, the US Food and Drug Administration (FDA) approved flibanserin as a treatment for hypoactive sexual desire disorder (HSDD) in premenopausal women, despite concern about suboptimal risk-benefit trade-offs. OBJECTIVE To conduct a systematic review and meta-analysis of randomized clinical trials assessing efficacy and safety of flibanserin for the treatment of HSDD in women. DATA SOURCES Medical databases (among others, Embase, Medline, Psycinfo) and trial registries were searched from inception to June 17, 2015. Reference lists of retrieved studies were searched for additional publications. STUDY SELECTION Randomized clinical trials assessing treatment effects of flibanserin in premenopausal and postmenopausal women were eligible. No age, language, or date restrictions were applied. Abstract and full-text selection was done by 2 independent reviewers. DATA EXTRACTION AND SYNTHESIS Data were extracted by one reviewer and checked by a second reviewer. Results were pooled using 2 approaches depending on the blinding risk of bias. MAIN OUTCOMES AND MEASURES Primary efficacy outcomes included number of satisfying sexual events (SSEs), eDiary sexual desire, and Female Sexual Function Index (FSFI) desire. Safety outcomes included, among others, 4 common adverse events (AEs): dizziness, somnolence, nausea, and fatigue. RESULTS Five published and 3 unpublished studies including 5914 women were included. Pooled mean differences for SSE change from baseline were 0.49 (95% CI, 0.32-0.67) between 100-mg flibanserin and placebo, 1.63 (95% CI, 0.45-2.82) for eDiary desire, and 0.27 (95% CI, 0.17-0.38) for FSFI desire. The risk ratio for study discontinuation due to AEs was 2.19 (95% CI, 1.50-3.20). The risk ratio for dizziness was 4.00 (95% CI, 2.56-6.27) in flibanserin vs placebo, 3.97 (95% CI, 3.01-5.24) for somnolence, 2.35 (95% CI, 1.85-2.98) for nausea, and 1.64 (95% CI, 1.27-2.13) for fatigue. Women's mean global impression of improvement scores indicated minimal improvement to no change. CONCLUSIONS AND RELEVANCE Treatment with flibanserin, on average, resulted in one-half additional SSE per month while statistically and clinically significantly increasing the risk of dizziness, somnolence, nausea, and fatigue. Overall, the quality of the evidence was graded as very low. Before flibanserin can be recommended in guidelines and clinical practice, future studies should include women from diverse populations, particularly women with comorbidities, medication use, and surgical menopause.

BackgroundStudies suggest that expectations powerfully shape clinical outcomes. For subjective outcomes in adequately blinded trials, health improvements are substantial and largely explained by non-specific factors.The objective of this study was to investigate if unblinding in randomized controlled trials (RCTs) is associated with enhanced placebo effects for intervention groups and nocebo effects for placebo groups. For these effects, a secondary objective was to explore potential moderating factors.MethodsWe included RCTs that investigated the efficacy of phosphodiesterase-5 (PDE-5) inhibitors for male erectile dysfunction by comparing one PDE-5 inhibitor to placebo. In addition, to be included studies must have reported scores for change from baseline, or baseline and final International Index of Erectile Functioning-Erectile Functioning domain score (IIEF-EF), and be published in either English, French, Dutch, or German.We searched for both published and unpublished relevant trials using PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials, a clinical trials register (clinicaltrials.gov) and the Food and Drug Administration clinical reviews through March 2012.We evaluated the blinding status of trials with the Cochrane Risk of Bias Tool, using the domains of allocation sequence concealment, blinding of participants, healthcare providers and outcome assessors. Across these four domains, studies that scored low risk of bias were judged to be adequately blinded and studies that scored unclear or high risk of bias were judged to be inadequately blinded.ResultsWe included 110 studies (205 journal publications and 2 unpublished sources) that involved 23,877 participants; 93 (85%), 51 (46%), 93 (85%) and 93 (85%) studies were assessed with an unclear risk of bias for allocation concealment, blinding of participant, blinding of caregiver and blinding of outcome assessor, respectively. None of the studies reported testing of blinding.None of the 205 journal publications provided sufficient details to assess allocation concealment, blinding of participants, caregivers and outcome assessors. After contacting authors for additional information, we judged five studies to be adequately (n = 1,202) and 16 to be inadequately (n = 3,006) blinded. The IIEF-EF score for placebo groups in adequately blinded trials versus inadequately blinded trials was 1.92 points (95% CI, 0.64 to 3.20) versus 1.56 (95% CI, 0.93 to 2.20), respectively. The IIEF-EF score for intervention groups in adequately blinded trials versus inadequately blinded trials was 9.40 (95% CI, 6.96 to 11.83) versus 8.33 (95% CI, 7.29 to 9.37), respectively. In a secondary analysis, prior experience with the drug affected the scores; in placebo groups with participants naïve to the intervention the score was 2.89 (95% CI, 2.33 to 3.45) versus -0.11 (95% CI, -2.06 to 1.84) with participants having prior experience. In the intervention groups, these scores were 7.99 (95% CI, 6.85 to 9.14) versus 8.33 (95% CI, 7.51 to 9.16), respectively.Unblinding lowe...

BackgroundPatients’ expectations of treatment effects may contribute to positive (placebo) and negative (nocebo) outcomes. The effect of patient expectations may be pronounced in subjectively assessed conditions, such as male erectile dysfunction. The aim of this project is to examine the magnitude of expectancy in trials of phosphodiesterase-5 inhibitors. We hypothesize that randomized controlled trials with inadequate blinding will report enhanced placebo effects for intervention groups and nocebo effects for placebo groups, compared with adequately blinded studies.Methods/designWe will quantify the magnitude of expectancy by comparing the effect estimates of trials with inadequate and adequate blinding. Blinding will be assessed using four domains from the Cochrane ‘risk-of-bias’ tool: allocation concealment; blinding of patient; caregiver; and outcome assessor. Our secondary aim is to identify factors that can modify expectations, such as prior experience with the intervention and drug side effects.We will perform an electronic search using a combination of controlled vocabulary and free text words in the following databases: MEDLINE, EMBASE, CENTRAL, and a clinical trials register. We will include randomized controlled trials, with either parallel or crossover design, that compare one phosphodiesterase-5 inhibitor with a placebo. The study’s primary aim should be to investigate the efficacy of phosphodiesterase-5 inhibitors for treating male erectile dysfunction. Screening will take place at two levels: abstracts and titles, followed by full text reports. Two reviewers will independently extract data on the primary outcome and assess risk of bias.We will meta-analyze treatment effects, if appropriate, to assess the magnitude of enhanced placebo effects and nocebo effects in intervention and placebo groups, respectively. We will explore possible mediators of placebo and nocebo effects with subgroup and meta-regression analyses.DiscussionTreatments may confer significant costs and risk of adverse effects; it is important, therefore, to determine whether the effects of treatments are larger than expectancy alone. If treatment expectations can be used in a non-deceptive way to produce clinically advantageous outcomes, then it may be possible to incorporate such mechanisms into evidence-based healthcare decision-making.

OBJECTIVE The objective of this study was to assess the benefits and risks of a lockdown in Belgium, with focus on mental health. Consequently, projecting the cost effectiveness of remedial measures.METHODS For benefits; in estimating health savings, we compared Belgium (lockdown) and Sweden (lockdown-light) for COVID-19 related deaths, peak intensive care unit load and peak hospitalisations load. We also calculated the years of life lost (YLL). For risks; we assessed the mental health and wellbeing, using the most common dimensions: anxiety and depression. GAD-7 and PHQ-9 scores were extracted from a survey and compared to a similar representative survey in 2018. Disability-adjusted life years (DALYs) were calculated for and we assessed non-COVID-19 related-deaths from excess mortality. Cost-utility analysis was performed with a 1-year time horizon. Hence, considering the Quality-adjusted Life Years (QALYs), Incremental Cost-effectiveness Ratio (ICER) and the potential impact providing adequate treatment compared to standard care.RESULTS Lockdown versus lockdown-light gave no COVID-19 related benefits. COVID-19 related risks during lockdown saw an increase of 4,231 deaths; 667 extra ICU admissions on peak day, 3213 extra hospital admissions on peak day and 140 extra non-COVID-19 related deaths. Additionally, 140 extra deaths occured due to a non-COVID-19 cause. 1,034,365 (9,0%) of Belgian population reported increased anxiety and/or depression. Risk-benefit analysis; COVID-19 related deaths yielded an extra 3,145 YLL, total psychological burden of 104,515 (74,025-139,762) DALYs and the total loss of societal value is considered between €3.0 billion and €5.6 billion. Cost-utility analysis; ICER for psychological treatment for depression was €11,510/QALY gained. In total psychotherapy could create 181,714 (34,134-213,654) QALYs and a 1 year net benefit of € 5.2 billion.CONCLUSION We found no evidence that a lockdown versus lockdown-light results in less COVID-19 related mortality and morbidity. The Belgian lockdown created an obvious +104,515 (74,025-139,762) DALYs psychological burden in Belgium. Adequate investment in psychological help would provide individual relief and may improve a person’s immunological response. Also, within a 1-year time horizon, taking into account the loss of value in healthy functioning people, the net benefit is €0.9 billion.

OBJECTIVE Immunological mind-body research suggests mental health may also be important in the COVID-19 pandemic. This study aimed to investigate the potential influence of mental health as a protective factor for COVID-19 related mortality in the general population. The second goal was to examine this among populations of countries most affected by COVID-19 related mortality. METHODS Data sources were the Global Burden of Disease report 2017 and publicly reported situational reports of COVID-19. We described variables; calculated the spearman′s correlation coefficient, calculated the percentage of the variability of the data that is explained by the association. We explored inter-relationships among other variables: aged 70 or older, cardiovascular disease, obesity and diabetes. A correlation matrix with plotted scatter matrix diagrams was produced. RESULTS Across 181 countries, the mean total COVID-19 related survivors per million was 999,949 (sd=125), median=999,993. The variable had a lognormal distribution; the mean mentally healthy per 100,000 was 85,411 (sd=1,871), median=85,634. The test of normality resulted in p-value < 0.001. Correlation of mentally healthy per 100,0000 and totals of COVID-19 related survivors was 𝝆s=0.29 (n=181, 95% CI 0.16-0.43). The variance explained by the relation between mental healthy and totals of COVID-19 related survivors was 8.4% (2.6-18.5%). Across countries most affected by COVID-19 related mortality 𝝆s=0.49 (n=45, 0.28-0.70), explaining 24.2% (7.7-49.3%). CONCLUSION A weak association was found between the psychological well-being of a population and COVID-19 related survival. This relationship explained between 2.6 and 18.5% of COVID-19 related survival. For countries most affected by COVID-19 related death, this association was moderate and explained between 7.7 and 49.3%. Confirmation of these important observational findings is needed with future individual patient data research.

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