A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial)

Background

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.

Methods and Findings

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 (p = 0.9). For neuropsychiatric symptoms, there was no significant difference between the continue treatment and placebo groups (n = 56 and 53, respectively) in the estimated mean change in NPI scores between baseline and 6 mo; estimated mean difference in deterioration (favouring continue treatment) −2.4 (95% CI −8.2 to 3.5), adjusted for baseline value (p = 0.4). Both results became more pronounced at 12 mo. There was some evidence to suggest that those patients with initial NPI ≥ 15 benefited on neuropsychiatric symptoms from continuing treatment.

Conclusions

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.Trial registration: Cochrane Central Registry of Controlled Trials/National Research Register (#ISRCTN33368770).     

NBD-labeled derivatives of the immunomodulatory drug FTY720 as tools for metabolism and mode of action studies

Fluorescently labeled chiral analogs of the immunomodulatory drug FTY720 and its corresponding phosphates with variable aliphatic spacers between the aromatic ring and the NBD label have been synthesized. Determining the influence of the spacer on the in vitro phosphorylation rate by SPHK1 and 2 resulted in the identification of NBD-(R)-AAL 1c,d which are phosphorylated with an efficiency comparable to that of the unlabeled FTY720 analog (R)-AAL. Furthermore, the NBD-(R)-AAL phosphates 10c,d were proven to be a functional S1P receptor agonist.     

Speech results of the Zürich approach in the treatment of unilateral cleft lip and palate

The purpose of this study was to describe perceptually the speech articulation, voice quality, and velopharyngeal competency of subjects with complete unilateral cleft lip and palate treated by the Zürich approach. The mean age of the 37 subjects was 10.5 years. Although only one subject had had secondary palatal management, no subject was rated as exhibiting a severe articulation or nasality problem. Subjects were rated as exhibiting adequate to marginal velopharyngeal competency 94.5 percent of the time, and the incidence of compensatory articulation errors was low. In comparison with other studies that evaluated the two-stage palatal repair, the Zürich approach appears to give the better results. The type of initial soft palate repair is probably the significant factor which contributes to the better speech of these subjects.     

Identifying and ameliorating nutrient limitations to reconstructing a forest ecosystem on mined land

Nutrient deficiency is commonly a limiting factor in reconstructing ecosystems on disturbed areas such as mines, quarries, and construction sites. An open‐cut coal mine in southeastern Australia is being used as a model to explore strategies for reconstructing a sustainable forest ecosystem on a spoil substrate. This study aimed to identify the nutrients limiting forest establishment and ways of ameliorating these. A pot trial, using two endemic Myrtaceae tree species, found that nitrogen was the most growth‐limiting nutrient followed by phosphorus. To overcome these spoil nutrient deficiencies, a field trial compared the application of forest topsoil to the addition of two rates of inorganic fertilizer, gypsum, or biosolids on the response of a range of native forest plant species directly seeded into the substrate. Only biosolids significantly increased total nitrogen levels in the spoil. However, all treatments significantly decreased spoil pH, thereby increasing nutrient availability. Topsoil produced the highest plant density of native species due to contributions from its seed bank. Biosolids increased growth of Corymbia maculata. The higher rate of fertilizer addition improved seedling establishment of Mimosaceae and the survival of Myrtaceae species. High nutrient treatments increased weed and grass densities, which may have reduced the nutrient benefit for native species. In conclusion, biosolids and the high rate of fertilizer application ameliorated the nitrogen and phosphorus deficiency of spoil to support growth and survival of reintroduced native species. However, potential benefits were attenuated by competition from accompanying weed growth that could be managed by implementing a control program.