Adverse effects of Z-drugs for sleep disturbance in people living with dementia: a population-based cohort study.

BACKGROUND: Sleep disturbance is common in dementia and often treated with Z-drugs (zopiclone, zaleplon, and zolpidem). While some observational studies suggest that Z-drugs are associated with adverse events such as falls and fracture risks in older people, this has not been studied in dementia. METHODS: We used data from 27,090 patients diagnosed with dementia between January 2000 and March 2016 from the Clinical Practice Research Datalink linked to Hospital Episodes Statistics data in England. We compared adverse events for 3532 patients newly prescribed Z-drugs by time-varying dosage to (1) 1833 non-sedative-users with sleep disturbance; (2) 10,214 non-sedative-users with proximal GP consultation matched on age, sex, and antipsychotic use; and (3) 5172 patients newly prescribed benzodiazepines. We defined higher dose Z-drugs and benzodiazepines as prescriptions equivalent to ≥ 7.5 mg zopiclone or > 5 mg diazepam daily. Cox regression was used to estimate hazard ratios (HRs) for incident fracture, hip fracture, fall, mortality, acute bacterial infection, ischaemic stroke/transient ischaemic attack, and venous thromboembolism over a 2-year follow-up, adjusted for demographic- and health-related covariates. RESULTS: The mean (SD) age of patients was 83 (7.7) years, and 16,802 (62%) were women. Of 3532 patients prescribed Z-drugs, 584 (17%) were initiated at higher doses. For patients prescribed higher dose Z-drugs relative to non-users with sleep disturbance, the HRs (95% confidence interval) for fractures, hip fractures, falls, and ischaemic stroke were 1.67 (1.13-2.46), 1.96 (1.16-3.31), 1.33 (1.06-1.66), and 1.88 (1.14-3.10), respectively. We observed similar associations when compared to non-sedative-users with proximal GP consultation. Minimal or inconsistent excess risks were observed at ≤ 3.75 mg zopiclone or equivalent daily, and for mortality, infection, and venous thromboembolism. We observed no differences in adverse events for Z-drugs compared to benzodiazepines, except lower mortality rates with Z-drugs (HR [95% confidence interval] of 0.73 [0.64-0.83]). CONCLUSIONS: Higher dose Z-drug use in dementia is associated with increased fracture and stroke risks, similar or greater to that for higher dose benzodiazepines. Higher dose Z-drugs should be avoided, if possible, in people living with dementia, and non-pharmacological alternatives preferentially considered. Prescriptions for higher dose Z-drugs in dementia should be regularly reviewed. TRIAL REGISTRATION: ENCePP e-register of studies, EUPAS18006.

Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy.

Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo.

UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy.

Deafferentation of motor neurons as a result of defective sensory-motor connectivity is a critical early event in the pathogenesis of spinal muscular atrophy, but the underlying molecular pathways remain unknown. We show that restoration of ubiquitin-like modifier-activating enzyme 1 (UBA1) was sufficient to correct sensory-motor connectivity in the spinal cord of mice with spinal muscular atrophy. Aminoacyl-tRNA synthetases, including GARS, were identified as downstream targets of UBA1. Regulation of GARS by UBA1 occurred via a non-canonical pathway independent of ubiquitylation. Dysregulation of UBA1/GARS pathways in spinal muscular atrophy mice disrupted sensory neuron fate, phenocopying GARS-dependent defects associated with Charcot-Marie-Tooth disease. Sensory neuron fate was corrected following restoration of UBA1 expression and UBA1/GARS pathways in spinal muscular atrophy mice. We conclude that defective sensory motor connectivity in spinal muscular atrophy results from perturbations in a UBA1/GARS pathway that modulates sensory neuron fate, thereby highlighting significant molecular and phenotypic overlap between spinal muscular atrophy and Charcot-Marie-Tooth disease.

The electronic frailty index as an indicator of community healthcare service utilisation in the older population.

BACKGROUND: older people with frailty are particularly high users of healthcare services, however a lack of standardised recording of frailty in different healthcare electronic datasets has limited investigations into healthcare service usage and demand of the older frail population. OBJECTIVES: to investigate the community service demand of frail patients using the electronic frailty index (eFI) as a measure of frailty. STUDY DESIGN AND SETTING: a retrospective cohort study using anonymised linked healthcare patient data from primary care, community services and acute hospitals in Norfolk. PARTICIPANTS: patients aged 65 and over who had an eFI assessment score established in their primary care electronic patient record in Norwich based General Practices. RESULTS: we include data from 22,859 patients with an eFI score. Frailty severity increased with age and was associated with increased acute hospital admission within a 6-month window. Patients with a frail eFI score were also more likely to have a community service referral within a 6-month window of frailty assessment, with a RR of 1.84 (1.76-1.93) for mild frailty, 1.96 (1.83-2.09) for moderate frailty and 2.95 (2.76-3.14) for severe frailty scores. We also found that frail patients had more community referrals per patient then those classified as fit and required more care plans per community referral. CONCLUSIONS: eFI score was an indicator of community service use, with increasing severity of frailty being associated with higher community healthcare requirements. The eFI may help planning of community services for the frail population.

Non-benzodiazepine hypnotic use for sleep disturbance in people aged over 55 years living with dementia: a series of cohort studies.

BACKGROUND: Sleep disturbance affects around 60% of people living with dementia and can negatively affect their quality of life and that of their carers. Hypnotic Z-drugs (zolpidem, zopiclone and zaleplon) are commonly used to treat insomnia, but their safety and efficacy have not been evaluated for people living with dementia. OBJECTIVES: To estimate the benefits and harms of Z-drugs in people living with dementia with sleep disturbance. DESIGN: A series of observational cohort studies using existing data from (1) primary care linked to hospital admission data and (2) clinical cohort studies of people living with dementia. DATA SOURCES: Primary care study - Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office for National Statistics mortality data. Clinical cohort studies - the Resource Use and Disease Course in Dementia - Nursing Homes (REDIC) study, National Alzheimer's Coordinating Centre (NACC) clinical data set and the Improving Well-being and Health for People with Dementia (WHELD) in nursing homes randomised controlled trial. SETTING: Primary care study - 371 primary care practices in England. Clinical cohort studies - 47 nursing homes in Norway, 34 Alzheimer's disease centres in the USA and 69 care homes in England. PARTICIPANTS: Primary care study - NHS England primary care patients diagnosed with dementia and aged > 55 years, with sleep disturbance or prescribed Z-drugs or low-dose tricyclic antidepressants, followed over 2 years. Clinical cohort studies - people living with dementia consenting to participate, followed over 3 years, 12 years and 9 months, for REDIC, NACC and WHELD, respectively. INTERVENTIONS: The primary exposure was prescription or use of Z-drugs. Secondary exposures included prescription or use of benzodiazepines, low-dose tricyclic antidepressants and antipsychotics. MAIN OUTCOME MEASURES: Falls, fractures, infection, stroke, venous thromboembolism, mortality, cognitive function and quality of life. There were insufficient data to investigate sleep disturbance. RESULTS: The primary care study and combined clinical cohort studies included 6809 and 18,659 people living with dementia, with 3089 and 914 taking Z-drugs, respectively. New Z-drug use was associated with a greater risk of fractures (hazard ratio 1.40, 95% confidence interval 1.01 to 1.94), with risk increasing with greater cumulative dose (p = 0.002). The hazard ratio for Z-drug use and hip fracture was 1.59 (95% confidence interval 1.00 to 2.53) and for mortality was 1.34 (95% confidence interval 1.10 to 1.64). No excess risks of falls, infections, stroke or venous thromboembolism were detected. Z-drug use also did not have an impact on cognition, neuropsychiatric symptoms, disability or quality of life. LIMITATIONS: Primary care study - possible residual confounding because of difficulties in identifying patients with sleep disturbance and by dementia severity. Clinical cohort studies - the small numbers of people living with dementia taking Z-drugs and outcomes not necessarily being measured before Z-drug initiation restricted analyses. CONCLUSIONS: We observed a dose-dependent increase in fracture risk, but no other harms, with Z-drug use in dementia. However, multiple outcomes were examined, increasing the risk of false-positive findings. The mortality association was unlikely to be causal. Further research is needed to confirm the increased fracture risk. Decisions to prescribe Z-drugs may need to consider the risk of fractures, balanced against the impact of improved sleep for people living with dementia and that of their carers. Our findings suggest that when Z-drugs are prescribed, falls prevention strategies may be needed, and that the prescription should be regularly reviewed. FUTURE WORK: More research is needed on safe and effective management strategies for sleep disturbance in people living with dementia. STUDY REGISTRATION: This study is registered as European Union electronic Register of Post-Authorisation Studies (EU PAS) 18006. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 1. See the NIHR Journals Library website for further project information.

WHAT WAS THE PROBLEM?: Poor sleep is common in people living with dementia. It can worsen their own and their carer's quality of life. Sleeping tablets called Z-drugs (zolpidem, zopiclone and zaleplon) are often given to people with dementia. Some studies suggest that Z-drugs may be harmful, but no studies have looked into the effects of Z-drugs for people with dementia. Good sleep is important, but we need to understand if Z-drugs cause harm. WHAT DID WE DO?: Using existing medical records, we compared the quality of life, memory and number of falls, infections, strokes, broken bones and deaths for a group of people living with dementia taking a Z-drug, with those for a group not taking any sleep drug. WHAT DID WE FIND?: Z-drug users were no more likely to suffer falls, infection or stroke, but they were more likely to break a bone. We also found that Z-drug users died earlier, but we could not be sure that this was as a result of taking the Z-drug. Using Z-drugs did not appear to affect quality of life or memory. We talked to carers and health-care practitioners, who told us that decisions about Z-drugs need to balance a range of complicated health and social factors. WHAT DOES THIS MEAN?: We found that people living with dementia who take Z-drugs are more likely to break a bone or to die sooner than similar people with dementia who are not taking Z-drugs. However, we cannot be certain that these problems are caused by Z-drugs, as many other factors can also lead to broken bones and death. Further work is needed to clarify the risk of broken bones, but if sleep problems can be managed in other ways then this may be preferable. Patients and family carers should be involved in decisions about Z-drugs, so that they can balance the possible harms against the benefits.

Sonic hedgehog functions upstream of disrupted-in-schizophrenia 1 (disc1): implications for mental illness.

DISRUPTED-IN-SCHIZOPHRENIA (DISC1) has been one of the most intensively studied genetic risk factors for mental illness since it was discovered through positional mapping of a translocation breakpoint in a large Scottish family where a balanced chromosomal translocation was found to segregate with schizophrenia and affective disorders. While the evidence for it being central to disease pathogenesis in the original Scottish family is compelling, recent genome-wide association studies have not found evidence for common variants at the DISC1 locus being associated with schizophrenia in the wider population. It may therefore be the case that DISC1 provides an indication of biological pathways that are central to mental health issues and functional studies have shown that it functions in multiple signalling pathways. However, there is little information regarding factors that function upstream of DISC1 to regulate its expression and function. We herein demonstrate that Sonic hedgehog (Shh) signalling promotes expression of disc1 in the zebrafish brain. Expression of disc1 is lost in smoothened mutants that have a complete loss of Shh signal transduction, and elevated in patched mutants which have constitutive activation of Shh signalling. We previously demonstrated that disc1 knockdown has a dramatic effect on the specification of oligodendrocyte precursor cells (OPC) in the hindbrain and Shh signalling is known to be essential for the specification of these cells. We show that disc1 is prominently expressed in olig2-positive midline progenitor cells that are absent in smo mutants, while cyclopamine treatment blocks disc1 expression in these cells and mimics the effect of disc1 knock down on OPC specification. Various features of a number of psychiatric conditions could potentially arise through aberrant Hedgehog signalling. We therefore suggest that altered Shh signalling may be an important neurodevelopmental factor in the pathobiology of mental illness.