Update on the EFFECTS study of fluoxetine for stroke recovery: a randomised controlled trial in Sweden

Studies have suggested that fluoxetine might improve neurological recovery after stroke, but the results remain inconclusive. The EFFECTS (Efficacy oF Fluoxetine – a randomisEd Controlled Trial in Stroke) reached its recruitment target of 1500 patients in June 2019. The purpose of this article is to present all amendments to the protocol and describe how we formed the EFFECTS trial collaboration in Sweden. Methods In this investigator-led, multicentre, parallel-group, randomised, placebo-controlled trial, we enrolled non-depressed stroke patients aged 18 years or older between 2 and 15 days after stroke onset. The patients had a clinical diagnosis of stroke (ischaemic or intracerebral haemorrhage) with persisting focal neurological deficits. Patients were randomised to fluoxetine 20 mg or matching placebo capsules once daily for 6 months. Results Seven amendments were made and included clarification of drug interaction between fluoxetine and metoprolol and the use of metoprolol for severe heart failure as an exclusion criterion, inclusion of data from central Swedish registries and the Swedish Stroke Register, changes in informed consent from patients, and clarification of design of some sub-studies. EFFECTS recruited 1500 patients at 35 centres in Sweden between 20 October 2014 and 28 June 2019. We plan to unblind the data in January 2020 and report the primary outcome in May 2020. Conclusion EFFECTS will provide data on the safety and efficacy of 6 months of treatment with fluoxetine after stroke in a Swedish health system setting. The data from EFFECTS will also contribute to an individual patient data meta-analysis

Effects of Fluoxetine on Outcomes at 12 Months After Acute Stroke:Results From EFFECTS, a Randomized Controlled Trial

Background and Purpose: The EFFECTS (Efficacy of Fluoxetine—a Randomised Controlled Trial in Stroke) recently reported that 20 mg fluoxetine once daily for 6 months after acute stroke did not improve functional outcome but reduced depression and increased fractures and hyponatremia at 6 months. The purpose of this predefined secondary analysis was to identify if any effects of fluoxetine were maintained or delayed over 12 months. Methods: EFFECTS was an investigator-led, randomized, placebo-controlled, double-blind, parallel group trial in Sweden that enrolled adult patients with stroke. Patients were randomized to 20 mg oral fluoxetine or matching placebo for 6 months and followed for another 6 months. The primary outcome was functional outcome (modified Rankin Scale), at 6 months. Predefined secondary outcomes for these analyses included the modified Rankin Scale, health status, quality of life, fatigue, mood, and depression at 12 months. Results: One thousand five hundred patients were recruited from 35 centers in Sweden between 2014 and 2019; 750 were allocated fluoxetine and 750 placebo. At 12 months, modified Rankin Scale data were available in 715 (95%) patients allocated fluoxetine and 712 (95%) placebo. The distribution of modified Rankin Scale categories was similar in the 2 groups (adjusted common odds ratio, 0.92 [95% CI, 0.76–1.10]). Patients allocated fluoxetine scored worse on memory with a median value of 89 (interquartile range, 75–100) versus 93 (interquartile range, 82–100); P =0.0021 and communication 93 (interquartile range, 82–100) versus 96 (interquartile range, 86–100); P =0.024 domains of the Stroke Impact Scale compared with placebo. There were no other differences in secondary outcomes. Conclusions: Fluoxetine after acute stroke had no effect on functional outcome at 12 months. Patients allocated fluoxetine scored worse on memory and communication on the Stroke Impact Scale compared with placebo, but this is likely to be due to chance. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02683213

Cbx4 maintains the epithelial lineage identity and cell proliferation in the developing stratified epithelium

During development, multipotent progenitor cells establish lineage-specific programmers of gene activation and silencing underlying their differentiation into specialized cell types. We show that the Polycomb component Cbx4 serves as a critical determinant that maintains the epithelial identity in the developing epidermis by repressing nonepidermal gene expression programs. Cbx4 ablation in mice results in a marked decrease of the epidermal thickness and keratinocyte (KC) proliferation associated with activation of numerous neuronal genes and genes encoding cyclin-dependent kinase inhibitors (p16/p19 and p57). Furthermore, the chromodomain- and SUMO E3 ligase–dependent Cbx4 activities differentially regulate proliferation, differentiation, and expression of nonepidermal genes in KCs. Finally, Cbx4 expression in KCs is directly regulated by p63 transcription factor, whereas Cbx4 overexpression is capable of partially rescuing the effects of p63 ablation on epidermal development. These data demonstrate that Cbx4 plays a crucial role in the p63-regulated program of epidermal differentiation, maintaining the epithelial identity and proliferative activity in KCs via repression of the selected nonepidermal lineage and cell cycle inhibitor genes

Safety and efficacy of fluoxetine on functional recovery after acute stroke (EFFECTS): a randomised, double-blind, placebo-controlled trial

Background Studies have suggested that fluoxetine could improve neurological recovery after stroke. The Efficacy oF Fluoxetine—a randomisEd Controlled Trial in Stroke (EFFECTS) trial aimed to assess whether administration of oral fluoxetine for 6 months after acute stroke improves functional outcome. Methods EFFECTS was an investigator-led, multicentre, randomised, placebo-controlled, double-blind, parallel group trial that enrolled patients aged 18 years or older between 2 and 15 days after stroke onset in 35 stroke and rehabilitation centres in Sweden. Eligible patients had a clinical diagnosis of ischaemic or intracerebral haemorrhage, brain imaging that was consistent with intracerebral haemorrhage or ischaemic stroke, and had at least one persisting focal neurological deficit. A web-based randomisation system that incorporated a minimisation algorithm was used to randomly assign (1:1) participants to receive oral fluoxetine 20 mg once daily or matching placebo capsules for 6 months. Patients, care providers, investigators, and outcomes assessors were masked to the allocation. The primary outcome was functional status, measured with the modified Rankin Scale (mRS) at 6 months, analysed in all patients with available mRS data at the 6-month follow-up; we did an ordinal analysis adjusted for the minimisation variables used in the randomisation. This trial is registered with EudraCT, 2011-006130-16; ISRCTN, 13020412; and ClinicalTrials.gov, NCT02683213. Findings Between Oct 20, 2014, and June 28, 2019, 1500 patients were enrolled, of whom 750 were randomly assigned to fluoxetine and 750 were randomly assigned to placebo. At 6 months, mRS data were available for 737 (98%) patients in the fluoxetine group and 742 (99%) patients in the placebo group. There was no effect of fluoxetine on the primary outcome—distribution across mRS score categories—compared with placebo (adjusted common odds ratio 0·94 [95% CI 0·78 to 1·13]; p=0·42). The proportion of patients with a new diagnosis of depression was lower with fluoxetine than with placebo (54 [7%] patients vs 81 [11%] patients; difference −3·60% [–6·49 to −0·71]; p=0·015), but fluoxetine was associated with more bone fractures (28 [4%] vs 11 [2%]; difference 2·27% [0·66 to 3·87]; p=0·0058) and hyponatraemia (11 [1%] vs one [<1%]; difference 1·33% [0·43 to 2·23]; p=0·0038) at 6 months. Interpretation Functional outcome after acute stroke did not improve with oral fluoxetine 20 mg once daily for 6 months. Fluoxetine reduced the occurrence of depression but increased the risk of bone fractures and hyponatraemia. Our results do not support the use of fluoxetine after acute stroke

Input rates, decay losses and accumulation rates of carbon in bogs during the last millennium: internal processes and environmental changes

In peatlands the balance between litter input and decay loss in the oxic acrotelm determines the rate of carbon input to the anoxic catotelm with carbon lost at very slow rate. In the acrotelm the C/N-quotient decreases with depth and indicates the loss of carbon from the acrotelm. On one boreo-nemoral and three subalpine ombrotrophic bogs in Sweden the carbon losses in the acrotelm plus the apparent carbon-accummlation rates in the catotelm for the last millennium revealed a constant carbon-sequestering rate up to the end of the nineteenth century equalling that in recent Sphagnum-dominated communities. On the boreo-nemoral bog the carbon-accumulation rate in the catotelm decreased by 50% over the same period while it remained constant on the subalpine bogs. A catotelm with permafrost may have provided more constant conditions for the carbon accumulation than a rising water level creating anoxic conditions. Due to vegetation changes, the recent carbon sequestering in the peat-forming communities is lower than previously and only just enough to compensate for the integrated losses. It is argued that because of internal processes the bogs up to the end of the nineteenth century had obtained or were approaching a steady-state with regard to the carbon input to the catotelm and the supply of mineral nutrients. In contrast, an increased climatic humidity around 1000 cal. BP resulted in high carbon-accumulation rates in the boreo-nemoral bog. Climate could have triggered the recent vegetation changes, but an increased nitrogen deposition is also a probable reason

Influence of vascular plant photosynthetic rate on CH4 emission from peat monoliths from southern boreal Sweden

Peat monoliths taken from a boreal peatland system were incubated at two different light intensities to investigate the effect of the photosynthetic rate of vascular plants (Eriophorum angustifolium) on net CH4 emission. The experimental set-up consisted of six replicate monoliths as controls and six where the photosynthetic active radiation (PAR) was reduced by 60%. NEP and total system respiration decreased significantly in response to reduced PAR. No significant changes in CH4 emission were found, but two different trends were noted. Methane emissions from the shaded monoliths initially seemed to be higher than emissions from the controls. After approximately four weeks the trend was reversed. The pattern may have been caused by “leakage” of organic compounds from inactivated roots that fueled CH4 production. It is suggested that a new balanced exchange of potential substrate carbon between the plants and the surrounding peat was established. Comparably less easily degradable carbon compounds would then become available for CH4 production. The fact that there appeared to be an effect of decreased carbon flow on CH4 emission is further supported by a tendency for lower concentrations of organic acids in porewater in the shaded monoliths at the end of the experiment. These results indicate a possible lagtime on the order of weeks before changes in photosynthesis rates and NEP have an effect onCH4 emission rates. Nevertheless it confirms the linkage between CO2 and CH4 cycling in wetland ecosystems

Interferences between Sphagnum and vascular plants: effects on plant community structure and peat formation

The interference between vascular plants and peat mosses with respect to nitrogen and phosphorus was studied in a fertilization experiment and with respect to competition for light in a removal experiment in poor fens with either soligenous or topogenous hydrology using Narthecium ossifragum (L.) Huds. and three species of Sphagnum sect. Sphagnum as targets. Adding fertilizer either on the moss surface or below it confirmed the hypotheses of an asymmetric competition for nutrients, viz. that the Sphagnum mosses relied on the atmospheric supply while Narthecium depended on mineralization in the peat. The results of the removal experiments and the negatively correlated growth of Narthecium and Sphagnum mosses demonstrated a symmetric competition for light. The intensity of the competition for light increased as the availability of N and P increased. The nutrient resources in the total biomass decreased with decreasing standing crop of Narthecium. Only with a considerable amount of mineral nutrients in the biomass has Narthecium the capacity to grow ahead of Sphagnum, because the asymmetric competition for N and P gives Sphagnum the capacity to reduce the performance of vascular plants. The mosses are more efficient in their use of nutrients and produce a decay-resistant litter inducing low mineralization and increasing the peat accumulation rate, and that withdraws N and P from the rhizosphere. The Sphagnum mosses thus act as ecological engineers structuring the plant community and determining the carbon balance of the system. The development of ombrotrophic conditions through peat accumulation seems less probable on soligenous than on topogenous mires owing to the higher mineralization rate there supporting the growth of the vascular plants. Correspondingly, disturbances of the Sphagnum cover, such as through airborne pollutants, increase the productivity of the vascular plants and decrease the capacity for carbon accumulation