) [7–11,20–22]. Additional evidence has also highlighted accelerated cognitive decline as an important potential negative consequence of prolonged use of neuroleptics [16,23]. A meta-analysis [17] has confirmed this observation, indicating 0.7 of a Mini Mental State Examination (MMSE) point (95% confidence interval [CI] 0.38 to 1.09) greater decline over 6–12 wk in neuroleptic-treated patients compared to those treated with placebo, which appears modest but represents a doubling in the expected rate of cognitive deterioration over this period. In the US the Food and Drug Administration [22] has warned about the risk of increased mortality and stroke with neuroleptics in people with dementia, and most practice guidelines recommend nonpharmacological approaches as the first-line treatment for agitation and other neuropsychiatric symptoms (e.g., [24]). However, there is still considerable debate as to the place of neuroleptics in the management of severe and distressing symptoms that are intractable to other treatment approaches, especially when there is potential risk to the patient or to others. 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. Methods Participants 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 [25]; (c) patient had either a MMSE [26] score > 6 or a Severe Battery Impairment [27] score > 30; and (d) patient was taking at least 10 mg chlorpromazine equivalents (CPZe) of a typical neuroleptic or at least 0.5 mg daily of risperidone. 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 [28,29]; (d) the patient was likely to be unable to take capsules. Ethics 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, http://www.nres.npsa.nhs.uk/). Consent 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. Interventions 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 (Table 1). Table 1 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. Objectives 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 [15]; (c) to examine the impact on parkinsonism; and (d) to determine the impact on global clinician rated outcome. Outcomes Primary outcomes. The primary outcome was the total SIB score [27] (change from baseline to 6 mo). This is a well-validated instrument designed to evaluate global cognitive functioning in individuals who are too impaired to complete standard neuropsychological tests. There are 40 questions in the SIB, assessing social interaction, memory, orientation, language, attention, praxis, visuospatial ability, construction, and orienting to name. A total score is obtained by summing all questions and ranged from 0 to 100. A higher score indicates higher cognitive ability. Secondary outcomes. 1. Standardised Mini Mental State Examination (SMMSE) [26]: A widely used instrument for assessing cognitive mental status. It assesses orientation, attention, immediate and short-term recall, language, and the ability to follow simple verbal and written commands. The maximum total score is 30. A higher total score indicates higher cognitive function. A standardized approach to the administration has been published and was adopted in the current study [26]. 2. FAS test of Verbal Fluency [30]: A verbal fluency test for which the total score is presented as the sum of all acceptable words generated. 3. Bristol Activities of Daily Living Scale (BADLS) [31]: A 20-item questionnaire to measure daily living abilities, specifically in patients with dementia. The maximum score is 60. 4. Sheffield Test for Acquired Language Disorders (STALD) [32]: Developed as a nonspecialist clinical aid to help identify dysphasia. The test assesses receptive and expressive skills. It gives a total score ranging from 0 to 26. 5. NPI [33]: A caregiver-administered questionnaire that assesses 12 behaviours of patients on the basis of frequency and severity: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability, aberrant motor behaviour, night-time behaviours, and appetite/eating behaviours. Each behaviour is scored by multiplying the frequency and severity (i.e., frequency × severity); the higher the score, the greater the neuropsychiatric impairment. A total score can be calculated by summing the scores of all behaviours (range 1 to 144). Lower scores indicate less frequent/severe. 6. Functional Assessment Staging (FAST) [34]: Has seven main stages that consist of physical and instrumental active daily living, which are intended to project the progression of loss of function in patients with dementia. 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 [35]. A score of 8 or more indicates significant parkinsonism [35]. 8. Clinician's Global Impression of Change (CGIC): A widely used and validated rating scale [36] based on the health-care provider's “general clinical impressions” with or without the informant input (i.e., family members). It evaluates global function and is scored from 1 (very much improved) to 7 (very much worsened). 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 Table 2. Table 2 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. Sample Size 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 [37], the same sample size gives 80% power to the 5% level of significance to detect an effect size of 0.43 (regarded conservatively as a medium effect size). As we expected the SIB to be a more sensitive measure than MMSE, it was anticipated that the sample size would have more than sufficient power to detect a clinically important difference. Randomisation 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 ( 14 there was a five-point, albeit nonsignificant, advantage for people continuing to receive neuroleptics (estimated difference −5.33, 95% CI −15.82 to 5.17). Figure 3 Subgroup Analysis (Change in NPI from Baseline to 6 Months) Cognition, language, and function. For the SMMSE, there was no significant difference between the continue treatment and placebo groups (n = 44 and 40, respectively) in the estimated mean change in SMMSE scores between baseline and 6 mo (Table 6), 1.0 points (SD 4.2) deterioration for the placebo group, and a 1.8 (SD 3.6) deterioration for the continue treatment group; estimated mean difference in deterioration (favouring placebo) −1.0 (95% CI −2.7 to 0.7), adjusted for baseline value (p = 0.2). For the BADLS, likewise there was no significant difference between the continue treatment and placebo groups (n = 54 and 52, respectively) in the estimated mean change in BADLS scores between baseline and 6 mo, 0.2 points (SD 7.2) worsening for the placebo group, and a 1.8 (SD 8.9) worsening for the continue treatment group; estimated mean difference in improvement (favouring placebo) 1.7 (95% CI −1.2 to 4.6), adjusted for baseline value (p = 0.2). For the STALD (receptive skills), once again there was no significant difference between the continue treatment and placebo groups (n = 34 and 39 respectively) in the estimated mean change in STALD (receptive skills) scores between baseline and 6 mo, 0.3 points (SD 2.1) deterioration for the placebo group, and a 0.5 (SD 1.7) deterioration for the continue treatment group; estimated mean difference in deterioration (favouring placebo) −0.2 (95% CI −1.1 to 0.6), adjusted for baseline value (p = 0.6). For the STALD there was no significant difference between the continue treatment and placebo groups (n = 34 and 39, respectively) in the estimated mean change in receptive language scores between baseline and 6 mo. For expressive language there was no significant difference of placebo compared to the treatment group; estimated mean difference (favouring placebo) −1.0 (95% CI −2.0 to 0.04), adjusted for baseline value (p = 0.06). However, for the FAS, there was strong evidence, i.e., a highly significant difference between the continue treatment and placebo groups (n = 34 and 31, respectively) in the estimated mean change in FAS totals between baseline and 6 mo. There was 0.6 points (SD 6.2) improvement for the placebo group compared to a 3.2 (SD 6.6) deterioration for the continue treatment group; estimated mean difference (favouring placebo) −4.5 (95% CI −7.3 to −1.7), adjusted for baseline value (p = 0.002). Parkinsonism. For the M-UPDRS, there was a slight but nonsignificant difference between the continue treatment and placebo groups (n = 41 and 43, respectively) in the estimated mean change in M-UPDRS scores between baseline and 6 mo, 0.4 points (SD 3.2) improvement for the placebo group compared to a 0.8 (SD 4.1) deterioration for the continue treatment group; estimated mean difference (favouring placebo) 1.1 (95% CI −0.4 to 2.6), adjusted for baseline value (p = 0.1). Global Outcome 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 p = 0.9 for both). Prespecified Sensitivity Analyses 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, p = 0.5), NPI, SMMSE, UPDRS, BADLS, STALD, and FAS all remained consistent when missing data were replaced using multiple imputation techniques. In addition, the result for sensitivity analysis of SIB excluding participants whose baseline SIB was 90, i.e., excluding patients unlikely to benefit from treatment (mean difference −0.2, 95% CI −9.2 to 8.9, p = 0.9) was again consistent with the primary result. Prespecified subgroup analysis. There was no evidence of any interaction between treatment group and the various subgroups (Figures 3 and 4). Figure 4 Subgroup Analysis (Change in SIB from Baseline to 6 Months) Post-Hoc Additional Exploratory Sensitivity Analysis 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 14 had an almost 5 point advantage (albeit nonsignificant) if they remained on neuroleptics, whereas there was no benefit for people with NPI scores below this threshold. For patients with more severe neuropsychiatric symptoms, there were modest benefits at 6 mo and more substantial advantages at 12 mo, which have to be weighed against the potential for serious adverse events. Some of the changes in NPI score are likely to be related to natural symptom course, or a Hawthorne effect, or regression to the mean, although there should be no imbalance in these factors between groups. There were no differences between groups for global clinician-rated outcome, and in an additional descriptive evaluation there appeared to be no difference in emergent delusions or agitation between groups. 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 [14,39]; and evidence is emerging that cholinesterase inhibitors [40] or memantine [41] may be safer, effective alternatives for some symptoms. The authors of the recent CATIE study [17], a large, pragmatic, 36-wk placebo-controlled trial of atypical neuroleptics in AD, concluded that the modest benefits were not sufficient to justify therapy in the presence of the increased risk of serious adverse events. Clinicians should certainly try to replace atypical neuroleptics with safer management approaches. Taking into consideration CATIE, the results of 6- to 12-wk placebo-controlled trials, and our own data, we would suggest that there is, however, a limited place for atypical neuroleptics in the maintenance treatment of severe neuropsychiatric manifestations (particularly aggression) in AD when there is tangible risk or severe distress, and the symptoms have been refractory to other treatment approaches. 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 [16]. There are numerous possible explanations for this difference, although it may be noted that unlike quetiapine, none of the atypical antipsychotics used in the current study had substantial antimuscarinic properties, and it is possible that antimuscarinic properties may exacerbate the impact of neuroleptics upon cognition. Although this is speculative, it is consistent with a study comparing cognition in patients with AD treated with either risperidone or olanzapine, where olanzapine treatment was associated with greater impairment of attentional and executive performance related to anticholinergic activity [42]. Within the current study there was a significant detrimental impact upon expressive language function, an important skill to enable social communication and maintain quality of life in people with AD residing in care facilities. Further work is needed to examine the effects on different aspects of cognitive function, to clarify the differential impact of individual neuroleptic drugs, and to determine whether the impact upon cognition is sufficient to interfere with everyday activities. 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. Conclusion 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. Supporting Information Text S1 CONSORT Checklist (44 KB PDF) Click here for additional data file.
