The ‘patient voice’: patients who experience antidepressant withdrawal symptoms are often dismissed, or misdiagnosed with relapse, or a new medical condition

Background: Stopping antidepressants commonly causes withdrawal symptoms, which can be severe and long-lasting. National Institute for Health and Care Excellence (NICE) guidance has been recently updated to reflect this; however, for many years withdrawal (discontinuation) symptoms were characterised as ‘usually mild and self-limiting over a week’. Consequently, withdrawal symptoms might have been misdiagnosed as relapse of an underlying condition, or new onset of another medical illness, but this has never been studied. Method: This paper outlines the themes emerging from 158 respondents to an open invitation to describe the experience of prescribed psychotropic medication withdrawal for petitions sent to British parliaments. The accounts include polypharmacy (mostly antidepressants and benzodiazepines) but we focus on antidepressants because of the relative lack of awareness about their withdrawal effects compared with benzodiazepines. Mixed method analysis was used, including a ‘lean thinking’ approach to evaluate common failure points. Results: The themes identified include: a lack of information given to patients about the risk of antidepressant withdrawal; doctors failing to recognise the symptoms of withdrawal; doctors being poorly informed about the best method of tapering prescribed medications; patients being diagnosed with relapse of the underlying condition or medical illnesses other than withdrawal; patients seeking advice outside of mainstream healthcare, including from online forums; and significant effects on functioning for those experiencing withdrawal. Discussion: Several points for improvement emerge: the need for updating of guidelines to help prescribers recognise antidepressant withdrawal symptoms and to improve informed consent processes; greater availability of non-pharmacological options for managing distress; greater availability of best practice for tapering medications such as antidepressants; and the vital importance of patient feedback. Although the patients captured in this analysis might represent medication withdrawal experiences that are more severe than average, they highlight the current inadequacy of health care systems to recognise and manage prescribed drug withdrawal, and patient feedback in general

Dihydropyrimidine-thiones and clioquinol synergize to target beta-amyloid cellular pathologies through a metal-dependent mechanism

The lack of therapies for neurodegenerative diseases arises from our incomplete understanding of their underlying cellular toxicities and the limited number of predictive model systems. It is critical that we develop approaches to identify novel targets and lead compounds. Here, a phenotypic screen of yeast proteinopathy models identified dihydropyrimidine-thiones (DHPM-thiones) that selectively rescued the toxicity caused by β-amyloid (Aβ), the peptide implicated in Alzheimer’s disease. Rescue of Aβ toxicity by DHPM-thiones occurred through a metal-dependent mechanism of action. The bioactivity was distinct, however, from that of the 8-hydroxyquinoline clioquinol (CQ). These structurally dissimilar compounds strongly synergized at concentrations otherwise not competent to reduce toxicity. Cotreatment ameliorated Aβ toxicity by reducing Aβ levels and restoring functional vesicle trafficking. Notably, these low doses significantly reduced deleterious off-target effects caused by CQ on mitochondria at higher concentrations. Both single and combinatorial treatments also reduced death of neurons expressing Aβ in a nematode, indicating that DHPM-thiones target a conserved protective mechanism. Furthermore, this conserved activity suggests that expression of the Aβ peptide causes similar cellular pathologies from yeast to neurons. Our identification of a new cytoprotective scaffold that requires metal-binding underscores the critical role of metal phenomenology in mediating Aβ toxicity. Additionally, our findings demonstrate the valuable potential of synergistic compounds to enhance on-target activities, while mitigating deleterious off-target effects. The identification and prosecution of synergistic compounds could prove useful for developing AD therapeutics where combination therapies may be required to antagonize diverse pathologies.D.F.T was funded by NRSA Fellowship NIH 5F32NS061419. D.F.T. and S.L. were supported by WIBR funds in support of research on Regenerative Disease, the Picower/JPB Foundation, and the Edward N. and Della L. Thome Foundation. G.A.C. and S.L. were funded by a Howard Hughes Medical Institute (HHMI) Collaborative Innovation Award. L.E.B., R.T., and S.E.S. were funded by NIH GM086180, NIH GM067041, and NIH GM111625. (5F32NS061419 - NRSA Fellowship NIH; WIBR funds in support of research on Regenerative Disease; Picower/JPB Foundation; Edward N. and Della L. Thome Foundation; Howard Hughes Medical Institute (HHMI) Collaborative Innovation Award; GM086180 - NIH; NIH GM067041 - NIH; NIH GM111625 - NIH)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705239/Accepted manuscrip

Effective anisotropy of thin nanomagnets: beyond the surface anisotropy approach

We study the effective anisotropy induced in thin nanomagnets by the nonlocal demagnetization field (dipole-dipole interaction). Assuming a magnetization independent of the thickness coordinate, we reduce the energy to an inhomogeneneous onsite anisotropy. Vortex solutions exist and are ground states for this model. We illustrate our approach for a disk and a square geometry. In particular, we obtain good agreement between spin-lattice simulations with this effective anisotropy and micromagnetic simulations.Comment: ReVTeX, 14 pages, 6 figure

Testing asteroseismology with Gaia DR2: Hierarchical models of the Red Clump

Asteroseismology provides fundamental stellar parameters independent of distance, but subject to systematics under calibration. Gaia DR2 has provided parallaxes for a billion stars, which are offset by a parallax zero-point. Red Clump (RC) stars have a narrow spread in luminosity, thus functioning as standard candles to calibrate these systematics. This work measures how the magnitude and spread of the RC in the Kepler field are affected by changes to temperature and scaling relations for seismology, and changes to the parallax zero-point for Gaia. We use a sample of 5576 RC stars classified through asteroseismology. We apply hierarchical Bayesian latent variable models, finding the population level properties of the RC with seismology, and use those as priors on Gaia parallaxes to find the parallax zero-point offset. We then find the position of the RC using published values for the zero-point. We find a seismic temperature insensitive spread of the RC of ~0.03 mag in the 2MASS K band and a larger and slightly temperature-dependent spread of ~0.13 mag in the Gaia G band. This intrinsic dispersion in the K band provides a distance precision of ~1% for RC stars. Using Gaia data alone, we find a mean zero-point of -41 $\pm$ 10 $\mu$as. This offset yields RC absolute magnitudes of -1.634 $\pm$ 0.018 in K and 0.546 $\pm$ 0.016 in G. Obtaining these same values through seismology would require a global temperature shift of ~-70 K, which is compatible with known systematics in spectroscopy.Comment: Accepted for publication in MNRA

Effects of Daily Zinc, Daily Multiple Micronutrient Powder, or Therapeutic Zinc Supplementation for Diarrhea Prevention on Physical Growth, Anemia, and Micronutrient Status in Rural Laotian Children: A Randomized Controlled Trial.

ObjectivesTo evaluate the optimal zinc supplementation strategy for improving growth and hematologic and micronutrient status in young Laotian children.Study designIn total, 3407 children aged 6-23 months were randomized to receive either daily preventive zinc tablets (7 mg/d), high-zinc, low-iron micronutrient powder (10 mg/d zinc, 6 mg/d iron, and 13 other micronutrients), therapeutic zinc supplementation for diarrhea (20 mg/d for 10 days per episode), or daily placebo powder; all were followed for ~9 months. Anthropometry, hemoglobin, zinc, and iron status were assessed at baseline and endline. Analyses were by intention-to-treat, using linear and modified Poisson regression.ResultsAt baseline, mean (±SD) age was 14.2 ± 5.1 months and stunting and anemia prevalence were 37.9% and 55.6%, respectively. At endline, zinc deficiency in the preventive zinc (50.7%) and micronutrient powder (59.1%) groups were significantly lower than in the therapeutic zinc (79.2%) and control groups (78.6%; P < .001), with no impact on stunting (37.1%-41.3% across the groups, P = .37). The micronutrient powder reduced iron deficiency by 44%-55% compared with other groups (P < .001), with no overall impact on anemia (P = .14). Micronutrient powder tended to reduce anemia by 11%-16% among children who were anemic at baseline (P = .06).ConclusionsDespite improving zinc status, preventive zinc and micronutrient powder had no impact on growth. The micronutrient powder improved iron status and tended to reduce anemia among the subset of previously anemic children.Trial registrationClinicalTrials.govNCT02428647