Van Reekum R, Clarke D, Conn D, et al. A randomized, placebo-controlled trial of the discontinuation of long-term antipsychotics in dementia. International Psychogeriatrics 2002;14:197-210.
PubMed link: https://www.ncbi.nlm.nih.gov/pubmed/12243210
| Methods | Study design: Randomized double-blind placebo-controlled study with a parallel-design
Number of groups: Two groups |
| Participants | Number of participants: 34 randomized, 18 completed
· Active deprescribing group: 17 randomized, 11 completed · Control group: 17 randomized, 7 completed Age: 84.4 ± 4.6 years Sex: 16 female, 17 male Participants with dementia: All · MMSE: 8.8 ± 8.6 · Length of time since dementia onset: 5.9 ± 33 years · Dementia type, Alzheimer’s Disease n=10, vascular Dementia n=4, dementia not otherwise specified n=3 Inclusion criteria: · Dementia · Currently receiving antipsychotics for 6 months or greater Exclusion criteria: · History of antipsychotic discontinuation having failed, because of a clinically significant increase in psychosis or agitation (as indicated by the treating physician reinstating antipsychotic treatment or increasing the dose) in the past 6 months · History of schizophrenia · Antipsychotic use intended only for the treatment of nausea · Diagnosis of delirium DSM-IV criteria · Global rating score of three on the Behavioral Pathology in Alzheimer’s Disease Rating Scale at the time of screening, a week before the start of the study, or within the 2 weeks of the pre-trial period Concomitant medicines: Standard order for lorazepam 0.5-1mg every 8 hours as required for agitation. All other as required medicines for behavior were discontinued. Country: Canada Setting: Residential aged care facilities – two residential aged care facilities, and the geriatric chronic care floors of an academic health science center |
| Interventions | Medicine: Antipsychotics
· Risperidone n=12 · Thioridazine n=6 · Loxapine n=6 · Perphenazine n=3 · Olanzapine n = 3 · Haloperidol n=2 · Nozinan n = 1 · Treatment Follow-up duration: 1.8 ± 1.9 years · Daily baseline dose (in chlorpromazine equivalence): 24.9 ± 15.9mg Withdrawal schedule: · Week 1: half the original dose · Week 2: quarter of the original dose · Week 3: cease Comparator: Placebo compared to continued therapy |
| Outcomes | Behavioral Pathology in Alzheimer’s Disease Rating Scale
Neuropsychiatric Inventory Retrospective Overt Aggression Scale Cognitive Function assessed by the MMSE and Mattis Dementia Rating Scale Functional level assessed by the Blessed Dementia Scale – activities of daily living and motivational behavior sub-scale Extrapyramidal symptoms assessed by the Extrapyramidal Symptom Rating Scale Clinical global impression scale Behavioral deteriorations leading to study withdrawal Lorazepam use as required |
| Dates | Dates: Not described
Follow-up duration: 26 weeks |
| Funding sources | Alzheimer Society of Canada. Dr. van Reekum is supported by the Kunin-Lunenfeld Applied Research Unit of Baycrest Center and is engaged in further research supported by the Alzheimer’s Society of Canada. |
| Notes | Few absolute numbers reported – predominantly descriptive, and relative outcomes reported. |
Risk of bias table
| Bias | Authors’ judgment | Support for judgment |
| Random sequence generation (selection bias) | Low risk | “A random number table was used to allocate subjects to receive either continued antipsychotic treatment at the current dose or to receive identical placebo.” |
| Allocation concealment (selection bias) | Unclear risk | Not described. |
| Blinding of participants and personnel (performance bias) | Low risk | “During all study periods, medications, including placebo, were placed into identical capsules to maintain blindness.” |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not described for outcome assessors. |
| Incomplete outcome data (attrition bias) | High risk | It appears that those who dropped out of the study were excluded from the analysis other than to assess if the two groups were similar in their dropout rates.
“The total number of subjects who were withdrawn from the study early was 16, with ten in the placebo group and six in the active treatment group. Therefore, the rate of early study withdrawal was 58.8% in the placebo group and 37.5% in the active treatment group. The difference in the rate of early study withdrawal was not statistically significant (relative risk [= 1.57,95%confidence interval [CI] 0.76-3.26). Subjects were withdrawn from the study early due to medical illness (1 participant: 2 participants), death (1 participant: 2 participants), extrapyramidal symptoms (3 participant: 0 participants), and exacerbation of behavioral problems (4 participant: 3 participants). All of these differences were statistically non-significant at p > 0.1 (Fisher’s Exact Test). Much of the difference in overall apparent early study withdrawal rate appears to be accounted for by the three subjects in the placebo group who were withdrawn because of worsening of extrapyramidal symptoms.” |
| Selective reporting (reporting bias) | High risk | The following outcomes were not reported:
– Neuropsychiatric symptoms (assessed using Neuropsychiatric Index) The presentation of the results was slightly imprecise with use of the descriptor “trend” many times. If this had been supplemented by more raw data rather than only p-values, better interpretation may be possible. |
| Other bias | Low risk | Funding appears independent. |
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