Designing clinically useful psychopharmacological trials: challenges and ways forward

Chevance, Astrid; Ravaud, Philippe; Cornelius, Victoria; Mayo‐Wilson, Evan; Furukawa, Toshi A.

doi:10.1016/s2215-0366(22)00041-4

Cited by 11 publications

(13 citation statements)

References 84 publications

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“…To our knowledge, this is the first study to make the proof of concept of a method to select AEs to be included in trials and to provide a ranking of AEs of antidepressants based on their importance from the point of view of patients and HCPs. These findings could set the foundation of a Core Outcome Set for harms32 to be measured in all primary and secondary studies involving antidepressants for depression. These important AEs should be systematically evaluated and reported properly in RCTs and their meta-analysis, in order to provide evidence-based information to support treatment decisions in clinical practice 33…”

Section: Discussionmentioning

confidence: 99%

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

Chevance

Tomlinson

Ravaud

et al. 2022

Evid Based Mental Health

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BackgroundNon-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.ObjectiveTo identify the most important NSAEs of antidepressants for patients and clinicians, to be evaluated in RCTs and meta-analyses.MethodsWe 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.FindingsWe 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%).ConclusionsThese most important NSAEs should be systematically reported in antidepressant trials.Clinical implicationsThe most important NSAEs should contribute to the core outcome set for harms in depression.

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Section: Discussionmentioning

confidence: 99%

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

Chevance

Tomlinson

Ravaud

et al. 2022

Evid Based Mental Health

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“…A total of 150 participants were randomized to simvastatin (n = 77; median [IQR] age, 40 [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] female and 33 [45%] male). Of the 150 participants included in the intention-to-treat analysis, at the end of the study, 8 (5%) withdrew (3 randomized to simvastatin and 5 to placebo) and 6 (4%) were unavailable for follow-up.…”

Section: Resultsmentioning

confidence: 99%

“… 37 , 38 Randomized clinical trials of psychopharmacotherapy conducted in LMICs, such as Pakistan, are needed to identify unexpected harms that can be caused by extrapolating the results of RCTs from populations of high-income countries to those in LMICs. 39 Conversely, Pakistan is an LMIC where diet, nutritional status, and other lifestyle factors, such as exercise and potential exposure to immune-related illness, differ from those in high-income countries. Given this study’s sample size, it is expected that these factors were balanced across both groups.…”

Section: Discussionmentioning

confidence: 99%

Effect of Adjunctive Simvastatin on Depressive Symptoms Among Adults With Treatment-Resistant Depression

et al. 2023

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ImportanceImmune-metabolic disturbances have been implicated in the pathophysiology of major depressive disorder and may be more prominent in individuals with treatment-resistant depression (TRD). Preliminary trials suggest that lipid-lowering agents, including statins, may be useful adjunctive treatments for major depressive disorder. However, no adequately powered clinical trials have assessed the antidepressant efficacy of these agents in TRD.ObjectiveTo assess the efficacy and tolerability of adjunctive simvastatin compared with placebo for reduction of depressive symptoms in TRD.Design, Setting, and ParticipantsThis 12-week, double-blind, placebo-controlled randomized clinical trial was conducted in 5 centers in Pakistan. The study involved adults (aged 18-75 years) with a Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) major depressive episode that had failed to respond to at least 2 adequate trials of antidepressants. Participants were enrolled between March 1, 2019, and February 28, 2021; statistical analysis was performed from February 1 to June 15, 2022, using mixed models.InterventionParticipants were randomized to receive standard care plus 20 mg/d of simvastatin or placebo.Main Outcomes and MeasuresThe primary outcome was the difference between the 2 groups in change in Montgomery-Åsberg Depression Rating Scale total scores at week 12. Secondary outcomes included changes in scores on the 24-item Hamilton Rating Scale for Depression, the Clinical Global Impression scale, and the 7-item Generalized Anxiety Disorder scale and change in body mass index from baseline to week 12. C-reactive protein and plasma lipids were measured at baseline and week 12.ResultsA total of 150 participants were randomized to simvastatin (n = 77; median [IQR] age, 40 [30-45] years; 43 [56%] female) or placebo (n = 73; median [IQR] age, 35 [31-41] years; 40 [55%] female). A significant baseline to end point reduction in Montgomery-Åsberg Depression Rating Scale total score was observed in both groups and did not differ significantly between groups (estimated mean difference for simvastatin vs placebo, −0.61; 95% CI, −3.69 to 2.46; P = .70). Similarly, there were no significant group differences in any of the secondary outcomes or evidence for differences in adverse effects between groups. A planned secondary analysis indicated that changes in plasma C-reactive protein and lipids from baseline to end point did not mediate response to simvastatin.Conclusions and RelevanceIn this randomized clinical trial, simvastatin provided no additional therapeutic benefit for depressive symptoms in TRD compared with standard care.Trial RegistrationClinicalTrials.gov Identifier: NCT03435744

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“…We think several practices would support this endeavour 13. They are not exhaustive—other steps could also enhance the usefulness of trials for practice 16. Nor are they particularly novel.…”

Section: Optimising Learningmentioning

confidence: 99%

“…[13] They are not exhaustive -other steps could also enhance the usefulness of trials for practice. [16] Nor are they particularly novel. But they are easily overlooked.…”

Section: Optimising Learningmentioning

confidence: 99%

How can we optimise learning from trials in child and adolescent mental health?

Axford

Berry

Lloyd

et al. 2022

Evid Based Mental Health

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Improving child and adolescent mental health requires the careful development and rigorous testing of interventions and delivery methods. This includes universal school-based mindfulness training, evaluated in the My Resilience in Adolescence (MYRIAD) trial reported in this special edition. While discovering effective interventions through randomised controlled trials is our ultimate aim, null or negative results can and should play an important role in progressing our understanding of what works. Unfortunately, alongside publication bias there can be a tendency to ignore, spin or unfairly undermine disappointing findings. This creates research waste that can increase risk and reduce benefits for future service users. We advocate several practices to help optimise learning from all trials, whatever the results: stronger intervention design reduces the likelihood of foreseeable null or negative results; an evidence-informed conceptual map of the subject area assists with understanding how results contribute to the knowledge base; mixed methods trial designs aid explanation of outcome results; various open science practices support the dispassionate analysis of data and transparent reporting of trial findings; and preparation for null or negative results helps to temper stakeholder expectations and increase understanding of why we conduct trials in the first place. To embed these practices, research funders must be willing to pay for pilot studies and ‘thicker’ trials, and publishers should judge trials according to their conduct and not their outcome. MYRIAD is an exemplar of how to design, conduct and report a trial to optimise learning, with important implications for practice.

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Designing clinically useful psychopharmacological trials: challenges and ways forward

Cited by 11 publications

References 84 publications

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

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

Effect of Adjunctive Simvastatin on Depressive Symptoms Among Adults With Treatment-Resistant Depression

How can we optimise learning from trials in child and adolescent mental health?

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