Pharmacological interventions for treatment-resistant depression in adults

BACKGROUND: Although antidepressants are often a first-line treatment for adults with moderate to severe depression, many people do not respond adequately to medication, and are said to have treatment-resistant depression (TRD). Little evidence exists to inform the most appropriate 'next step' treatment for these people. OBJECTIVES: To assess the effectiveness of standard pharmacological treatments for adults with TRD. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (March 2016), CENTRAL, MEDLINE, Embase, PsycINFO and Web of Science (31 December 2018), the World Health Organization trials portal and ClinicalTrials.gov for unpublished and ongoing studies, and screened bibliographies of included studies and relevant systematic reviews without date or language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) with participants aged 18 to 74 years with unipolar depression (based on criteria from DSM-IV-TR or earlier versions, International Classification of Diseases (ICD)-10, Feighner criteria or Research Diagnostic Criteria) who had not responded to a minimum of four weeks of antidepressant treatment at a recommended dose. Interventions were: (1) increasing the dose of antidepressant monotherapy; (2) switching to a different antidepressant monotherapy; (3) augmenting treatment with another antidepressant; (4) augmenting treatment with a non-antidepressant. All were compared with continuing antidepressant monotherapy. We excluded studies of non-standard pharmacological treatments (e.g. sex hormones, vitamins, herbal medicines and food supplements). DATA COLLECTION AND ANALYSIS: Two reviewers used standard Cochrane methods to extract data, assess risk of bias, and resolve disagreements. We analysed continuous outcomes with mean difference (MD) or standardised mean difference (SMD) and 95% confidence interval (CI). For dichotomous outcomes, we calculated a relative risk (RR) and 95% CI. Where sufficient data existed, we conducted meta-analyses using random-effects models. MAIN RESULTS: We included 10 RCTs (2731 participants). Nine were conducted in outpatient settings and one in both in- and outpatients. Mean age of participants ranged from 42 - 50.2 years, and most were female. One study investigated switching to, or augmenting current antidepressant treatment with, another antidepressant (mianserin). Another augmented current antidepressant treatment with the antidepressant mirtazapine. Eight studies augmented current antidepressant treatment with a non-antidepressant (either an anxiolytic (buspirone) or an antipsychotic (cariprazine; olanzapine; quetiapine (3 studies); or ziprasidone (2 studies)). We judged most studies to be at a low or unclear risk of bias. Only one of the included studies was not industry-sponsored. There was no evidence of a difference in depression severity when current treatment was switched to mianserin (MD on Hamilton Rating Scale for Depression (HAM-D) = -1.8, 95% CI -5.22 to 1.62, low-quality evidence)) compared with continuing on antidepressant monotherapy. Nor was there evidence of a difference in numbers dropping out of treatment (RR 2.08, 95% CI 0.94 to 4.59, low-quality evidence; dropouts 38% in the mianserin switch group; 18% in the control). Augmenting current antidepressant treatment with mianserin was associated with an improvement in depression symptoms severity scores from baseline (MD on HAM-D -4.8, 95% CI -8.18 to -1.42; moderate-quality evidence). There was no evidence of a difference in numbers dropping out (RR 1.02, 95% CI 0.38 to 2.72; low-quality evidence; 19% dropouts in the mianserin-augmented group; 38% in the control). When current antidepressant treatment was augmented with mirtazapine, there was little difference in depressive symptoms (MD on Beck Depression Inventory (BDI-II) -1.7, 95% CI -4.03 to 0.63; high-quality evidence) and no evidence of a difference in dropout numbers (RR 0.50, 95% CI 0.15 to 1.62; dropouts 2% in mirtazapine-augmented group; 3% in the control). Augmentation with buspirone provided no evidence of a benefit in terms of a reduction in depressive symptoms (MD on Montgomery and Asberg Depression Rating Scale (MADRS) -0.30, 95% CI -9.48 to 8.88; low-quality evidence) or numbers of drop-outs (RR 0.60, 95% CI 0.23 to 1.53; low-quality evidence; dropouts 11% in buspirone-augmented group; 19% in the control). Severity of depressive symptoms reduced when current treatment was augmented with cariprazine (MD on MADRS -1.50, 95% CI -2.74 to -0.25; high-quality evidence), olanzapine (MD on HAM-D -7.9, 95% CI -16.76 to 0.96; low-quality evidence; MD on MADRS -12.4, 95% CI -22.44 to -2.36; low-quality evidence), quetiapine (SMD -0.32, 95% CI -0.46 to -0.18; I2 = 6%, high-quality evidence), or ziprasidone (MD on HAM-D -2.73, 95% CI -4.53 to -0.93; I2 = 0, moderate-quality evidence) compared with continuing on antidepressant monotherapy. However, a greater number of participants dropped out when antidepressant monotherapy was augmented with an antipsychotic (cariprazine RR 1.68, 95% CI 1.16 to 2.41; quetiapine RR 1.57, 95% CI: 1.14 to 2.17; ziprasidone RR 1.60, 95% CI 1.01 to 2.55) compared with antidepressant monotherapy, although estimates for olanzapine augmentation were imprecise (RR 0.33, 95% CI 0.04 to 2.69). Dropout rates ranged from 10% to 39% in the groups augmented with an antipsychotic, and from 12% to 23% in the comparison groups. The most common reasons for dropping out were side effects or adverse events. We also summarised data about response and remission rates (based on changes in depressive symptoms) for included studies, along with data on social adjustment and social functioning, quality of life, economic outcomes and adverse events. AUTHORS' CONCLUSIONS: A small body of evidence shows that augmenting current antidepressant therapy with mianserin or with an antipsychotic (cariprazine, olanzapine, quetiapine or ziprasidone) improves depressive symptoms over the short-term (8 to 12 weeks). However, this evidence is mostly of low or moderate quality due to imprecision of the estimates of effects. Improvements with antipsychotics need to be balanced against the increased likelihood of dropping out of treatment or experiencing an adverse event. Augmentation of current antidepressant therapy with a second antidepressant, mirtazapine, does not produce a clinically important benefit in reduction of depressive symptoms (high-quality evidence). The evidence regarding the effects of augmenting current antidepressant therapy with buspirone or switching current antidepressant treatment to mianserin is currently insufficient. Further trials are needed to increase the certainty of these findings and to examine long-term effects of treatment, as well as the effectiveness of other pharmacological treatment strategies

Nutritional deficiencies in homeless persons with problematic drinking:A systematic review

BACKGROUND: A significant proportion of homeless people drink alcohol excessively and this can lead to malnutrition and consequent medical problems. The aim of this review was to assess the evidence on the range of nutritional deficiencies in the homeless problem-drinking populations. METHODS: We conducted a comprehensive search of nine scientific literature databases and 13 grey literature sources. We included studies of any design that included homeless population with problem-drinking and reported measures of nutritional deficiencies in urine or blood. Study selection and data extraction was done by one reviewer and checked by another. Data on malnutrition profile were summarized narratively. RESULTS: We found nine studies reporting nutritional deficiencies in homeless populations with problem-drinking. The oldest study was from the 1950s and the most recent from 2013. The following nutrients were reported across studies: vitamins B1, B2, B6, B9, B12, C, A, and E; haemoglobin; and albumin. The most common deficiencies reported were of vitamin B1 (prevalence of deficiency was 0, 2, 6, 45, and 51% in five studies) and vitamin C (29, 84, and 95% in three studies). None of the studies were assessed to be at a low risk of bias. CONCLUSIONS: The limited, low quality and relatively old evidence suggests that homeless people who drink heavily may be deficient in vitamin C, thiamine, and other nutrients. New, well conducted studies are needed in order to optimally inform public health interventions aimed at improving deficiencies in this population

Quality of reporting and risk of bias:a review of randomised trials in occupational health

OBJECTIVES: To assess the reporting quality of randomisation and allocation methods in occupational health and safety (OHS) trials in relation to Consolidated Standards of Reporting Trials (CONSORT) requirements of journals, risk of bias (RoB) and publication year. METHODS: We systematically searched for randomised controlled trials (RCTs) in PubMed between 2010 and May 2019 in 18 OHS journals. We measured reporting quality as percentage compliance with the CONSORT 2010 checklist (items 8–10) and RoB with the ROB V.2.0 tool (first domain). We tested the mean difference (MD) in % in reporting quality between CONSORT-requiring and non-requiring journals, trials with low, some concern and high RoB and publications before and after 2015. RESULTS: In 135 articles reporting on 129 RCTs, average reporting quality was at 37.4% compliance (95% CI 31.9% to 43.0%), with 10% of articles reaching 100% compliance. Reporting quality was significantly better in CONSORT-requiring journals than non-requiring journals (MD 31.0% (95% CI 21.4% to 40.7%)), for studies at low RoB than high RoB (MD 33.1% (95% CI 16.1% to 50.2%)) and with RoB of some concern (MD 39.8% (95% CI 30.0% to 49.7%)). Reporting quality did not improve over time (MD −5.7% (95% CI −16.8% to 5.4%). CONCLUSIONS: Articles in CONSORT-requiring journals and of low RoB studies show better reporting quality. Low reporting quality is linked to unclear RoB judgements (some concern). Reporting quality did not improve over the last 10 years and CONSORT is insufficiently implemented. Concerted efforts by editors and authors are needed to improve CONSORT implementation

Quality of family relationships and outcomes of dementia: A systematic review

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. Objectives To evaluate the association between the quality of relationship between a person with dementia and their family carer and outcomes for the person with dementia. Design Systematic review. Eligibility criteria Cohort studies of people with clinically diagnosed dementia and their main carers. Exposures of interest were any elements of relationship quality, for example, attachment style, expressed emotion and coping style. Our primary outcome was institutionalisation, and secondary outcomes were hospitalisation, death, quality of life and behavioural and psychiatric symptoms of dementia ('challenging behaviour'). Data sources MEDLINE, Embase, Web of Science, PsycInfo, the Cochrane Library and Opengrey were searched from inception to May 2017. Study appraisal and synthesis methods The Newcastle-Ottawa Scale was used to assess risk of bias. A narrative synthesis of results was performed due to differences between studies. Results Twenty studies were included. None of the studies controlled for all prespecified confounding factors (age, gender, socioeconomic status and severity of dementia). Reporting of results was inadequate with many studies simply reporting whether associations were statistically significant' without providing effect size estimates or CIs. There was a suggestion of an association between relationship factors and global challenging behaviour. All studies evaluating global challenging behaviour provided statistical evidence of an association (most P values below 0.02). There was no consistent evidence for an association for any other outcome assessed. Conclusions There is currently no strong or consistent evidence on the effects of relationship factors on institutionalisation, hospitalisation, death or quality of life for people with dementia. There was a suggestion of an association between relationship factors and challenging behaviour, although the evidence for this was weak. To improve our ability to support those with dementia and their families, further robust studies are needed. PROSPERO registration number CRD42015020518

Variations in policies for accessing elective musculoskeletal procedures in the English National Health Service:A documentary analysis

OBJECTIVE: The overall aim of this study was to investigate how commissioning policies for accessing clinical procedures compare in the context of the English National Health Service. Our primary objective was to compare policy wording and categorise any variations identified. Our secondary objective was to explore how any points of variation relate to national guidance. METHODS: This study entailed documentary analysis of commissioning policies that stipulated criteria for accessing eight elective musculoskeletal procedures. For each procedure, we retrieved policies held by regions with higher and lower rates of clinical activity relative to the national average. Policies were subjected to content and thematic analysis, using constant comparison techniques. Matrices and descriptive reports were used to compare themes across policies for each procedure and derive categories of variation that arose across two or more procedures. National guidance relating to each procedure were identified and scrutinised, to explore whether these provided context for explaining the policy variations. RESULTS: Thirty-five policy documents held by 14 geographic regions were included in the analysis. Policies either focused on a single procedure/treatment or covered several procedures/treatments in an all-encompassing document. All policies stipulated criteria that needed to be fulfilled prior to accessing treatment, but there were inconsistences in the evidence cited. Policies varied in recurring ways, with respect to specification of non-surgical treatments and management, requirements around time spent using non-surgical approaches, diagnostic requirements, requirements around symptom severity and disease progression, and use of language, in the form of terms and phrases (‘threshold modifiers’) which could open up or restrict access to care. National guidance was identified for seven of the procedures, but this guidance did not specify criteria for accessing the procedures in question, making direct comparisons with regional policies difficult. CONCLUSIONS: This, to our knowledge, is the first study to identify recurring ways in which policies for accessing treatment can vary within a single-payer system with universal coverage. The findings raise questions around whether formulation of commissioning policies should receive more central support to promote greater consistency – especially where evidence is uncertain, variable or lacking

Personal protective equipment for preventing highly infectious diseases due to exposure to contaminated body fluids in healthcare staff

Background: In epidemics of highly infectious diseases, such as Ebola, severe acute respiratory syndrome (SARS), or coronavirus (COVID-19), healthcare workers (HCW) are at much greater risk of infection than the general population, due to their contact with patients' contaminated body fluids. Personal protective equipment (PPE) can reduce the risk by covering exposed body parts. It is unclear which type of PPE protects best, what is the best way to put PPE on (i.e. donning) or to remove PPE (i.e. doffing), and how to train HCWs to use PPE as instructed. Objectives: To evaluate which type of full-body PPE and which method of donning or doffing PPE have the least risk of contamination or infection for HCW, and which training methods increase compliance with PPE protocols. Search methods: We searched CENTRAL, MEDLINE, Embase and CINAHL to 20 March 2020. Selection criteria: We included all controlled studies that evaluated the effect of full-body PPE used by HCW exposed to highly infectious diseases, on the risk of infection, contamination, or noncompliance with protocols. We also included studies that compared the effect of various ways of donning or doffing PPE, and the effects of training on the same outcomes. Data collection and analysis: Two review authors independently selected studies, extracted data and assessed the risk of bias in included trials. We conducted random-effects meta-analyses were appropriate. Main results: Earlier versions of this review were published in 2016 and 2019. In this update, we included 24 studies with 2278 participants, of which 14 were randomised controlled trials (RCT), one was a quasi-RCT and nine had a non-randomised design. Eight studies compared types of PPE. Six studies evaluated adapted PPE. Eight studies compared donning and doffing processes and three studies evaluated types of training. Eighteen studies used simulated exposure with fluorescent markers or harmless microbes. In simulation studies, median contamination rates were 25% for the intervention and 67% for the control groups. Evidence for all outcomes is of very low certainty unless otherwise stated because it is based on one or two studies, the indirectness of the evidence in simulation studies and because of risk of bias. Types of PPE. The use of a powered, air-purifying respirator with coverall may protect against the risk of contamination better than a N95 mask and gown (risk ratio (RR) 0.27, 95% confidence interval (CI) 0.17 to 0.43) but was more difficult to don (non-compliance: RR 7.5, 95% CI 1.81 to 31.1). In one RCT (59 participants), people with a long gown had less contamination than those with a coverall, and coveralls were more difficult to doff (low-certainty evidence). Gowns may protect better against contamination than aprons (small patches: mean difference (MD) −10.28, 95% CI −14.77 to −5.79). PPE made of more breathable material may lead to a similar number of spots on the trunk (MD 1.60, 95% CI −0.15 to 3.35) compared to more water-repellent material but may have greater user satisfaction (MD −0.46, 95% CI −0.84 to −0.08, scale of 1 to 5). Modified PPE versus standard PPE. The following modifications to PPE design may lead to less contamination compared to standard PPE: sealed gown and glove combination (RR 0.27, 95% CI 0.09 to 0.78), a better fitting gown around the neck, wrists and hands (RR 0.08, 95% CI 0.01 to 0.55), a better cover of the gown-wrist interface (RR 0.45, 95% CI 0.26 to 0.78, low-certainty evidence), added tabs to grab to facilitate doffing of masks (RR 0.33, 95% CI 0.14 to 0.80) or gloves (RR 0.22, 95% CI 0.15 to 0.31). Donning and doffing. Using Centers for Disease Control and Prevention (CDC) recommendations for doffing may lead to less contamination compared to no guidance (small patches: MD −5.44, 95% CI −7.43 to −3.45). One-step removal of gloves and gown may lead to less bacterial contamination (RR 0.20, 95% CI 0.05 to 0.77) but not to less fluorescent contamination (RR 0.98, 95% CI 0.75 to 1.28) than separate removal. Double-gloving may lead to less viral or bacterial contamination compared to single gloving (RR 0.34, 95% CI 0.17 to 0.66) but not to less fluorescent contamination (RR 0.98, 95% CI 0.75 to 1.28). Additional spoken instruction may lead to fewer errors in doffing (MD −0.9, 95% CI −1.4 to −0.4) and to fewer contamination spots (MD −5, 95% CI −8.08 to −1.92). Extra sanitation of gloves before doffing with quaternary ammonium or bleach may decrease contamination, but not alcohol-based hand rub. Training. The use of additional computer simulation may lead to fewer errors in doffing (MD −1.2, 95% CI −1.6 to −0.7). A video lecture on donning PPE may lead to better skills scores (MD 30.70, 95% CI 20.14 to 41.26) than a traditional lecture. Face-to-face instruction may reduce noncompliance with doffing guidance more (odds ratio 0.45, 95% CI 0.21 to 0.98) than providing folders or videos only. Authors' conclusions: We found low- to very low-certainty evidence that covering more parts of the body leads to better protection but usually comes at the cost of more difficult donning or doffing and less user comfort, and may therefore even lead to more contamination. More breathable types of PPE may lead to similar contamination but may have greater user satisfaction. Modifications to PPE design, such as tabs to grab, may decrease the risk of contamination. For donning and doffing procedures, following CDC doffing guidance, a one-step glove and gown removal, double-gloving, spoken instructions during doffing, and using glove disinfection may reduce contamination and increase compliance. Face-to-face training in PPE use may reduce errors more than folder-based training. We still need RCTs of training with long-term follow-up. We need simulation studies with more participants to find out which combinations of PPE and which doffing procedure protects best. Consensus on simulation of exposure and assessment of outcome is urgently needed. We also need more real-life evidence. Therefore, the use of PPE of HCW exposed to highly infectious diseases should be registered and the HCW should be prospectively followed for their risk of infection

Antipsychotic polypharmacy and metabolic syndrome in schizophrenia:A review of systematic reviews

Abstract Background There is conflicting evidence on the association between antipsychotic polypharmacy and metabolic syndrome in schizophrenia. We conducted a review of published systematic reviews to evaluate evidence on the association between metabolic syndrome (diabetes, hypertension, and hyperlipidaemia) and exposure to antipsychotic polypharmacy in schizophrenia. Methods We searched five electronic databases, complemented by reference screening, to find systematic reviews that investigated the association of antipsychotic polypharmacy in schizophrenia with hypertension, diabetes, or hyperlipidaemia. Selection of reviews, data extraction and review quality were conducted independently by two people and disagreements resolved by discussion. Results were synthesised narratively. Results We included 12 systematic reviews, which reported heterogeneous results, mostly with narrative syntheses and without pooled data. The evidence was rated as low quality. There was some indication of a possible protective effect of drug combinations including aripiprazole for diabetes and hyperlipidaemias, compared to other combinations and/or monotherapy. Only one review reported the association between APP and hypertension. The most frequently reported combinations of medication included clozapine, possibly representing a sample of patients with treatment resistant illness. No included review reported results separately by setting (primary or secondary care). Conclusions Further robust studies are needed to elucidate the possible protective effect of aripiprazole. Long-term prospective studies are required for accurate appraisal of diabetes risk, hypertension and hyperlipidaemia in patients exposed to antipsychotic polypharmacy