Countermeasures to prevent and treat coronavirus disease 2019 (COVID-19) are a global health priority. We enrolled a cohort of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-recovered ...participants, developed neutralization assays to investigate antibody responses, adapted our high-throughput antibody generation pipeline to rapidly screen more than 1800 antibodies, and established an animal model to test protection. We isolated potent neutralizing antibodies (nAbs) to two epitopes on the receptor binding domain (RBD) and to distinct non-RBD epitopes on the spike (S) protein. As indicated by maintained weight and low lung viral titers in treated animals, the passive transfer of a nAb provides protection against disease in high-dose SARS-CoV-2 challenge in Syrian hamsters. The study suggests a role for nAbs in prophylaxis, and potentially therapy, of COVID-19. The nAbs also define protective epitopes to guide vaccine design.
There has been a steady increase in the number of primary care patients receiving long-term maintenance antidepressant treatment, despite limited evidence of a benefit of this treatment beyond 8 ...months.
The ANTidepressants to prevent reLapse in dEpRession (ANTLER) trial investigated the clinical effectiveness and cost-effectiveness of antidepressant medication in preventing relapse in UK primary care.
This was a Phase IV, double-blind, pragmatic, multisite, individually randomised parallel-group controlled trial, with follow-up at 6, 12, 26, 39 and 52 weeks. Participants were randomised using minimisation on centre, type of antidepressant and baseline depressive symptom score above or below the median using Clinical Interview Schedule - Revised (two categories). Statisticians were blind to allocation for the outcome analyses.
General practices in London, Bristol, Southampton and York.
Individuals aged 18-74 years who had experienced at least two episodes of depression and had been taking antidepressants for ≥ 9 months but felt well enough to consider stopping their medication. Those who met an
, Tenth Revision, diagnosis of depression or with other psychiatric conditions were excluded.
At baseline, participants were taking citalopram 20 mg, sertraline 100 mg, fluoxetine 20 mg or mirtazapine 30 mg. They were randomised to either remain on their current medication or discontinue medication after a tapering period.
The primary outcome was the time, in weeks, to the beginning of the first depressive episode after randomisation. This was measured by a retrospective Clinical Interview Schedule - Revised that assessed the onset of a depressive episode in the previous 12 weeks, and was conducted at 12, 26, 39 and 52 weeks. The depression-related resource use was collected over 12 months from medical records and patient-completed questionnaires. Quality-adjusted life-years were calculated using the EuroQol-5 Dimensions, five-level version.
Between 9 March 2017 and 1 March 2019, we randomised 238 participants to antidepressant continuation (the maintenance group) and 240 participants to antidepressant discontinuation (the discontinuation group). The time to relapse of depression was shorter in the discontinuation group, with a hazard ratio of 2.06 (95% confidence interval 1.56 to 2.70;
< 0.0001). By 52 weeks, relapse was experienced by 39% of those who continued antidepressants and 56% of those who discontinued antidepressants. The secondary analysis revealed that people who discontinued experienced more withdrawal symptoms than those who remained on medication, with the largest difference at 12 weeks. In the discontinuation group, 37% (95% confidence interval 28% to 45%) of participants remained on their randomised medication until the end of the trial. In total, 39% (95% confidence interval 32% to 45%) of participants in the discontinuation group returned to their original antidepressant compared with 20% (95% confidence interval 15% to 25%) of participants in maintenance group. The health economic evaluation demonstrated that participants randomised to discontinuation had worse utility scores at 3 months (-0.037, 95% confidence interval -0.059 to -0.015) and fewer quality-adjusted life-years over 12 months (-0.019, 95% confidence interval -0.035 to -0.003) than those randomised to continuation. The discontinuation pathway, besides giving worse outcomes, also cost more extra £2.71 per patient over 12 months (95% confidence interval -£36.10 to £37.07) than the continuation pathway, although the cost difference was not significant.
Patients who discontinue long-term maintenance antidepressants in primary care are at increased risk of relapse and withdrawal symptoms. However, a substantial proportion of patients can discontinue antidepressants without relapse. Our findings will give patients and clinicians an estimate of the likely benefits and harms of stopping long-term maintenance antidepressants and improve shared decision-making. The participants may not have been representative of all people on long-term maintenance treatment and we could study only a restricted range of antidepressants and doses. Identifying patients who will not relapse if they discontinued antidepressants would be clinically important.
Current Controlled Trials ISRCTN15969819 and EudraCT 2015-004210-26.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 25, No. 69. See the NIHR Journals Library website for further project information.
Depression is usually managed in primary care and antidepressants are often the first-line treatment, but only half of those treated respond to a single antidepressant.
To investigate whether or not ...combining mirtazapine with serotonin-noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressants results in better patient outcomes and more efficient NHS care than SNRI or SSRI therapy alone in treatment-resistant depression (TRD).
The MIR trial was a two-parallel-group, multicentre, pragmatic, placebo-controlled randomised trial with allocation at the level of the individual.
Participants were recruited from primary care in Bristol, Exeter, Hull/York and Manchester/Keele.
Eligible participants were aged ≥ 18 years; were taking a SSRI or a SNRI antidepressant for at least 6 weeks at an adequate dose; scored ≥ 14 points on the Beck Depression Inventory-II (BDI-II); were adherent to medication; and met the
, Tenth Revision, criteria for depression.
Participants were randomised using a computer-generated code to either oral mirtazapine or a matched placebo, starting at a dose of 15 mg daily for 2 weeks and increasing to 30 mg daily for up to 12 months, in addition to their usual antidepressant. Participants, their general practitioners (GPs) and the research team were blind to the allocation.
The primary outcome was depression symptoms at 12 weeks post randomisation compared with baseline, measured as a continuous variable using the BDI-II. Secondary outcomes (at 12, 24 and 52 weeks) included response, remission of depression, change in anxiety symptoms, adverse events (AEs), quality of life, adherence to medication, health and social care use and cost-effectiveness. Outcomes were analysed on an intention-to-treat basis. A qualitative study explored patients' views and experiences of managing depression and GPs' views on prescribing a second antidepressant.
There were 480 patients randomised to the trial (mirtazapine and usual care,
= 241; placebo and usual care,
= 239), of whom 431 patients (89.8%) were followed up at 12 weeks. BDI-II scores at 12 weeks were lower in the mirtazapine group than the placebo group after adjustment for baseline BDI-II score and minimisation and stratification variables difference -1.83 points, 95% confidence interval (CI) -3.92 to 0.27 points;
= 0.087. This was smaller than the minimum clinically important difference and the CI included the null. The difference became smaller at subsequent time points (24 weeks: -0.85 points, 95% CI -3.12 to 1.43 points; 12 months: 0.17 points, 95% CI -2.13 to 2.46 points). More participants in the mirtazapine group withdrew from the trial medication, citing mild AEs (46 vs. 9 participants).
This study did not find convincing evidence of a clinically important benefit for mirtazapine in addition to a SSRI or a SNRI antidepressant over placebo in primary care patients with TRD. There was no evidence that the addition of mirtazapine was a cost-effective use of NHS resources. GPs and patients were concerned about adding an additional antidepressant.
Voluntary unblinding for participants after the primary outcome at 12 weeks made interpretation of longer-term outcomes more difficult.
Treatment-resistant depression remains an area of important, unmet need, with limited evidence of effective treatments. Promising interventions include augmentation with atypical antipsychotics and treatment using transcranial magnetic stimulation.
Current Controlled Trials ISRCTN06653773; EudraCT number 2012-000090-23.
This project was funded by the NIHR Health Technology Assessment programme and will be published in full in
; Vol. 22, No. 63. See the NIHR Journals Library website for further project information.
The current study demonstrates the application of an analytic approach for incorporating multiple time trends in order to examine the impact of cohort effects on individual trajectories of eight ...drugs of abuse. Parallel analysis of two independent, longitudinal studies of high-risk youth that span ages 10 to 40 across 23 birth cohorts between 1968 and 1991 was conducted. The two studies include the Michigan Longitudinal Study (current analytic sample of n = 579 over 12 cohorts between 1980 and 1991 and across ages 10–27) and the Adolescent/Adult and Family Development Project (current analytic sample of n = 849 over 11 cohorts between 1968 and 1978 and across ages 10–40). A series of nonlinear, multi-level growth models controlled simultaneously for cohort and age trends in substance use trajectories. Evidence was found for both age and cohort effects across most outcomes as well as several significant age-by-cohort interactions. Findings suggest cohort trends in developmental trajectories of substance use are sample and drug-specific in the adolescent and early to mid-adult years. Thus, studies that do not control for both trends may confound cohort and developmental trends in substance use. For this reason, demonstration of one analytic approach that can be used to examine both time trends simultaneously is informative for future multi-cohort longitudinal studies where change over time is of interest.
This article addresses important future directions for the study of addictions, emphasizing the incorporation of developmental perspectives into how we think about substance use and disorder as ...unfolding processes over time and context for a heterogeneous group of individuals. These perspectives articulate complexities in the developmental processes that underlie change and continuity in human behavior over time. We consider two key developmental concepts, namely, "time" and "heterogeneity." We argue that a lack of attention to time sampling creates ambiguity in the meaning of time-linked assessments, challenges in discerning which of multiple clocks may govern behavior, and the inability in some instances to distinguish which of multiple etiological processes may be driving behavior within our samples. Moreover, artificial divisions among disorders that commonly co-occur with substance use are a barrier to the further integration of the study and treatment of addictions with that of psychopathology. Similar to recent changes in the study of psychiatric disorders more broadly, we argue that identifying common deficits among commonly comorbid disorders, rather than patterns of comorbidity per se, is key to identifying early emerging risk factors for substance use and disorder, with important implications for identifying risk populations and developmental periods as well as potentially malleable intervention targets. Attention to time sampling in theory-driven research designs and attempts to identify more homogenous groups of individuals who use and eventually abuse substances over time are two examples of ways to better understand some of the complexity underlying the development of addictions.
The rapid spread of SARS-CoV-2 variants poses a constant threat of escape from monoclonal antibody and vaccine countermeasures. Mutations in the ACE2 receptor binding site on the surface S protein ...have been shown to disrupt antibody binding and prevent viral neutralization. Here, we used a directed evolution-based approach to engineer three neutralizing antibodies for enhanced binding to S protein. The engineered antibodies showed increased in vitro functional activity in terms of neutralization potency and/or breadth of neutralization against viral variants. Deep mutational scanning revealed that higher binding affinity reduces the total number of viral escape mutations. Studies in the Syrian hamster model showed two examples where the affinity-matured antibody provided superior protection compared to the parental antibody. These data suggest that monoclonal antibodies for antiviral indications would benefit from affinity maturation to reduce viral escape pathways and appropriate affinity maturation in vaccine immunization could help resist viral variation.
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•Cryo-EM analysis of Class 2 and Class 3 SARS-CoV-2 neutralizing monoclonal antibodies•Engineered antibodies with higher affinity neutralize emerging SARS-CoV-2 variants•The higher affinity antibodies reduce the pathways for viral escape•Engineered antibodies improve protection in hamster model
Immunology; Virology; Structural biology.
According to neo-institutional theory, the survival of institutions in society is predicated on a cultural discourse. Dubbed "the institutional myth," this discourse reflects the core values, ...practices and aspirations of an institution and legitimizes its existence to internal and external stakeholders alike. In this paper we suggest that recent attacks on mainstream news outlets-notably President Trump's accusations that they constitute "fake news"-have led journalists to defend the journalistic institutional myth as part of their efforts to re-legitimize their profession. Our findings indicate that journalists seek to bolster and uphold their institutional myth through a range of discursive strategies ranging from highlighting established journalistic norms and practices and emphasizing journalism's central role in the maintenance of democracy, to attacking the accuser and calls to action in which journalists make a case for ignoring the president's rhetorical assaults and continuing to do their job.
...we shall conclude by examining some of the crucial ways stead (and her perspectives upon polti) is positioned within successively dominant paradigms of mass institutionalized teaching of novel ...writing.
In this review, we consider the potential service needs of children of substance abusing parents based on what we know about the risk outcomes faced by these children and the parenting deficits often ...present in these families. Importantly, our review does not address the etiological role of parental substance abuse in children's negative outcomes but instead we discuss the complex inter-related risk factors that often co-occur with and exacerbate risk associated with parental alcohol and drug use. We first review studies showing the elevated risk that children of substance abusing parents face in general for poorer academic functioning; emotional, behavioral, and social problems; and an earlier onset of substance use, faster acceleration in substance use patterns, and higher rates of alcohol and drug use disorders. We then review studies showing contextual risk factors for children of substance abusing parents, including parenting deficits (less warmth, responsiveness, and physical and verbal engagement as well as harsher and more over-involved interaction styles), greater risk for child maltreatment, and less secure attachment patterns. We conclude with a discussion of future directions for research and guidelines for professionals working with children and their families where parental substance abuse is present.
Patients with depression who are treated in primary care practices may receive antidepressants for prolonged periods. Data are limited on the effects of maintaining or discontinuing antidepressant ...therapy in this setting.
We conducted a randomized, double-blind trial involving adults who were being treated in 150 general practices in the United Kingdom. All the patients had a history of at least two depressive episodes or had been taking antidepressants for 2 years or longer and felt well enough to consider stopping antidepressants. Patients who had received citalopram, fluoxetine, sertraline, or mirtazapine were randomly assigned in a 1:1 ratio to maintain their current antidepressant therapy (maintenance group) or to taper and discontinue such therapy with the use of matching placebo (discontinuation group). The primary outcome was the first relapse of depression during the 52-week trial period, as evaluated in a time-to-event analysis. Secondary outcomes were depressive and anxiety symptoms, physical and withdrawal symptoms, quality of life, time to stopping an antidepressant or placebo, and global mood ratings.
A total of 1466 patients underwent screening. Of these patients, 478 were enrolled in the trial (238 in the maintenance group and 240 in the discontinuation group). The average age of the patients was 54 years; 73% were women. Adherence to the trial assignment was 70% in the maintenance group and 52% in the discontinuation group. By 52 weeks, relapse occurred in 92 of 238 patients (39%) in the maintenance group and in 135 of 240 (56%) in the discontinuation group (hazard ratio, 2.06; 95% confidence interval, 1.56 to 2.70; P<0.001). Secondary outcomes were generally in the same direction as the primary outcome. Patients in the discontinuation group had more symptoms of depression, anxiety, and withdrawal than those in the maintenance group.
Among patients in primary care practices who felt well enough to discontinue antidepressant therapy, those who were assigned to stop their medication had a higher risk of relapse of depression by 52 weeks than those who were assigned to maintain their current therapy. (Funded by the National Institute for Health Research; ANTLER ISRCTN number, ISRCTN15969819.).
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