Placebo effects in randomized trials of pharmacological and neurostimulation interventions for mental disorders: An umbrella review.

There is a growing literature exploring the placebo response within specific mental disorders, but no overarching quantitative synthesis of this research has analyzed evidence across mental disorders. We carried out an umbrella review of meta-analyses of randomized controlled trials (RCTs) of biological treatments (pharmacotherapy or neurostimulation) for mental disorders. We explored whether placebo effect size differs across distinct disorders, and the correlates of increased placebo effects. Based on a pre-registered protocol, we searched Medline, PsycInfo, EMBASE, and Web of Knowledge up to 23.10.2022 for systematic reviews and/or meta-analyses reporting placebo effect sizes in psychopharmacological or neurostimulation RCTs. Twenty meta-analyses, summarising 1,691 RCTs involving 261,730 patients, were included. Placebo effect size varied, and was large in alcohol use disorder (g = 0.90, 95% CI [0.70, 1.09]), depression (g = 1.10, 95% CI [1.06, 1.15]), restless legs syndrome (g = 1.41, 95% CI [1.25, 1.56]), and generalized anxiety disorder (d = 1.85, 95% CI [1.61, 2.09]). Placebo effect size was small-to-medium in obsessive-compulsive disorder (d = 0.32, 95% CI [0.22, 0.41]), primary insomnia (g = 0.35, 95% CI [0.28, 0.42]), and schizophrenia spectrum disorders (standardized mean change = 0.33, 95% CI [0.22, 0.44]). Correlates of larger placebo response in multiple mental disorders included later publication year (opposite finding for ADHD), younger age, more trial sites, larger sample size, increased baseline severity, and larger active treatment effect size. Most (18 of 20) meta-analyses were judged 'low' quality as per AMSTAR-2. Placebo effect sizes varied substantially across mental disorders. Future research should explore the sources of this variation. We identified important gaps in the literature, with no eligible systematic reviews/meta-analyses of placebo response in stress-related disorders, eating disorders, behavioural addictions, or bipolar mania.

Lung cancer screening.

Randomised controlled trials, including the National Lung Screening Trial (NLST) and the NELSON trial, have shown reduced mortality with lung cancer screening with low-dose CT compared with chest radiography or no screening. Although research has provided clarity on key issues of lung cancer screening, uncertainty remains about aspects that might be critical to optimise clinical effectiveness and cost-effectiveness. This Review brings together current evidence on lung cancer screening, including an overview of clinical trials, considerations regarding the identification of individuals who benefit from lung cancer screening, management of screen-detected findings, smoking cessation interventions, cost-effectiveness, the role of artificial intelligence and biomarkers, and current challenges, solutions, and opportunities surrounding the implementation of lung cancer screening programmes from an international perspective. Further research into risk models for patient selection, personalised screening intervals, novel biomarkers, integrated cardiovascular disease and chronic obstructive pulmonary disease assessments, smoking cessation interventions, and artificial intelligence for lung nodule detection and risk stratification are key opportunities to increase the efficiency of lung cancer screening and ensure equity of access.

Pulmonary fibrosis and lung cancer: an analysis of the Clinical Practice Research Datalink linked to the National Cancer Registration Dataset.

We quantified the proportion of diagnoses of pulmonary fibrosis (PF) among 25 136 people with lung cancer and 250 583 matched controls and compared the natural history of lung cancer in people with and without PF. Diagnoses of PF were more common in people with lung cancer than those without (1.5% vs 0.8%, OR 1.97; 95% CI 1.77 to 2.21). Within people with PF, squamous cell carcinoma was more (22.9% vs 19.1%), and adenocarcinoma was less common (18.0% vs 21.3%). People with PF were less likely to have stage 4 disease at diagnosis (OR 0.43, 95% CI 0.28 to 0.65) but their survival was worse.

Uptake and 4-week quit rates from an opt-out co-located smoking cessation service delivered alongside community-based low-dose computed tomography screening within the Yorkshire Lung Screening Trial.

BACKGROUND: Up to 50% of those attending for low-dose computed tomography screening for lung cancer continue to smoke and co-delivery of smoking cessation services alongside screening may maximise clinical benefit. Here we present data from an opt-out co-located smoking cessation service delivered alongside the Yorkshire Lung Screening Trial (YLST). METHODS: Eligible YLST participants were offered an immediate consultation with a smoking cessation practitioner (SCP) at their screening visit with ongoing smoking cessation support over subsequent weeks. RESULTS: Of 2150 eligible participants, 1905 (89%) accepted the offer of an SCP consultation during their initial visit, with 1609 (75%) receiving ongoing smoking cessation support over subsequent weeks. Uptake of ongoing support was not associated with age, ethnicity, deprivation or educational level in multivariable analyses, although men were less likely to engage (adjusted OR (ORadj) 0.71, 95% CI 0.56-0.89). Uptake was higher in those with higher nicotine dependency, motivation to stop smoking and self-efficacy for quitting. Overall, 323 participants self-reported quitting at 4 weeks (15.0% of the eligible population); 266 were validated by exhaled carbon monoxide (12.4%). Multivariable analyses of eligible smokers suggested 4-week quitting was more likely in men (ORadj 1.43, 95% CI 1.11-1.84), those with higher motivation to quit and previous quit attempts, while those with a stronger smoking habit in terms of cigarettes per day were less likely to quit. CONCLUSIONS: There was high uptake for co-located opt-out smoking cessation support across a wide range of participant demographics. Protected funding for integrated smoking cessation services should be considered to maximise programme equity and benefit.

Placebo Effects Are Small on Average in the 7.5% CO2 Inhalational Model of Generalized Anxiety.

BACKGROUND: Anxiety disorders are highly prevalent and socio-economically costly. Novel pharmacological treatments for these disorders are needed because many patients do not respond to current agents or experience unwanted side effects. However, a barrier to treatment development is the variable and large placebo response rate seen in trials of novel anxiolytics. Despite this, the mechanisms that drive placebo responses in anxiety disorders have been little investigated, possibly due to low availability of convenient experimental paradigms. We aimed to develop and test a novel protocol for inducing placebo anxiolysis in the 7.5% CO2 inhalational model of generalized anxiety in healthy volunteers. METHODS: Following a baseline 20-minute CO2 challenge, 32 healthy volunteers were administered a placebo intranasal spray labelled as either the anxiolytic "lorazepam" or "saline." Following this, participants surreptitiously underwent a 20-minute inhalation of normal air. Post-conditioning, a second dose of the placebo was administered, after which participants completed another CO2 challenge. RESULTS: Participants administered sham "lorazepam" reported significant positive expectations of reduced anxiety (P = .001), but there was no group-level placebo effect on anxiety following CO2 challenge post-conditioning (Ps > .350). Surprisingly, we found many participants exhibited unexpected worsening of anxiety, despite positive expectations. CONCLUSIONS: Contrary to our hypothesis, our novel paradigm did not induce a placebo response, on average. It is possible that effects of 7.5% CO2 inhalation on prefrontal cortex function or behavior in line with a Bayesian predictive coding framework attenuated the effect of expectations on subsequent placebo response. Future studies are needed to explore these possibilities.

Academic psychiatry is everyone's business.

This editorial considers the value and nature of academic psychiatry by asking what defines the specialty and psychiatrists as academics. We frame academic psychiatry as a way of thinking that benefits clinical services and discuss how to inspire the next generation of academics.

Odor exposure during imprinting periods increases odorant-specific sensitivity and receptor gene expression in coho salmon (Oncorhynchus kisutch).

Pacific salmon are well known for their homing migrations; juvenile salmon learn odors associated with their natal streams prior to seaward migration, and then use these retained odor memories to guide them back from oceanic feeding grounds to their river of origin to spawn several years later. This memory formation, termed olfactory imprinting, involves (at least in part) sensitization of the peripheral olfactory epithelium to specific odorants. We hypothesized that this change in peripheral sensitivity is due to exposure-dependent increases in the expression of odorant receptor (OR) proteins that are activated by specific odorants experienced during imprinting. To test this hypothesis, we exposed juvenile coho salmon, Oncorhynchus kisutch, to the basic amino acid odorant l-arginine during the parr-smolt transformation (PST), when imprinting occurs, and assessed sensitivity of the olfactory epithelium to this and other odorants. We then identified the coho salmon ortholog of a basic amino acid odorant receptor (BAAR) and determined the mRNA expression levels of this receptor and other transcripts representing different classes of OR families. Exposure to l-arginine during the PST resulted in increased sensitivity to that odorant and a specific increase in BAAR mRNA expression in the olfactory epithelium relative to other ORs. These results suggest that specific increases in ORs activated during imprinting may be an important component of home stream memory formation and this phenomenon may ultimately be useful as a marker of successful imprinting to assess management strategies and hatchery practices that may influence straying in salmon.

Dietary Exposure to Environmentally Relevant Levels of Chemical Contaminants Reduces Growth and Survival in Juvenile Chinook Salmon.

Chemical pollution can degrade aquatic ecosystems. Chinook salmon in contaminated habitats are vulnerable to health impacts from toxic exposures. Few studies have been conducted on adverse health outcomes associated with current levels and mixtures of contaminants. Fewer still address effects specific to the juvenile life-stage of salmonids. The present study evaluated contaminant-related effects from dietary exposure to environmentally relevant concentrations and mixture profiles in juvenile Chinook salmon from industrialized waterways in the U.S. Pacific Northwest using two end points: growth assessment and disease susceptibility. The dose and chemical proportions were reconstituted based on environmental sampling and analysis using the stomach contents of juvenile Chinook salmon recently collected from contaminated, industrialized waterways. Groups of fish were fed a mixture with fixed proportions of 10 polychlorinated biphenyls (PCBs), 3 dichlorodiphenyltrichloroethanes (DDTs), and 13 polycyclic aromatic hydrocarbons (PAHs) at five concentrations for 35 days. These contaminant compounds were selected because of elevated concentrations and the widespread presence in sediments throughout industrialized waterways. Fork length and otolith microstructural growth indicators were significantly reduced in fish fed environmentally relevant concentrations of these contaminants. In addition, contaminant-exposed Chinook salmon were more susceptible to disease during controlled challenges with the pathogen Aeromonas salmonicida. Our results indicate that dietary exposure to contaminants impairs growth and immune function in juvenile Chinook salmon, thereby highlighting that current environmental exposure to chemicals of potential management concern threatens the viability of exposed salmon.

Eye movement desensitisation and reprocessing for survivors of life-threatening medical events.

OBJECTIVES: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of eye movement desensitisation and reprocessing (EMDR), a psychological intervention programme, on symptoms related to traumatic stress in survivors of life-threatening medical events. SECONDARY OBJECTIVES: to evaluate whether the effects of EMDR differ according to the nature of the medical event (associated diagnosis or setting), measured outcome (post-traumatic stress disorder (PTSD), anxiety, depression, or quality of life), or intervention (online, face-to-face, group or individual sessions).

Sleep Problems and Gambling Disorder: Cross-Sectional Relationships in a Young Cohort.

AIMS: To investigate the potential association between gambling disorder and symptoms of sleep problems (including insomnia and excessive daytime sleepiness). It was hypothesised that, compared to controls, individuals with gambling disorder would have significantly greater disturbance of sleep, as indicated by increased scores in: (1) sleep items on the Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Rating Scale for Depression (HAM-D); (2) total score on the HAM-A and HAM-D; and (3) the Epworth Sleepiness Scale (ESS). METHODS: Secondary analysis of previously published data from 152 young adults, aged 18-29 years. Individuals were stratified into three groups: controls, those at risk of gambling disorder, and those with gambling disorder. One-way ANOVAs with post-hoc tests were conducted to determine whether groups differed significantly in sleep item scores and total scores of the HAM-A and HAM-D, and the ESS. RESULTS: HAM-D scale insomnia item scores were significantly higher in the disorder group, when compared to controls, this being particularly marked for middle and late insomnia. The HAM-A item score indicated significantly worse sleep quality in the disorder group, compared to at risk and control groups. Total HAM-A and HAM-D scores were significantly higher in the disorder group, but ESS scores did not differ significantly. CONCLUSION: Measures of disruptions in sleep were significantly higher in gambling disorder than controls. Anxiety and depressive symptom severity was also significantly higher in the gambling disorder group. Further research could have implications for identification and treatment of sleep disorders and psychiatric comorbidities in gambling disorder.

Defining the road map to a UK national lung cancer screening programme.

Lung cancer screening with low-dose CT was recommended by the UK National Screening Committee (UKNSC) in September, 2022, on the basis of data from trials showing a reduction in lung cancer mortality. These trials provide sufficient evidence to show clinical efficacy, but further work is needed to prove deliverability in preparation for a national roll-out of the first major targeted screening programme. The UK has been world leading in addressing logistical issues with lung cancer screening through clinical trials, implementation pilots, and the National Health Service (NHS) England Targeted Lung Health Check Programme. In this Policy Review, we describe the consensus reached by a multiprofessional group of experts in lung cancer screening on the key requirements and priorities for effective implementation of a programme. We summarise the output from a round-table meeting of clinicians, behavioural scientists, stakeholder organisations, and representatives from NHS England, the UKNSC, and the four UK nations. This Policy Review will be an important tool in the ongoing expansion and evolution of an already successful programme, and provides a summary of UK expert opinion for consideration by those organising and delivering lung cancer screenings in other countries.

Impact of the SARS-CoV-2 pandemic on lung cancer survival in England: an analysis of the rapid cancer registration dataset.

Early changes in lung cancer care can affect survival. Given the decrease in diagnosis during lockdowns, we calculated their impact on survival using National Lung Cancer Audit data. Percentage survival and HRs for death were compared between 2019 and lockdown periods of 2020. Decreased survival was observed from the first national lockdown onwards and within 90 days of diagnosis. HRs were highest for people diagnosed at the end of 2020 at 1.26 (95% CI 1.20 to 1.32) for death within 90 days and 1.51 (95% CI 1.42 to 1.60) for death between 91 and 270 days. Further work is needed on measures to mitigate this impact.

Impact of radiographer immediate reporting of X-rays of the chest from general practice on the lung cancer pathway (radioX): a randomised controlled trial.

The National Optimal Lung Cancer Pathway recommends rapid progression from abnormal chest X-rays (CXRs) to CT. The impact of the more rapid reporting on the whole pathway is unknown. The aim of this study was to determine the impact of immediate reporting of CXRs requested by primary care by radiographers on the time to diagnosis of lung cancer. METHOD: People referred for CXR from primary care to a single acute district general hospital in London attended sessions that were prerandomised to either immediate radiographer (IR) reporting or standard radiographer (SR) reporting within 24 hours. CXRs were subsequently reported by radiologists blind to the radiographer reports to test the reliability of the radiographer report. Radiographer and local radiologist discordant cases were reviewed by thoracic radiologists, blinded to reporter. RESULTS: 8682 CXRs were performed between 21 June 2017 and 4 August 2018, 4096 (47.2%) for IR and 4586 (52.8%) for SR. Lung cancer was diagnosed in 49, with 27 (55.1%) for IR. The median time from CXR to diagnosis of lung cancer for IR was 32 days (IQR 19, 70) compared with 63 days (IQR 29, 78) for SR (p=0.03).8258 CXRs (95.1%) were reported by both radiographers and local radiologists. In the 1361 (16.5%) with discordance, the reviewing thoracic radiologists were equally likely to agree with local radiologist and radiographer reports. CONCLUSIONS: Immediate reporting of CXRs from primary care reduces time to diagnosis of lung cancer by half, likely due to rapid progress to CT. Radiographer reports are comparable to local radiologist reports for accuracy. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN21818068. Registered on 20 June 2017.

Developing a Pan-European Technical Standard for a Comprehensive High-quality Lung Cancer CT Screening Program. An ERS Technical Standard.

Screening for lung cancer with low radiation dose computed tomography (LDCT) has a strong evidence base. The European Council adopted a recommendation in November 2022 that lung cancer screening be implemented using a stepwise approach. The imperative now is to ensure that implementation follows an evidence-based process that delivers clinical and cost effectiveness. This ERS Taskforce was formed to provide a technical standard for a high-quality lung cancer screening program. METHOD: A collaborative group was convened to include members of multiple European societies (see below). Topics were identified during a scoping review and a systematic review of the literature was conducted. Full text was provided to members of the group for each topic. The final document was approved by all members and the ERS Scientific Advisory Committee. RESULTS: Ten topics were identified representing key components of a screening program. The action on findings from the LDCT were not included as they are addressed by separate international guidelines (nodule management and clinical management of lung cancer) and by a linked taskforce (incidental findings). Other than smoking cessation, other interventions that are not part of the core screening process were not included (e.g. pulmonary function measurement). Fifty-three statements were produced and areas for further research identified. CONCLUSION: This European collaborative group has produced a technical standard that is a timely contribution to implementation of LCS. It will serve as a standard that can be used, as recommended by the European Council, to ensure a high quality and effective program.

ERS/ESTS/ESTRO/ESR/ESTI/EFOMP statement on management of incidental findings from low dose CT screening for lung cancer.

BACKGROUND: Screening for lung cancer with low radiation dose computed tomography has a strong evidence base, is being introduced in several European countries and is recommended as a new targeted cancer screening programme. The imperative now is to ensure that implementation follows an evidence-based process that will ensure clinical and cost effectiveness. This European Respiratory Society (ERS) task force was formed to provide an expert consensus for the management of incidental findings which can be adapted and followed during implementation. METHODS: A multi-European society collaborative group was convened. 23 topics were identified, primarily from an ERS statement on lung cancer screening, and a systematic review of the literature was conducted according to ERS standards. Initial review of abstracts was completed and full text was provided to members of the group for each topic. Sections were edited and the final document approved by all members and the ERS Science Council. RESULTS: Nine topics considered most important and frequent were reviewed as standalone topics (interstitial lung abnormalities, emphysema, bronchiectasis, consolidation, coronary calcification, aortic valve disease, mediastinal mass, mediastinal lymph nodes and thyroid abnormalities). Other topics considered of lower importance or infrequent were grouped into generic categories, suitable for general statements. CONCLUSIONS: This European collaborative group has produced an incidental findings statement that can be followed during lung cancer screening. It will ensure that an evidence-based approach is used for reporting and managing incidental findings, which will mean that harms are minimised and any programme is as cost-effective as possible.

European Respiratory Society guideline on various aspects of quality in lung cancer care.

This European Respiratory Society guideline is dedicated to the provision of good quality recommendations in lung cancer care. All the clinical recommendations contained were based on a comprehensive systematic review and evidence syntheses based on eight PICO (Patients, Intervention, Comparison, Outcomes) questions. The evidence was appraised in compliance with the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Evidence profiles and the GRADE Evidence to Decision frameworks were used to summarise results and to make the decision-making process transparent. A multidisciplinary Task Force panel of lung cancer experts formulated and consented the clinical recommendations following thorough discussions of the systematic review results. In particular, we have made recommendations relating to the following quality improvement measures deemed applicable to routine lung cancer care: 1) avoidance of delay in the diagnostic and therapeutic period, 2) integration of multidisciplinary teams and multidisciplinary consultations, 3) implementation of and adherence to lung cancer guidelines, 4) benefit of higher institutional/individual volume and advanced specialisation in lung cancer surgery and other procedures, 5) need for pathological confirmation of lesions in patients with pulmonary lesions and suspected lung cancer, and histological subtyping and molecular characterisation for actionable targets or response to treatment of confirmed lung cancers, 6) added value of early integration of palliative care teams or specialists, 7) advantage of integrating specific quality improvement measures, and 8) benefit of using patient decision tools. These recommendations should be reconsidered and updated, as appropriate, as new evidence becomes available.

Clinical trials in cancer screening, prevention and early diagnosis (SPED): a systematic mapping review.

BACKGROUND: Global annual cancer incidence is forecast to rise to 27.5 M by 2040, a 62% increase from 2018. For most cancers, prevention and early detection are the most effective ways of reducing mortality. This study maps trials in cancer screening, prevention, and early diagnosis (SPED) to identify areas of unmet need and highlight research priorities. METHODS: A systematic mapping review was conducted to evaluate all clinical trials focused on cancer SPED, irrespective of tumour type. The National Cancer Research Institute (NCRI) portfolio, EMBASE, PubMed and Medline were searched for relevant papers published between 01/01/2007 and 01/04/2020. References were exported into Covidence software and double-screened. Data were extracted and mapped according to tumour site, geographical location, and intervention type. RESULTS: One hundred seventeen thousand seven hundred one abstracts were screened, 5157 full texts reviewed, and 2888 studies included. 1184 (52%) trials focussed on screening, 554 (24%) prevention, 442 (20%) early diagnosis, and 85 (4%) a combination. Colorectal, breast, and cervical cancer comprised 61% of all studies compared with 6.4% in lung and 1.8% in liver cancer. The latter two are responsible for 26.3% of global cancer deaths compared with 19.3% for the former three. Number of studies varied markedly according to geographical location; 88% were based in North America, Europe, or Asia. CONCLUSIONS: This study shows clear disparities in the volume of research conducted across different tumour types and according to geographical location. These findings will help drive future research effort so that resources can be directed towards major challenges in cancer SPED.

Validity of root cause analysis in investigating adverse events in psychiatry.

Root cause analysis (RCA), imported from high-reliability industries into health two decades ago, is the mandated methodology to investigate adverse events in most health systems. In this analysis, we argue that the validity of RCA in health and in psychiatry must be established, given the impact of these investigations on mental health policy and practice.

Latency to selective serotonin reuptake inhibitor vs benzodiazepine treatment in patients with panic disorder: a naturalistic study.

BACKGROUND: Panic disorder (PD) is a prevalent and impairing anxiety disorder with previous reports suggesting that the longer the condition remains untreated, the greater the likelihood of nonresponse. However, patients with PD may wait for years before receiving a guideline-recommended pharmacological treatment. The widespread prescription of benzodiazepines (BDZ) for managing anxiety symptoms and disorders might delay the administration of pharmacotherapy according to guidelines (eg, selective serotonin reuptake inhibitors, SSRIs). The present study aimed to determine the mean duration of untreated illness (DUI) in a sample of PD patients, to quantify and compare DUI-SSRI to DUI-BDZ, and to compare findings with those from previous investigations. METHODS: Three hundred and fourteen patients with a Diagnostic and Statistical Manual of Mental Disorders, fifth edition diagnosis of PD were recruited from an Italian outpatient psychotherapy unit, and epidemiological and clinical variables were retrieved from medical records. Descriptive statistical analyses were undertaken for sociodemographic and clinical variables, Wilcoxon matched-pair signed rank test was applied to compare the distribution of DUI-SSRI vs DUI-BDZ, and Welch's t test was performed to compare findings with those from previous studies. RESULTS: The mean DUI-SSRI of the total sample was 64.25 ± 112.74 months, while the mean DUI-BDZ was significantly shorter (35.09 ± 78.62 months; P < 0.0001). A significantly longer DUI-SSRI, compared to findings from previous studies, was also observed. CONCLUSIONS: The present results confirm a substantial delay in implementing adequate pharmacological treatments in patients with PD, and highlight the discrepancy between recommendations from international treatment guidelines and common clinical practice in relation to BDZ prescription.

Selective serotonin reuptake inhibitors, post-treatment sexual dysfunction and persistent genital arousal disorder: A systematic review.

PURPOSE: Adverse effects of selective serotonin reuptake inhibitors (SSRIs) on sexual function have been an important area of research for many years. However, the duration of SSRI-associated sexual adverse effects, and their possible persistence after treatment discontinuation, is still uncertain. The aims of the current systematic review were first to identify existing evidence of sexual dysfunction following SSRI discontinuation, and to provide an account of reported symptoms and proposed treatment options; and second, to establish whether current literature allows accurate estimates of the prevalence of such sexual dysfunction. METHODS: A systematic review was conducted on PubMed, Embase, and Google Scholar; papers with clinical data regarding patients with persistent sexual dysfunction after SSRI treatment suspension were included. RESULTS: Overall, two retrospective interventional studies, six observational studies and 11 case reports were judged eligible for inclusion. It was not possible to determine reliable estimates of prevalence. Similarly, a cause-effect relationship between SSRI exposure and persistent sexual impairment could not be ascertained. Nonetheless, the potential for continued sexual disturbances despite discontinuation could not be entirely ruled out. CONCLUSIONS: There is a need to investigate a possible dose-response relationship between SSRI exposure and persistent sexual adverse effects. Treatment options for persistent dysfunctions remain limited, but novel therapeutic approaches may be required in order to address an otherwise neglected need for sexual well-being.