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 [11
], and became more substantial over further follow-up. It would be more usual in a study of this type to hypothesise equivalence or the absence of an advantage to the treatment that is being removed, and there is certainly no evidence at all from these results suggesting any cognitive advantage favouring antipsychotics.
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 [15
], the change in NPI did not differ between the treatment groups. Participants with baseline NPI scores > 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
]; 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.
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.