Heterogeneity of outcome measures in depression trials and the relevance of the content of outcome measures to patients: a systematic review.

Research waste occurs when randomised controlled trial (RCT) outcomes are heterogeneous or overlook domains that matter to patients (eg, relating to symptoms or functions). In this systematic review, we reviewed the outcome measures used in 450 RCTs of adult unipolar and bipolar depression registered between 2018 and 2022 and identified 388 different measures. 40% of the RCTs used the same measure (Hamilton Depression Rating Scale [HAMD]). Patients and clinicians matched each item within the 25 most frequently used measures with 80 previously identified domains of depression that matter to patients. Seven (9%) domains were not covered by the 25 most frequently used outcome measures (eg, mental pain and irritability). The HAMD covered a maximum of 47 (59%) of the 80 domains that matter to patients. An interim solution to facilitate evidence synthesis before a core outcome set is developed would be to use the most common measures and choose complementary scales to optimise domain coverage. TRANSLATIONS: For the French and Dutch translations of the abstract see Supplementary Materials section.

Estimating the smallest worthwhile difference of antidepressants: a cross-sectional survey.

BACKGROUND: Approximately 30% of patients experience substantial improvement in depression after 2 months without treatment, and 45% with antidepressants. The smallest worthwhile difference (SWD) refers to an intervention's smallest beneficial effect over a comparison patients deem worthwhile given treatment burdens (harms, expenses and inconveniences), but is undetermined for antidepressants. OBJECTIVE: Estimating the SWD of commonly prescribed antidepressants for depression compared to no treatment. METHODS: The SWD was estimated as a patient-required difference in response rates between antidepressants and no treatment after 2 months. An online cross-sectional survey using Prolific, MQ Mental Health and Amazon Mechanical Turk crowdsourcing services in the UK and USA between October 2022 and January 2023 garnered participants (N=935) that were a mean age of 44.1 (SD=13.9) and 66% women (n=617). FINDINGS: Of 935 participants, 124 reported moderate-to-severe depressive symptoms but were not in treatment, 390 were in treatment and 495 reported absent-to-mild symptoms with or without treatment experiences. The median SWD was a 20% (IQR=10-30%) difference in response rates for people with moderate-to-severe depressive symptoms, not in treatment, and willing to consider antidepressants, and 25% (IQR=10-35%) for the full sample. CONCLUSIONS: Our observed SWDs mean that the current 15% antidepressant benefit over no treatment was sufficient for one in three people to accept antidepressants given the burdens, but two in three expected greater treatment benefits. IMPLICATIONS: While a minority may be satisfied with the best currently available antidepressants, more effective and/or less burdensome medications are needed, with more attention given to patient perspectives.

Are large prospective trials on antidepressants in mental disorders seeding trials? A descriptive study of trials registered on ClinicalTrials.gov.

OBJECTIVES: This descriptive study of registered trials aimed to identify large clinical trials on antidepressants for mental disorders: (1) to assess what proportion could be labelled as 'seeding trials' (trials for marketing purposes) and (2) to describe their methodological characteristics and outcomes. DESIGN: A search was conducted across all trials registered on ClinicalTrials.gov by drug name in March 2017. SETTING: All trials registered in the database of ClinicalTrials.gov were screened. Large registered studies were received and studies focusing prospectively on the effects of antidepressants in mental health disorders. Specific data items were extracted automatically, and subsequently inspected, corrected and completed by hand. PARTICIPANTS: Prospective studies were selected focusing on the effects of antidepressants in any mental health disorder with 800 participants or more planned for inclusion. MAIN OUTCOME MEASURES: Three members from the study team independently assessed the following 'seeding trial' characteristics in each registered study: a high level of involvement of the product manufacturer in the study design, in the data analysis and reporting of the study, an abnormally low ratio of patient numbers to study site, spin and/or omissions of clinically relevant findings in the abstracts, and conclusions that focused on secondary endpoints and surrogate markers. Secondary outcomes were the exploration of a functional outcome and suicidality. RESULTS: 31 trials were identified from clinical trials database. 18/31 were published (58%). 8 of these 18 (44%) studies were identified as possible seeding trials. 13/31 (42%) large trials planned to explore functioning and 5/31 (16%) suicidality. CONCLUSIONS: Large trials are rare in the field of antidepressant research. Some could be 'seeding trials'. Few explored suicidality. Identifying seeding trials from incomplete data entries in registries, especially when almost half of the studies were still unpublished, posed considerable challenges. The delay between our research and publication limits the strength of our conclusions. PROSPERO REGISTRATION NUMBER: CRD42017065591.

Prevalence and factors associated with depression and suicidal ideation among French students in 2016: A national study.

Depression is one of the leading causes of morbidity worldwide and increases the risk of suicide. Students are known as a population at risk for depression. This study aimed to evaluate the prevalence of 12 months major depressive episode (MDE) and suicidal thoughts in French students and investigate associated factors. A questionnaire was sent by email to a representative sample of the French student population between April 28th and June 27th 2016. MDE was assessed using the Composite International Diagnostic Interview Short Form (CIDI-SF). The response rate was 18.7% (N= 18,875). Prevalence of 12 months MDE was 15.8%, and suicidal thoughts was 9%. Factors associated with MDE were being a woman, study field (law/eco, human/social sciences, and medical), having failed midterms exams or dropout, refusal or stop social scholarship, and subjective financial difficulties. Factors associated with suicidal thoughts were study field (human/social sciences), having failed midterms exams or dropout, and important subjective financial difficulties. The use of CIDI-SF allows comparison with the 2017 French national study, and showed more MDE in students than in the general population. This is the only national study on French students before COVID 19 pandemic.

A new ranking index to identify the work-related psychosocial factors most impacting mental health: a cross-sectional study.

OBJECTIVES: In modern professional life, mental health prevention and promotion have become a major challenge for decision-makers. Devising appropriate actions requires better understanding the role played by each work-related psychosocial factor (WPSF). The objective of this study was to present a relevant tool to hierarchise WPSFs that jointly takes into account their importance (impact on mental health) and their prevalence (the proportion of the population exposed to WPSF). DESIGN: A cross-sectional study was conducted in March 2018 among 3200 French workers which are representative of the French working population. SETTING: France. PARTICIPANTS: Individuals aged 18-80 years who declared currently having a job (even a part-time job) whatever their occupation or status (employee or self-employed) were eligible. We excluded students, unemployed individuals, housewives/husbands and retired people. The mental health level was assessed using the General Health Questionnaire-28 and 44 items were gathered from theoretical models of WPSFs. We assessed two distinct multivariate methods for calculating WPSF importance: (1) weifila (weighted first last) method in a linear regression context and (2) random forests in a non-linear context. Both methods were adjusted on individual, health and job characteristics. RESULTS: The WPSF rankings obtained with the two methods to calculate importance are strongly consistent with each other (correlation coefficient=0.88). We highlighted nine WPSFs that are ranked high by both methods. In particular, irrespective of the chosen method, lack of communication, lack of social and hierarchy support and personal-professional life imbalance, emotional demands at work and dissatisfaction with the compensation received came out as top-ranking WPSFs. CONCLUSIONS: A total of nine WPSFs were identified as key for decision-making. The easy-to-use tools we propose can help decision-makers identify priority WPSFs and design effective strategies to promote mental health in the workplace.

How to measure mental pain: a systematic review assessing measures of mental pain.

QUESTION: Although mental pain is present in many mental disorders and is a predictor of suicide, it is rarely investigated in research or treated in care. A valid tool to measure it is a necessary first step towards better understanding, predicting and ultimately relieving this pain. STUDY SELECTION AND ANALYSIS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we performed a systematic review to identify all published standardised measures of mental pain. We used qualitative content analysis to evaluate the similarity of each measure, quantified via Jaccard Index scores ranging from no similarity (0) to full similarity (1). Finally, using the Consensus-based Standards for the selection of health Measurement INstruments (COSMIN) methodology, we evaluated each measure's development (assessing 35 features), its content validity (31 features) and if the latter was rated at least adequate, its other psychometric properties. FINDINGS: We identified 10 self-reported scales of mental pain in 2658 screened studies relying on diverse definitions of this construct. The highest average similarity coefficient for any given measure was 0.24, indicative of weak similarity (individual pairwise coefficients from 0 to 0.5). Little to no information was provided regarding the development and the content validity of all 10 scales. Therefore, their development and content validity were rated 'inadequate' or 'doubtful'. CONCLUSIONS AND CLINICAL IMPLICATIONS: There is not enough evidence of validity to recommend using one measure over others in research or clinical practice. Heterogeneous use of disparate measures across studies limits comparison and combination of their results in meta-analyses. Development by all stakeholders (especially patients) of a consensual patient-reported measure for mental pain is needed. PROSPERO REGISTRATION NUMBER: CRD42021242679.

Important adverse events to be evaluated in antidepressant trials and meta-analyses in depression: a large international preference study including patients and healthcare professionals.

BACKGROUND: Non-serious adverse events (NSAEs) should be captured and reported because they can have a significant negative impact on patients and treatment adherence. However, the reporting of NSAEs in randomised controlled trials (RCTs) is limited. OBJECTIVE: To identify the most important NSAEs of antidepressants for patients and clinicians, to be evaluated in RCTs and meta-analyses. METHODS: We conducted online international surveys in English, German and French, including (1) adults prescribed an antidepressant for a depressive episode and (2) healthcare professionals (HCPs) prescribing antidepressants. Participants ranked the 30 most frequent NSAEs reported in the scientific literature. We fitted logit models for sets of ranked items and calculated for each AE the probability to be ranked higher than the least important AE. We also identified additional patient-important AEs not included in the ranking task via open-ended questions. FINDINGS: We included 1631 patients from 44 different countries (1290 (79.1%) women, mean age 39.4 (SD 13), 289 (37.1%) with severe depression (PHQ-9 score ≥20)) and 281 HCPs (224 (79.7%) psychiatrists). The most important NSAEs for patients were insomnia (95.9%, 95% CI 95.2% to 96.5%), anxiety (95.2%, 95% CI 94.3% to 95.9%) and fatigue (94.6%, 95% CI 93.6% to 95.4%). The most important NSAEs for HCPs were sexual dysfunction (99.2%, 95% CI 98.5% to 99.6%), weight gain (98.9%, 95% CI 97.7% to 99.4%) and erectile problems (98.8%, 95% CI 97.7% to 99.4%). Participants reported 66 additional NSAEs, including emotional numbing (8.6%), trouble with concentration (7.6%) and irritability (6%). CONCLUSIONS: These most important NSAEs should be systematically reported in antidepressant trials. CLINICAL IMPLICATIONS: The most important NSAEs should contribute to the core outcome set for harms in depression.

Designing clinically useful psychopharmacological trials: challenges and ways forward.

The clinical guidelines that underpin the use of drugs for mental disorders are informed by evidence from randomised controlled trials (RCTs). RCTs are performed to obtain marketing authorisation from regulators. The methods used in these RCTs could be appropriate for early phases of drug development because they identify drugs with important harms and drugs that are efficacious for specific health problems and populations. RCTs done before marketing authorisation do not tend to address clinical questions that concern the effectiveness of a drug in heterogeneous and comorbid populations, the optimisation of drug sequencing and discontinuation, or the comparative benefits and harms of different drugs that could be used for the same health problem. This Review proposes an overview of some shortcomings of RCTs, at an individual level and at the whole portfolio level, and identifies some methods in planning, conducting, and carrying out analyses in RCTs that could enhance their ability to support therapeutic decisions. These suggestions include: identifying patient-important questions to be investigated by psychopharmacological RCTs; embedding pragmatic RCTs within clinical practice to improve generalisability to target populations; collecting evidence about drugs in overlooked populations; developing methods to facilitate the recruitment of patients with mental disorders and to reduce the number of patients who drop out, using specific methods; using core outcome sets to standardise the assessment of benefits and harms; and recording systematically serious objective outcomes, such as suicide or hospitalisation, to be evaluated in meta-analyses. This work is a call to address questions relevant to patients using diverse design of RCTs, thus contributing to the development of a patient-centred, evidence-based psychiatry.

Acceptability of and Willingness to Take Digital Pills by Patients, the Public, and Health Care Professionals: Qualitative Content Analysis of a Large Online Survey.

BACKGROUND: Digital pills are pills combined with a sensor, which sends a signal to a patch connected to a smartphone when the pills are ingested. Health care professionals can access patient data from digital pills online via their own interface, thus allowing them to check whether a patient took the drug. Digital pills were developed for the stated goal of improving treatment adherence. The US Food and Drug Administration approved the first digital pills in November 2017, but the manufacturer withdrew its application to the European Medicines Agency in July 2020 because of insufficient evaluation. OBJECTIVE: As recommended for the evaluation of health technologies, this study assesses the prospective acceptability of and willingness to take digital pills among patients, the public, and health care professionals. METHODS: Participants were patients who were receiving long-term treatment for a chronic condition, public participants (both groups recruited from a representative sample), and health care professionals. Participants answered 5 open-ended questions regarding the acceptability of digital pills and 1 close-ended question regarding the willingness to take digital pills, which were developed in a preliminary qualitative study. We explored the 5 theoretical dimensions of acceptability by performing an abductive qualitative content analysis of all free-text responses. We assessed data saturation with mathematical models. We fitted a multivariate logistic regression model to identify the sociodemographic and health characteristics associated with the willingness to take digital pills. RESULTS: Between January 29, 2020, and April 18, 2020, 767 patients, 1238 public participants, and 246 health care professionals provided 11,451 free-text responses. We identified 98 codes related to the acceptability of digital pills: 29 codes on perceived clinical effectiveness (eg, sensor safety cited by 66/2251 participants, 29.5%), 6 on perceived burden (eg, increased doctors' workload, 164/2251 participants, 7.3%), 25 on perceived ethicality (eg, policing, 345/2251 participants, 15.3%), 30 codes on perceived opportunity (eg, exclusively negative perception, 690/2251 participants, 30.7%), and 8 on affective attitude (eg, anger, 541/2251, 24%). Overall, 271/767 (35.3%) patients, 376/1238 (30.4%) public participants, and 39/246 (15.8%) health care professionals reported willingness to take digital pills. This willingness was associated with male sex (odds ratio 1.98, 95% CI 1.62-2.43) and current use of a connected device to record health settings (with a dose-response relationship). CONCLUSIONS: The prospective acceptability of and willingness to take digital pills were limited by clinical and ethical concerns both at the individual and societal level. Our results suggest that digital pills should not be considered a mere change in the form of drug administration but a complex intervention requiring specific evaluation before extended use in clinical routine practice as well as an ethical and legal framework to ensure safe and ethical collection and use of health data through a patient-centered approach.

Identifying outcomes for depression that matter to patients, informal caregivers, and health-care professionals: qualitative content analysis of a large international online survey.

BACKGROUND: Many clinical trials have assessed treatments for depressive disorders and bipolar depression. However, whether, and which, assessed outcome domains really matter to patients, informal caregivers, and health-care professionals remains unclear. METHODS: We did an international online survey in French, German, and English. Participants were adult patients with a history of depression, informal caregivers, and health-care professionals, recruited by purposeful sampling. To identify outcome domains, participants answered four open-ended questions about their expectations for depression treatment. We disseminated the survey without restriction via social media, patient and professional associations, and a media campaign. Four researchers independently did qualitative content analyses. We assessed data saturation using mathematical models to ensure the comprehensive identification of outcome domains. FINDINGS: Between April 5, 2018, and Dec 10, 2018, 1912 patients, 464 informal caregivers, and 627 health-care professionals from 52 countries provided 8183 open-ended answers. We identified 80 outcome domains related to symptoms (64 domains), such as mental pain (or psychological or psychic pain, 523 [17%] of 3003 participants) and motivation (384 [13%]), and functioning (16 domains), such as social isolation (541 [18%]). We identified 57 other outcome domains regarding safety of treatment, health care organisation, and social representation, such as stigmatisation (408 [14%]). INTERPRETATION: This study provides a list of outcome domains important to patients, informal caregivers, and health-care professionals. Unfortunately, many of these domains are rarely measured in clinical trials. Results from this study should set the foundation for a core outcome set for depression. FUNDING: Fondation pour la Recherche Medicale and NIHR Oxford Health Biomedical Research Centre.

Work-related psychosocial risk factors and psychiatric disorders: A cross-sectional study in the French working population.

PURPOSE: The study estimates the prevalence of probable psychiatric disorder in the working population, determines the proportion of people presenting a probable psychiatric disorder among people exposed to work-related psychosocial risk factors (PSRFs), and identifies which PSRF has the strongest association with having a probable psychiatric disorder. METHODS: A cross-sectional study conducted in March 2018 involved a representative sample of the French working population. The General Health Questionnaire 28 (GHQ-28) was used to estimate the prevalence of probable psychiatric disorder and 44 items were gathered from theoretical models of PSRFs. We used multiple logistic regression to estimate the association of each PSRF with having a probable psychiatric disorder, adjusted on individual, health, and job confounders. RESULTS: This study involved 3200 French participants. The proportion of probable psychiatric disorder was 22.2% [20.6; 24.0]. Ten PSRFs were significantly associated with it. The strongest association was for having problems handling professional and personal responsibilities (reported by 15% of the study population) (OR = 1.97 [1.52; 2.54]), with 45% pathological GHQ-28 scores (potential psychiatric cases) for people exposed to this PSRF versus 18% non-exposed. The next strongest association was lack of support of colleagues (reported by 28%) (OR = 1.63 [1.29; 2.06]). The third strongest association was feeling sometimes afraid when doing the job (reported by 63%) (OR = 1.53, [1.21; 1.93]). CONCLUSIONS: Our study identified 10 PSRFs associated with psychiatric disorder, with substantial exposure rate among the population. The results of our research could help develop recommendations to improve work environment.

Controversy and Debate Series on Core Outcome Sets. Paper 1: Improving the generalizability and credibility of core outcome sets (COS) by a large and international participation of diverse stakeholders.

Core outcome sets (COSs) are agreed-on standardized sets of outcomes that should be minimally measured in all trials of a given disease. To enhance the uptake of COSs in trials, their generalizability should be increased by a change in the number and diversity of stakeholders involved in their development. Also, their credibility should be improved by methods that allow the fair capture of participants' views. This article proposes three adjustments to the development of COSs. First, instead of a qualitative study with few participants, we propose to generate the outcome domains by mapping the expectations toward treatment of a large number of stakeholders, internationally, by using an online survey with open-ended questions. Second, we propose to separate preference elicitation from the decision-making process in the selection of core outcomes. Preference elicitation would rely on an international online ranking survey, whereas the decision-making process would involve a formalized discussion among all stakeholders. Third, we propose to involve a large number of participants, including patients, in an online survey to select outcome measurement instruments. Our propositions are low-cost and scalable and help with the involvement of more stakeholders in the development of COSs, thereby increasing their generalizability, credibility, and uptake in trials.

Power behind the throne: A clinical trial simulation study evaluating the impact of controllable design factors on the power of antidepressant trials.

OBJECTIVE: To evaluate the impact of controllable design factors on the power of antidepressants trials. METHODS: Using clinical trial simulation (CTS), we analyzed the combined impact on the power of trials of controllable design factors (sample size, outcome metrics, and disease severity at inclusion) and uncontrollable parameters (heterogeneity of diseases labeled "depression" in the source population and selective effects of drugs on items of the Hamilton Depression Rating Scale [HDRS], the most used outcome measurement tool). We elaborated 3,840 scenarios calibrated with real data, particularly the publication bias-corrected effect size. RESULTS: For an effect size of 0.26, simulations revealed that in trials with ≤650 participants, power was less than 80%. Among the tested outcome metrics, the "remission" outcome provided more robustness for sample heterogeneity, whereas the continuous outcome "HDRS changes" provided more robustness when investigating drugs with a selective effect on the HDRS items. For the "remission" outcome, the power of trials increased with increasing HDRS threshold at inclusion but decreased with the outcomes "response" and "HDRS changes. Drugs with a selective effect on the HDRS items could not reach the same power as for the reference drug. CONCLUSION: Our study allows for drawing recommendations to avoid underpowered trials of antidepressants.

Side effect profile and comparative tolerability of 21 antidepressants in the acute treatment of major depression in adults: protocol for a network meta-analysis.

INTRODUCTION: We have recently compared all second-generation as well as selected first-generation antidepressants in terms of efficacy and acceptability in the acute treatment of major depression. Here we present a protocol for a network meta-analysis aimed at extending these results, updating the evidence base and comparing all second-generation as well as selected first-generation antidepressants in terms of specific adverse events and tolerability in the acute treatment of major depression in adults. METHODS AND ANALYSIS: We will include all double-blind randomised controlled trials comparing one active drug with another or with placebo in the acute treatment major depression in adults. We will compare the following active agents: agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone and vortioxetine. The main outcomes will include the total number of patients experiencing specific adverse events; experiencing serious adverse events; and experiencing at least one adverse event. Published and unpublished studies will be retrieved through relevant database searches, trial registries and websites; reference selection and data extraction will be completed by at least two independent reviewers. For each outcome we will undertake a network meta-analysis to synthesise all evidence. We will use local and global methods to evaluate consistency. We will perform all analyses in R. We will assess the quality of evidence contributing to network estimates with the Confidence in Network Meta-Analysis web application. DISCUSSION: This work will provide an in- depth analysis and an insight into the specific adverse events of individual antidepressants. ETHICS AND DISSEMINATION: This review does not require ethical approval. PROSPERO REGISTRATION NUMBER: CRD42019128141.

Subsyndromal and syndromal depressive symptoms among older adults with schizophrenia spectrum disorder: Prevalence and associated factors in a multicenter study.

BACKGROUND: Few studies have examined the prevalence and correlates of subsyndromal and syndromal depressive symptoms (SSSD) among older adults with schizophrenia spectrum disorder. In this report, we examined the prevalence of SSSD and their associations with sociodemographic characteristics, clinical characteristics of schizophrenia, comorbidity, psychotropic medications, quality of life, functioning and mental health care utilization in a large, multicenter sample of older adults with schizophrenia spectrum disorder. METHODS: Data from the Cohort of individuals with Schizophrenia Aged 55 years or more (CSA) were used to examine the prevalence of SSSD, defined using the Center of Epidemiologic Studies Depression (CESD) scale. Clinical characteristics associated with SSSD were explored. RESULTS: Among 343 older adults with schizophrenia spectrum disorder, 78.1% had either subsyndromal (30.6%) or syndromal (47.5%) depressive symptoms. SSSD were independently associated with positive and negative symptoms, lower quality of life, non-late-onset psychosis, benzodiazepine use and urbanicity. There were no significant associations of SSSD with other sociodemographic characteristics and psychotropic medications, or with general medical conditions. We found no significant differences in the proportion of participants who were treated with antidepressants between those with syndromal depressive symptoms and those without depression (22.1% vs. 20.0%, p = 0.89). SSSD were not associated with higher mental health care utilization. LIMITATIONS: Data were cross-sectional and depression was not evaluated with a semi-structured interview. CONCLUSION: SSSD may be highly prevalent and under-assessed and/or undertreated among older adults with schizophrenia spectrum disorder. Our findings should alert clinicians about the need to assess systematically and regularly depression in this vulnerable population.

Latent class analysis of the feared situations of social anxiety disorder: A population-based study.

BACKGROUND: Little is known about differences in mental health comorbidity and quality of life in individuals with social anxiety disorder (SAD) according to the number and the types of feared situations. METHODS: Using a US nationally representative sample, the National Epidemiologic Survey on Alcohol and Related Conditions, we performed latent class analysis to compare the prevalence rates of mental disorders and quality of life measures across classes defined by the number and the types of feared social situations among individuals with SAD. RESULTS: Among the 2,448 participants with a lifetime diagnosis of SAD, we identified three classes of individuals who feared most social situations but differed in the number of feared social situations (generalized severe [N = 378], generalized moderate [N = 1,049] and generalized low [N = 443]) and a class of subjects who feared only performance situations [N = 578]. The magnitude of associations between each class and a wide range of mental disorders and quality of life measures were consistent with a continuum model, supporting that the deleterious effects of SAD on mental health may increase with the number of social situations feared. However, we found that individuals with the "performance only" specifier may constitute an exception to this model because these participants had significantly better mental health than other participants with SAD. CONCLUSIONS: Our findings give additional support to the recent changes made in the DSM-5, including the introduction of the "performance only" specifier and the removal of the "generalized" specifier to promote the dimensional approach of the number of social fears.