Mortality and adverse events associated with statin use in primary care patients with depression: a real-world, population-based cohort study.

BACKGROUND: New National Institute for Health and Care Excellence (NICE) guidance endorses the prescription of statins in larger population groups for the prevention of cardiovascular and cerebrovascular morbidity and mortality, especially in people with severe mental illness. However, the evidence base for their safety and risk/benefit balance in depression is not established. OBJECTIVES: This study aims to assess the real-world mortality and adverse events of statins in depressive disorders. METHODS: Population-based, nationwide (England), between-subject, cohort study. We used electronic health records (QResearch database) of people aged 18-100 years with first-episode depression, registered with English primary care practices over January 1998-August 2020 for 12(+) months, divided into statin users versus non-users.Primary safety outcomes included all-cause mortality and any adverse event measured at 2, 6 and 12 months. Multivariable logistic regression was employed to control for several potential confounders and calculate adjusted ORs (aORs) with 99% CIs. FINDINGS: From over 1 050 105 patients with depression (42.64% males, mean age 43.23±18.32 years), 21 384 (2.04%) died, while 707 111 (67.34%) experienced at least one adverse event during the 12-month follow-up. Statin use was associated with lower mortality over 12 months (range aOR2-12months 0.66-0.67, range 99% CI 0.60 to 0.73) and with lower adverse events over 6 months (range aOR2-6months 0.90-0.96, range 99% CI 0.91 to 0.99), but not at 1 year (aOR12months 0.99, 99% CI 0.96 to 1.03). No association with any other individual outcome measure (ie, any other neuropsychiatric symptoms) was identified. CONCLUSIONS: We found no evidence that statin use among people with depression increases mortality or other adverse events. CLINICAL IMPLICATIONS: Our findings support the safety of updated NICE guidelines for prescribing statins in people with depressive disorders.

Comparing interventions for early psychosis: a systematic review and component network meta-analysis.

Background: 'Early Intervention in Psychosis' (EIP) services have been associated with improved outcomes for early psychosis. However, these services are heterogeneous and many provide different components of treatment. The impact of this variation on the sustained treatment effects is unknown. Methods: We performed a systematic review and component network meta-analysis (cNMA) of randomised controlled trials (RCTs) that compared specialised intervention services for early psychosis. We searched CENTRAL (published and unpublished), EMBASE, MEDLINE, CINAHL, PsycINFO and Web of Science from inception to February 2023. Primary outcomes were negative and positive psychotic symptoms at 3-month and 1-year follow-up and treatment dropouts. Secondary outcomes were depressive symptoms and social functioning at 1-year follow-up. We registered a protocol for our study in PROSPERO (CRD42017057420). Findings: We identified 37 RCTs including 4599 participants. Participants' mean age was 25.8 years (SD 6.0) and 64.0% were men. We found evidence that psychological interventions (this component grouped all psychological treatment intended to treat, or ameliorate the consequences of, psychotic symptoms) are beneficial for reducing negative symptoms (iSMD -0.24, 95% CI -0.44 to -0.05, p = 0.014) at 3-month follow-up and may be associated with clinically relevant benefits in improving social functioning scores at 1-year follow-up (iSMD -0.52, 95% CI -1.05 to 0.01, p = 0.052). The addition of case management has a beneficial effect on reducing negative symptoms (iSMD -1.17, 95% CI -2.24 to -0.11, p = 0.030) and positive symptoms (iSMD -1.05, 95% CI -2.02 to -0.08, p = 0.033) at 1-year follow-up. Pharmacotherapy was present in all trial arms, meaning it was not possible to examine the specific effects of this component. Interpretation: Our findings suggest psychological interventions and case management in addition to pharmacotherapy as the core components of services for early psychosis to achieve sustained clinical benefits. Our conclusions are limited by the small number of studies and sparsely connected networks. Funding: National Institute for Health and Care Research.

Real-world outcomes of concomitant antidepressant and statin use in primary care patients with depression: a population-based cohort study.

BACKGROUND: Antidepressants are licensed for use in depressive disorders, but non-response and poor adherence to treatment affect a considerable number of patients. Pre-clinical and clinical evidence suggest that statins can augment the effects of antidepressants. However, the acceptability and tolerability of combining statins with antidepressants are unclear, and their add-on efficacy has only been shown in small, short-term clinical trials. Observational data can provide complementary information about treatment effects on larger samples over longer follow-ups. In this study, we therefore assessed the real-world acceptability, tolerability, and efficacy of concomitant antidepressant and statin treatment in depression. METHODS: We conducted a population-based cohort study investigating QResearch primary care research database, which comprises the anonymised electronic healthcare records of 35 + million patients over 1574 English general practices. Patients aged 18-100 years, registered between January 1998 and August 2020, diagnosed with a new episode of depression, and commencing an antidepressant were included. Using a between-subject design, we identified two study groups: antidepressant + statin versus antidepressant-only prescriptions. Outcomes of interest included the following: antidepressant treatment discontinuations due to any cause (acceptability) and due to any adverse event (tolerability) and effects on depressive symptoms (efficacy) measured as response, remission, and change in depression score on the Patient Health Questionnaire-9. All outcomes were assessed at 2, 6, and 12 months using multivariable regression analyses, adjusted for relevant confounders, to calculate adjusted odds ratios (aORs) or mean differences (aMDs) with 99% confidence intervals (99% CIs). RESULTS: Compared to antidepressant-only (N 626,335), antidepressant + statin (N 46,482) was associated with higher antidepressant treatment acceptability (aOR2months 0.88, 99% CI 0.85 to 0.91; aOR6months 0.81, 99% CI 0.79 to 0.84; aOR12months 0.78, 99% CI 0.75 to 0.81) and tolerability (aOR2months 0.92, 99% CI 0.87 to 0.98; aOR6months 0.94, 99% CI 0.89 to 0.99, though not long term aOR12 months 1.02, 99% CI 0.97 to 1.06). Efficacy did not differ between groups (range aOR2-12 months 1.00 and 1.02 for response and remission, range aOR2-12 months - 0.01 and - 0.02 for change in depression score). CONCLUSIONS: On real-world data, there is a positive correlation between antidepressant treatment adherence and statin use, partly explained by fewer dropouts due to adverse events. The main limitation of our study is its observational design, which restricts the potential to make causal inferences.

Predicting outcomes at the individual patient level: what is the best method?

OBJECTIVE: When developing prediction models, researchers commonly employ a single model which uses all the available data (end-to-end approach). Alternatively, a similarity-based approach has been previously proposed, in which patients with similar clinical characteristics are first grouped into clusters, then prediction models are developed within each cluster. The potential advantage of the similarity-based approach is that it may better address heterogeneity in patient characteristics. However, it remains unclear whether it improves the overall predictive performance. We illustrate the similarity-based approach using data from people with depression and empirically compare its performance with the end-to-end approach. METHODS: We used primary care data collected in general practices in the UK. Using 31 predefined baseline variables, we aimed to predict the severity of depressive symptoms, measured by Patient Health Questionnaire-9, 60 days after initiation of antidepressant treatment. Following the similarity-based approach, we used k-means to cluster patients based on their baseline characteristics. We derived the optimal number of clusters using the Silhouette coefficient. We used ridge regression to build prediction models in both approaches. To compare the models' performance, we calculated the mean absolute error (MAE) and the coefficient of determination (R2) using bootstrapping. RESULTS: We analysed data from 16 384 patients. The end-to-end approach resulted in an MAE of 4.64 and R2 of 0.20. The best-performing similarity-based model was for four clusters, with MAE of 4.65 and R2 of 0.19. CONCLUSIONS: The end-to-end and the similarity-based model yielded comparable performance. Due to its simplicity, the end-to-end approach can be favoured when using demographic and clinical data to build prediction models on pharmacological treatments for depression.

Participant Recruitment Issues in Child and Adolescent Psychiatry Clinical Trials with a Focus on Prevention Programs: A Meta-Analytic Review of the Literature.

Introduction: There is a strong need to conduct rigorous and robust trials for children and adolescents in mental health settings. One of the main barriers to meeting this requirement is the poor recruitment rate. Effective recruitment strategies are crucial for the success of a clinical trial, and therefore, we reviewed recruitment strategies in clinical trials on children and adolescents in mental health with a focus on prevention programs. Methods: We reviewed the literature by searching PubMed/Medline, the Cochrane Library database, and Web of Science through December 2022 as well as the reference lists of relevant articles. We included only studies describing recruitment strategies for pediatric clinical trials in mental health settings and extracted data on recruitment and completion rates. Results: The search yielded 13 studies that enrolled a total of 14,452 participants. Overall, studies mainly used social networks or clinical settings to recruit participants. Half of the studies used only one recruitment method. Using multiple recruitment methods (56.6%, 95%CI: 24.5-86.0) resulted in higher recruitment. The use of monetary incentives (47.0%, 95%CI: 24.6-70.0) enhanced the recruitment rate but not significantly (32.6%, 95%CI: 15.7-52.1). All types of recruitment methods showed high completion rates (82.9%, 95%CI: 61.7-97.5) even though prevention programs showed the smallest recruitment rate (76.1%, 95%CI: 50.9-94.4). Conclusions: Pediatric mental health clinical trials face many difficulties in recruitment. We found that these trials could benefit from faster and more efficient recruitment of participants when more than one method is implemented. Social networks can be helpful where ethically possible. We hope the description of these strategies will help foster innovation in recruitment for pediatric studies in mental health.

Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis.

BACKGROUND: Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder. METHODS: In this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with Open Science Framework, https://doi.org/10.17605/OSF.IO/PU4QJ. FINDINGS: We included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36-0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27-0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52-0·99; moderate], 0·70 [0·51-0·95; moderate] and 0·71 [0·52-0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28-3·13; very low]; zolpidem: 1·79 [1·25-2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01-3·33; low]), daridorexant (3·45 [1·41-8·33; low), and suvorexant (3·13 [1·47-6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27-2·78 [high to very low]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone: SMD 0·63 [95% CI 0·36-0·90; very low]; lemborexant: 0·41 [0·04-0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16-1·10; very low]) and zolpidem (0·60 [0·00-1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20-0·93; very low]; zolpidem: 0·43 [0·19-0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11-3·70; very low]). INTERPRETATION: Overall, eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice. FUNDING: UK National Institute for Health Research Oxford Health Biomedical Research Centre.

Sleep deprivation as a treatment for major depressive episodes: A systematic review and meta-analysis.

Sleep deprivation, alone or in combination with pharmacological treatment and as part of a chronotherapy package, is of potential use for people with major depressive episodes, however the evidence base is still conflicting. The aim of this systematic review and meta-analysis is to assess the clinical effects of sleep deprivation in comparison to any other intervention for the acute and long-term treatment of mood disorders. We searched electronic databases and trial registries (last update: 16th October 2021) for published and unpublished randomised controlled trials recruiting participants with a major depressive episode in unipolar or bipolar affective disorder. The clinical outcomes of interest were the reduction in depressive symptoms at different timepoints and the number of participants experiencing at least one side effect. Overall, 29 trials (1246 participants) were included. We did not find any difference in change in symptoms or all-cause discontinuation between interventions including SD compared to a control of the same intervention except without SD. In the included studies there were no available data for adverse events. Using the most methodologically rigorous approach, we did not find evidence that the addition of sleep deprivation to treatment packages leads to enhanced depressive outcomes.

Development and validation of a meta-learner for combining statistical and machine learning prediction models in individuals with depression.

BACKGROUND: The debate of whether machine learning models offer advantages over standard statistical methods when making predictions is ongoing. We discuss the use of a meta-learner model combining both approaches as an alternative. METHODS: To illustrate the development of a meta-learner, we used a dataset of 187,757 people with depression. Using 31 variables, we aimed to predict two outcomes measured 60 days after initiation of antidepressant treatment: severity of depressive symptoms (continuous) and all-cause dropouts (binary). We fitted a ridge regression and a multi-layer perceptron (MLP) deep neural network as two separate prediction models ("base-learners"). We then developed two "meta-learners", combining predictions from the two base-learners. To compare the performance across the different methods, we calculated mean absolute error (MAE, for continuous outcome) and the area under the receiver operating characteristic curve (AUC, for binary outcome) using bootstrapping. RESULTS: Compared to the best performing base-learner (MLP base-learner, MAE at 4.63, AUC at 0.59), the best performing meta-learner showed a 2.49% decrease in MAE at 4.52 for the continuous outcome and a 6.47% increase in AUC at 0.60 for the binary outcome. CONCLUSIONS: A meta-learner approach may effectively combine multiple prediction models. Choosing between statistical and machine learning models may not be necessary in practice.

Vitruvian plot: a visualisation tool for multiple outcomes in network meta-analysis.

OBJECTIVE: A network meta-analysis (NMA) usually assesses multiple outcomes across several treatment comparisons. The Vitruvian plot aims to facilitate communication of multiple outcomes from NMAs to patients and clinicians. METHODS: We developed this tool following the recommendations on the communication of benefit-risk information from the available literature. We collected and implemented feedback from researchers, statisticians, methodologists, clinicians and people with lived experience of physical and mental health issues. RESULTS: We present the Vitruvian plot, which graphically presents absolute estimates and relative performance of competing interventions against a common comparator for several outcomes of interest. We use two alternative colour schemes to highlight either the strength of statistical evidence or the confidence in the evidence. Confidence in the evidence is evaluated across six domains (within-study bias, reporting bias, indirectness, imprecision, heterogeneity and incoherence) using the Confidence in Network Meta-Analysis (CINeMA) system. CONCLUSIONS: The Vitruvian plot allows reporting of multiple outcomes from NMAs, with colourings appropriate to inform credibility of the presented evidence.

Mapping Child and Adolescent Mental Health Services and the Interface During Transition to Adult Services in Six Swiss Cantons.

Rationale: Transition in psychiatry refers to the period where young people transit from Child and Adolescent Mental Health Services (CAMHS) to Adult Mental Health Services (AMHS). Discontinuity of care during this period is well-documented but little is known about provisions and transition characteristics and policies across Switzerland. The aim of this article is to describe the architecture of public mental health providers in Switzerland and compare it to EU countries. Method: Two mapping surveys, developed previously for European countries, were adapted and sent to cantonal experts: the adapted European CAMHS Mapping Questionnaire (ECM-Q) assessing the architecture and functioning of CAMHS and the adapted Standardized Assessment Tool for Mental Health Transition (SATMeHT) to map CAMHS-AMHS interface. Results: Data were gathered from six cantons. Activity data and transition policies were comparable between Swiss regions and European countries. The percentage of young people below 19 years who were in care was above 2% in every responding canton with a higher proportion of boys than girls for patients <12 years of age. The transition occurred at the age of 18 years, civil majority, in each canton, and between 0 and 24% (3/7) and 25% and 49% (4/7) of young people were expected to transition. One canton (1/7) benefitted from written guidelines, at the CAMHS level only, regarding transition but none had guidelines for mapping CAMHS/AMHS interface even at the regional level. Conclusion: Despite the availability of resources and even if the possibilities of access to care are on average higher than in many European countries, issues regarding transition remain comparable in six Swiss cantons when compared to Europe. Meaning that beyond resources, it is the coordination between services that needs to be worked on. Importantly, implementing those changes would not require investing financial resources but rather working on the coordination between existing teams.

Suicidal behavior in juvenile bipolar disorder and major depressive disorder patients: Systematic review and meta-analysis.

OBJECTIVE: To assess rates and lethality of suicidal behavior in studies of children and adolescents diagnosed with major depressive disorder (MDD) or bipolar disorder (BD). METHODS: This PROSPERO-registered protocol (CRD-42019159676) systematically reviewed reports on suicidal behavior among juveniles (age ≤ 18 years), and pooled data on risk (% of subjects) and rates (%/year), followed by random-effects meta-analysis and multivariable linear regression modeling. RESULTS: Included were 41 reports (1995-2020) from 15 countries involving 104,801 juveniles (102,519 diagnosed with MDD, 2282 with BD), at risk for 0.80-12.5 years. Meta-analytically pooled suicide attempter-rates averaged 7.44%/year [95%CI: 5.63-9.25] with BD and 6.27%/year [5.13-7.41] with MDD. Meta-analysis of 5 studies with both diagnostic groups found significantly greater attempt risk with BD vs. MDD (OR = 1.59 [1.24-2.05], p < 0.0001). In 6 studies, suicide rate with juvenile mood disorders averaged 125 [56.9-236]/100,000/year, similar to adult rates, >30-times greater than in the general juvenile population, and higher among older adolescents. The ratio of attempts/suicides (A/S) was 52.6 among mood-disordered juveniles, indicating greater lethality than among juveniles in the general population (A/S ≥ 250), but somewhat less than in the estimated adult general population (A/S ca. 30). CONCLUSIONS: Rates of suicide attempts in juveniles with a major mood disorder averaged 6580/100,000/year, were greater in BD versus MDD observed under the same conditions, and greater with shorter periods of observation. Lethality (fatalities per suicide attempt) was greater in juveniles diagnosed with major affective disorders than in the juvenile general population, but less than in adults.

Clinical application of mindfulness-oriented meditation in children with ADHD: a preliminary study on sleep and behavioral problems.

OBJECTIVE: High incidence of sleep problems in children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD) has been described. Mindfulness meditation has emerged as a novel approach to sleep disturbances and insomnia remediation. This preliminary study tested the efficacy of Mindfulness-Oriented Meditation (MOM) training on sleep quality and behavioral problems in children with ADHD. DESIGN: Twenty-five children with ADHD aged 7-11 years underwent two programs three times per week for eight-weeks: the MOM training (15 children) and an Active Control Condition (10 children). MAIN OUTCOME MEASURES: Objective and subjective measures of sleep quality and behavioral measures were collected before and after the programs. RESULTS: Positive effects on sleep and behavioral measures were found only in the MOM group. CONCLUSION: Although they are preliminary, our results indicate that MOM training is a promising tool for ameliorating sleep quality and behavioral manifestations in ADHD.

The transition from restrictive anorexia nervosa to binging and purging: a systematic review and meta-analysis.

Numerous studies addressed the topic of behavioral and symptomatic changes in eating disorders. Rates of transition vary widely across studies, ranging from 0 to 70.8%, depending on the diagnoses taken into account and the study design. Evidence shows that the specific transition from restrictive-type anorexia nervosa (AN-R) to disorders involving binging and purging behaviors (BPB) is related to a worsening of the clinical picture and worse long-term outcomes. The aim of this systematic review and meta-analysis is to focus on this specific transition, review existing literature, and summarize related risk factors. Medline and PsycINFO databases were searched, including prospective and retrospective studies on individuals with AN-R. The primary outcome considered was the rate of onset of BPB. Twelve studies (N = 725 patients) were included in the qualitative and quantitative analysis. A total of 41.84% (95% CI 33.58-50.11) of patients with AN-R manifested BPB at some point during follow-up. Risk factors for the onset of BPB included potentially treatable and untreatable factors such as the family environment, unipolar depression and higher premorbid BMI. These findings highlight that patients with AN-R frequently transition to BPB over time, with a worsening of the clinical picture. Existing studies in this field are still insufficient and heterogeneous, and further research is needed. Mental health professionals should be aware of the frequent onset of BPB in AN-R and its risk factors and take this information into account in the treatment of AN-R. LEVEL OF EVIDENCE: Evidence obtained from a systematic review and meta-analysis, Level I.

The Standard of Care Definitions on COVID-19 Pharmacological Clinical Trials: A Systematic Review.

Background: Standard of Care (SoC) has been used with different significance across Randomized Clinical Trials (RCTs) on the treatment of Covid-19. In the context of a living systematic review on pharmacological interventions for COVID-19, we assessed the characteristics of the SoC adopted in the published RCTs. Methods: We performed a systematic review searching Medline, Pubmed, Embase, Cochrane Covid-19 register, international trial registers, medRxiv, bioRxiv, and arXiv up to April 10, 2021. We included all RCTs comparing any pharmacological intervention for Covid-19 against any drugs, placebo, or SoC. All trials selected have been classified as studies with SoC including treatments under investigation for COVID-19 (SoC+); studies with SoC without specifications regarding the potential therapies allowed (SoC-); studies including as control groups Placebo (P) or active controls (A+). Results: We included in our analysis 144 RCTs, comprising 78,319 patients. Most of these trials included SoC (108; 75.0%); some in all arms of the study (69.7%) or just as independent comparators (30.3%). Treatments under investigation for COVID-19 in other trials were included in the SoC (SoC+) in 67 cases (62.0%), Thirty-one different therapeutic agents (alone or in combination) were counted within the studies with SoC+: mostly hydroxychloroquine or chloroquine (28), lopinavir/ritonavir (20) or azithromycin (16). No specification was given regarding treatment allowed in the control groups (SoC-) in 41 studies (38.0%). Conclusion: Our analysis shows that the findings emerging from several clinical trials regarding the efficacy and safety of pharmacological intervention for COVID-19 might be jeopardized by the quality of control arms.

Statins in Depression: An Evidence-Based Overview of Mechanisms and Clinical Studies.

Background: Depression is a leading cause of disability, burdened by high levels of non-response to conventional antidepressants. Novel therapeutic strategies targeting non-monoaminergic pathways are sorely needed. The widely available and safe statins have several putative mechanisms of action, especially anti-inflammatory, which make them ideal candidates for repurposing in the treatment of depression. A large number of articles has been published on this topic. The aim of this study is to assess this literature according to evidence-based medicine principles to inform clinical practise and research. Methods: We performed a systematic review of the electronic databases MEDLINE, CENTRAL, Web of Science, CINAHL, and ClinicalTrials.gov, and an unstructured Google Scholar and manual search, until the 9th of April 2021, for all types of clinical studies assessing the effects of statins in depression. Results: Seventy-two studies were retrieved that investigated the effects of statins on the risk of developing depression or on depressive symptoms in both depressed and non-depressed populations. Fifteen studies specifically addressed the effects of statins on inflammatory-related symptoms of anhedonia, psychomotor retardation, anxiety, and sleep disturbances in depression. Most studies suggested a positive effect of statins on the occurrence and severity of depression, with fewer studies showing no effect, while a minority indicated some negative effects. Limitations: We provide a narrative report on all the included studies but did not perform any quantitative analysis, which limits the strength of our conclusions. Conclusions: Robust evidence indicates that statins are unlikely to lead to depressive symptoms in the general population. Promising data suggest a potential role for statins in the treatment of depression. Further clinical studies are needed, especially in specific subgroups of patients identified by pre-treatment assessments of inflammatory and lipid profiles.

The Investigational Clinical Center: a clinical-supportive and patient-centered trial unit model. Ten years of experience through normal and pandemic times of a large pediatric trial center in Italy.

Evidence-based medicine relies on appropriately designed, conducted and reported clinical trials (CTs) to provide the best proofs of efficacy and safety for pharmacological and non-pharmacological treatments. Modern clinical research features high complexity and requires a high workload for the management of trials-related activities, often hampering physicians' participation to clinical trials. Dealing with children in clinical research adds complexity: rare diseases, parents or legal guardian reluctance to engage and recruitment difficulties are major reasons of pediatric trials failure.However, because in pediatrics many treatments are prescribed off-label or are lacking, well-designed clinical trials are particularly needed. Clinical Trial Units (CTUs) are indeed an important asset in the implementation of clinical trials, but their support to investigators is limited to administrative and non-clinical tasks. In this paper we present the model of the Investigational Clinical Center (ICC) of the Bambino Gesù Children's Hospital in Rome. The ICC includes clinicians supporting the Principal Investigators for clinical management of enrolled patients in compliance of Good Clinical Practice, the legal framework of Clinical Trials. Furthermore, we present 10 years' experience in pediatric clinical trials and how it has been affected in 2020 by the COVID-19 pandemic. The activity of the ICC has been evaluated according to specific metrics of performance. The ICC model offers a complete support, helping investigators, patients and their families to overcome majority of barriers linked to clinical research, even in time of pandemic. We propose this organization as an innovative model for total-supportive and patient-centered clinical trial implementation.

Comparative Effectiveness of Pharmacological Interventions for Covid-19: A Systematic Review and Network Meta-Analysis.

Background: Several pharmacological interventions are now under investigation for the treatment of Covid-19, and the evidence is evolving rapidly. Our aim is to assess the comparative efficacy and safety of these drugs. Methods and Findings: We performed a systematic review and network meta-analysis searching Medline, Pubmed, Embase, Cochrane Covid-19 register, international trial registers, medRxiv, bioRxiv, and arXiv up to December 10, 2020. We included all randomised controlled trials (RCTs) comparing any pharmacological intervention for Covid-19 against any drugs, placebo or standard care (SC). Data extracted from published reports were assessed for risk of bias in accordance with the Cochrane tool, and using the GRADE framework. Primary outcomes were all-cause mortality, adverse events (AEs) and serious adverse events (SAEs). We estimated summary risk ratio (RR) using pairwise and network meta-analysis with random effects (Prospero, number CRD42020176914). We performed a systematic review and network meta-analysis searching Medline, Pubmed, Embase, Cochrane Covid-19 register, international trial registers, medRxiv, bioRxiv, and arXiv up to December 10, 2020. We included all randomised controlled trials (RCTs) comparing any pharmacological intervention for Covid-19 against any drugs, placebo or standard care (SC). Data extracted from published reports were assessed for risk of bias in accordance with the Cochrane tool, and using the GRADE framework. Primary outcomes were all-cause mortality, adverse events (AEs) and serious adverse events (SAEs). We estimated summary risk ratio (RR) using pairwise and network meta-analysis with random effects (Prospero, number CRD42020176914). We included 96 RCTs, comprising of 34,501 patients. The network meta-analysis showed in terms of all-cause mortality, when compared to SC or placebo, only corticosteroids significantly reduced the mortality rate (RR 0.90, 95%CI 0.83, 0.97; moderate certainty of evidence). Corticosteroids significantly reduced the mortality rate also when compared to hydroxychloroquine (RR 0.83, 95%CI 0.74, 0.94; moderate certainty of evidence). Remdesivir proved to be better in terms of SAEs when compared to SC or placebo (RR 0.75, 95%CI 0.63, 0.89; high certainty of evidence) and plasma (RR 0.57, 95%CI 0.34, 0.94; high certainty of evidence). The combination of lopinavir and ritonavir proved to reduce SAEs when compared to plasma (RR 0.49, 95%CI 0.25, 0.95; high certainty of evidence). Most of the RCTs were at unclear risk of bias (42 of 96), one third were at high risk of bias (34 of 96) and 20 were at low risk of bias. Certainty of evidence ranged from high to very low. Conclusion: At present, corticosteroids reduced all-cause mortality in patients with Covid-19, with a moderate certainty of evidence. Remdesivir appeared to be a safer option than SC or placebo, while plasma was associated with safety concerns. These preliminary evidence-based observations should guide clinical practice until more data are made public.

Statins for major depressive disorder: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The burden of depressive disorder is large and new treatment approaches are required. Repurposing widely available drugs such as statins may be a time- and cost-effective solution. Statins have anti-inflammatory and anti-oxidant properties which have been shown to be relevant to the pathophysiology of depression. This study assesses the efficacy, acceptability, tolerability, and safety of statins in major depressive disorder. METHODS: Our study is an update and extension of a previous meta-analysis published in 2016 by Salagre et al. We performed a systematic review (PubMed/MEDLINE, Cochrane CENTRAL, ISI Web of Science, CINAHL, and ClinicalTrials.gov until the 1st September 2020) and meta-analysis of randomized controlled trials using any statin against placebo or any other statin in the treatment of major depressive disorder. Our primary efficacy outcome measure was the mean value on any standardized scale for depressive symptoms at 8 weeks of treatment. We also calculated outcomes for efficacy, response, and remission at 2, 4, and 12 weeks, as well as acceptability (dropouts for any cause), tolerability (dropouts due to any adverse event), and safety (any adverse event) outcomes at the studies' endpoints. Furthermore, we conducted an exploratory network meta-analysis for the primary efficacy outcome to identify potential differences between statins. RESULTS: We retrieved five randomized controlled trials meeting our inclusion criteria: four used a statin in addition to an antidepressant and compared it to placebo plus antidepressant, and one compared two statins alone. and one comparing one statin with another. Statins compared to placebo in addition to antidepressants were efficacious at 8 weeks (N = 255, SMD = -0.48, 95% CI = -0.74 to -0. 22) and 12 weeks (N = 134, SMD = -0.47, 95% CI = -0.89 to -0.05, moderate certainty) with no difference for acceptability, tolerability, and safety (low certainty). An exploratory network meta-analysis suggested that the most lipophilic statins, especially simvastatin, could be more efficacious than less lipophilic or hydrophilic molecules. CONCLUSIONS: This systematic review suggests the efficacy, acceptability, tolerability, and safety of statins in addition to antidepressants in patients with major depressive disorder. Further clinical trials in different settings are required to test this result. TRIAL RGISTRATION: PROSPERO registration: CRD42020170938.