BACKGROUND:Fluoxetine's efficacy estimates in pediatric depression trials have declined to the range of placebo equivalence. We investigated whether changes in trial characteristics (number of study sites (NOSS), age, baseline severity, or added psychological interventions) could explain this trend. METHODS:We conducted a secondary exploratory analysis based on our recent meta-analyses of pediatric fluoxetine depression trials. The outcome was symptom change on the Children's Depression Rating Scale Revised (CDRS-R). We used meta-regression to explore the association between NOSS, age, depression severity, and the addition of psychological interventions with efficacy and placebo response. RESULTS:NOSS increased over time and was not significantly associated with outcomes. When log-transformed, NOSS was associated with decreased efficacy (B = 1.57, 95% CI 0.24 to 2.90, p = 0.02) and greater placebo response (B = -1.90, 95% CI -3.41 to -0.40, p = 0.01). However, these associations were driven by an outlying single-center trial rated as high risk of bias and did not survive p-value adjustment. Age, baseline severity, and psychological interventions were not significantly associated with efficacy or placebo response. CONCLUSION:NOSS increased over time but the apparent associations with decreased efficacy or increased placebo response were driven by an outlying trial at risk of bias. Age of participants, baseline severity, or added psychological interventions also failed to explain fluoxetine's diminished efficacy. Limitations include the potential ecological fallacy in analysis of age and baseline severity. Overall, these findings do not support the assumption that fluoxetine's meta-analytic efficacy estimates are substantially influenced by these trial characteristics.

In this commentary we review the recent approval of escitalopram for generalized anxiety disorder (GAD) in children and adolescents. We critically discuss the FDA approval document and the approval trial. In the approval trial, efficacy was not clinically meaningful, statistical significance uncertain, and there were significantly more adverse events with escitalopram than with placebo. Relative to placebo, children and adolescents exposed to escitalopram were more likely to become suicidal than to experience a clinically relevant improvement in anxiety. Overall, the harm/benefit ratio seems problematic for escitalopram for pediatric GAD.

Objectives: Non-suicidal self-injury (NSSI) is closely linked to negative emotions and is often preceded by urges to self-harm. Understanding the nature, precursors, and consequences of these urges is essential for improving psychological interventions. Methods: Using experience-sampling methodology (ESM), longitudinal data were collected from three young adults with varying frequencies of NSSI during a 14-day period. Participants completed brief questionnaires four times daily, yielding 166 assessments. Dynamic Exploratory Graph Analysis (dynEGA) was applied to construct individual affective networks related to self-harm urges. Results: NSSI urges were primarily predicted by negative affect. However, strong idiosyncratic differences emerged across participants’ affective networks. Due to this heterogeneity, no robust population-level network could be identified. Individuals differed substantially in how specific affects related to urge intensity. Moreover, only in a limited number of cases were urges directly associated with the actual performance of NSSI behavior. Conclusion: The results indicate associations between negative affect, self-harm urges, and behavior. Simultaneously, our results show that this dynamic is much more complex than previously assumed. The findings underscore the importance of individualized analyses in NSSI research. DynEGA proves to be a valuable method for examining person-specific affective network structures and dimensionality in individuals who engage in self-injury.

OBJECTIVES:To replicate Stone et al's (2022) finding that the distribution of response in clinical antidepressant trials is trimodal with large, medium-effect, and small subgroups. METHODS:To apply finite mixture modeling to pre-post Hamilton Depression Rating Scale (HDRS) differences (n = 2184) of STAR∗D study's level 1, a single-arm, open-label study. For a successful replication, the best fitting model had to be trimodal, with comparable components as in Stone et al. Secondary/sensitivity analyses repeated the analysis for different baseline levels of depression severity, imputed values, and patient-reported depression symptoms. RESULTS:The best fitting models were either bimodal or trimodal but the trimodal solution did not meet criteria for replication. The bimodal model had 1 component with HDRS mean change of M = -13.0, SD = 6.7 and included 65.3% of patients, and another component with M = -1.8, SD = 5.1, 34.7%, respectively. For the trimodal model, the component with the largest change (M = -14.3, SD = 6.4) applied to 52% of patients, which differed substantially from the large effect component in Stone et al (M = -18.8, SD = 5.1), which applied to 7.2%. Secondary/sensitivity analyses arrived at similar conclusions, and for patient-reported depression symptoms the best fitting models were unimodal or bimodal. CONCLUSION:This analysis failed to identify the trimodal distribution of response reported in Stone et al. In addition to being difficult to operationalize for regulatory purposes, results from mixture modeling are not sufficiently reliable to replace the more robust approach of comparing mean differences in depression rating scale scores between treatment arms.

Objective: To explain discrepant findings for fluoxetine's efficacy in three influential network meta-analyses (NMAs) of treatments for pediatric depression, which led to conflicting clinical recommendations. Design: Critical appraisal and re-analysis of three published NMAs. Data sources: NMAs published in two Lancet journals and in Cochrane, together with the trial datasets reported therein. Data synthesis: We compared efficacy estimates for fluoxetine versus placebo across NMAs. We identified and assessed an outlying trial included only in the Lancet NMAs using the INSPECT-SR instrument, and re-analysed the NMAs with and without this trial. Results: The larger effects reported in the Lancet NMAs (SMD -0.51, 95% CrI -0.99 to -0.03; and -0.51, -0.84 to -0.18) were driven by an inconsistent fluoxetine-placebo-nortriptyline loop, which the original NMA authors could not explain. We identified the cause of the inconsistency as a small outlier trial of fluoxetine versus nortriptyline that reported an implausibly large effect size (SMD > 4) favouring fluoxetine, and which was not included in the Cochrane NMA. Excluding this trial from the Lancet NMA datasets resolved the inconsistency and yielded efficacy estimates for fluoxetine that closely matched the Cochrane NMA (SMD -0.20, 95%CI -0.28 to -0.11). The outlier trial also showed multiple methodological concerns suggesting low trustworthiness. Conclusion: Discrepancies between the three NMAs were explained by the indirect influence of a single small trial with extreme and unreliable results. Removing this trial reconciled the Lancet NMAs with the Cochrane NMA, yielding a more reliable estimate of fluoxetine efficacy versus placebo. It also resolved the inconsistency. This case illustrates how inclusion of a single small problematic trial can substantially distort the clinically important results of NMAs. Our findings may alter the clinical risk/benefit assessment of fluoxetine for this indication. Other: No specific funding was involved in the study. ### Competing Interest Statement All authors have completed the Unified Competing Interest form and declare: RL and MP have no conflicts to declare. FN has no relation with any pharmaceutical company but received funding from the French National Research Agency (ANR-23-CE36-0006, for his work on research integrity), the French ministry of health and the French ministry of research. He is a work package leader in the OSIRIS project (Open Science to Increase Reproducibility in Science). The OSIRIS project has received funding from the European Union's Horizon Europe research and innovation program under the grant agreement No. 101094725. He is a work package leader for the doctoral network MSCA-DN SHARE-CTD (HORIZON-MSCA-2022-DN-01 101,120,360), funded by the EU. GvV is an employee of the Cochrane Collaboration. However, Cochrane was not involved with, and did not support, this work in any way. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data from two of the three network meta-analysis are publicly available, and all data that we used for the re-analysis of the three network meta-analyses are publicly available (links in text).

BACKGROUND:There has been debate about the frequency and severity of antidepressant withdrawal effects. METHODS:We set out to appraise and reanalyze an influential systematic review by Henssler and colleagues that concluded that withdrawal effects are not particularly common and rarely severe. We repeated the meta-analysis, including only studies where data were derived from systematic measures of withdrawal symptoms. RESULTS:Most data in the Henssler review are derived from pharmaceutical industry-sponsored efficacy studies in which withdrawal was a minor consideration. Shortcomings of the review include the use of spontaneously reported adverse events to estimate withdrawal symptoms, potential misclassification of withdrawal symptoms as relapse, inclusion of data from retrospective case-note studies, short duration of prior antidepressant use, short observation periods, the overlooking of differences between placebo and drug withdrawal effects, and the use of questionable proxies for severe withdrawal. There were also discrepancies and uncertainties in some figures used. In our reanalysis, we included only the five studies that used a systematic and relevant method to assess the incidence of any withdrawal symptom. Prior treatment was short-term (12 weeks or less) in all but one of these. The pooled percentage was 55% (95% confidence interval, CI, 31% to 81%; N = 601) without subtracting nocebo effects, with high heterogeneity. CONCLUSIONS:Henssler's review is based on unreliable data and does not provide an adequate basis for the evaluation of antidepressant withdrawal effects. Further good-quality research on antidepressant withdrawal is required.

Obective: Ketamine and esketamine have been claimed to possess anti-suicidal effects and potentially to transform suicide prevention. This study provides an updated overview of evidence from clinical trials to establish whether ketamine or esketamine reduce death, suicides, suicide attempts or suicidal ideation, compared to active or inert placebo among people with psychiatric disorders. Design: Systematic review and meta-analysis. Data sources: We searched EMBASE, PubMed and PsycINFO from inception until 02.12.2025. Eligibility criteria for selecting studies: Eligible for inclusion were randomised controlled trials which compared the effect of ketamine or esketamine with active or inert placebo for the treatment of people with psychiatric disorders. We included trials with concomitant treatments and excluded those where ketamine/esketamine were used as anaesthics. Data synthesis and study quality: Data were synthesised with meta-analysis, including methods for double-zero events. Risk of bias was assessed using the Cochrane Risk of Bias Tool and quality of the evidence was evaluated using GRADE guidelines. Results: We included 73 trials with a total of 5671 participants. The majority of trials (56) examined ketamine, 16 esketamine, and 1 arketamine. Twelve of the ketamine trials were cross-over trials and the rest were parallel group trials. A single dose was used in 35 trials. Median length of treatment and follow-up was 45 days. Rates of suicidal behaviour were 1.63% for ketamine/esketamine and 1.72% for placebo, with the 95% credible interval including the null-effect, OR = 0.98 \[0.58 to 1.60\] (Bayesian Analysis with weak priors). There were 42 (1.43%) suicide attempts, 6 (0.20%) suicides and 9 (0.31%) deaths with ketamine/esketamine compared to 41 (1.64%), 2 (0.08%) and 5 (0.20%) on placebo. Ketamine/esketamine significantly reduced suicide ideation up to 4 weeks (standardized mean differences [SMD] at 12h to 24h of -0.31 [-0.45 to -0.18], I2 = 26%), but effects were small after 24 hours and dropped to near zero after 4 weeks. Subgroup analysis for suicide ideation revealed that effects of esketamine were close to zero after 24 hours whereas effects for ketamine were small to medium for the first 4 weeks. Effects tended to be larger in trials involving suicidal patients. Repeated dosings were not superior to single doses. Quality assessment revealed unreliable blinding, selective reporting and - especially for suicidal behaviour - imprecision, leading to low or very low certainty ratings for suicidal behaviour and low or moderate certainty ratings for suicide ideation. Conclusions: There is insufficient evidence for a preventive effect of ketamine/esketamine for suicidal behaviour. The observed immediate but short-term effect on suicide ideation may be overestimated due to unblinding bias. Our review is the most comprehensive on suicidality to date, however, more evidence is needed to draw conclusions on suicidal behaviour. Other: No specific funding was involved. The protocol was registered with PROSPERO (CRD42023364156). ### Competing Interest Statement All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/ and declare: CV, MP, RC, TW, VS no support from any commercial organisation for the submitted work and have no other conflicts of interest to declare; JM has received royalties for books about psychiatric drugs; MH received support from a clinical research fellowship at NELFT (NHS), royalties from the Maudsley Deprescribing Guidelines, and is a co-founder of Outro Health, a digital clinic in the US where he receives consulting fees. ### Clinical Protocols ### Funding Statement No funding was involved ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data used in this study will be made publicly available via the OSF upon publication in a journal.

Background:The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial was designed to give guidance in selecting the best next-step treatment for depressed patients who did not remit during their first, and/or subsequent, antidepressant trial, with up to four trials per patient. Our prior research documented protocol violations which inflated STAR*D's reported cumulative remission rate by 91.4%. A similar reanalysis of the step-2 drug-switch trial has not been done until now. Methods:We reanalyzed the patient-level dataset of STAR*D's drug-switch treatment therapies-with fidelity to the original research protocol and related publications-to determine whether there were clinically-relevant differences in results compared to the original publication. Results:While our reanalysis largely comported with STAR*D's published findings of no significant differences between drug-switch treatments, we found the following discrepancies: Lower than reported step-2 remission rates ranging from 16.2 to 19.3% (versus 17.6 to 24.8%); A significant increase in treatment-emergent suicidal ideation during the step-2 drug-switch therapies ranging from 11.2 to 15.0% compared to step-1 citalopram treatment (9.0%); A four times greater number of severe suicidal behaviors reported by the treating clinicians compared to the published suicide-related Serious Adverse Events (16 versus 4); and A sustained remission rate of only 3.1 to 8.4%. Conclusion:Compared to the original publication, our reanalysis found lower remission rates and more suicidal risk than reported. This adds to the discrepancies found in our prior reanalysis and also to the finding that switching antidepressants is not well supported by the evidence.

OBJECTIVES:Fluoxetine is among the most used antidepressants for children and adolescents and frequently recommended as first-line pharmacological treatment for pediatric depression. However, in contrast to earlier studies and reviews, a Cochrane network meta-analysis from 2021 concluded that the estimated efficacy of fluoxetine was no longer clinically meaningful. We aimed to explain the discrepant findings between the recent Cochrane review and earlier reviews, and to explore if this was acknowledged in guidelines and treatment recommendations appearing since then. STUDY DESIGN AND SETTING:Meta-analytical aggregation of trial results over time, exploring potential biases, and a nonsystematic search for recent treatment guidelines/recommendations from major medical organizations. RESULTS:The estimated efficacy of fluoxetine in clinical trials declined over time into the range of clinical equivalence with placebo when more recent studies were included in analyses and when considering common thresholds of clinical significance. This remains unacknowledged in treatment guidelines and related publications, including some that continue to recommend fluoxetine as first-line pharmacological treatment. Finally, we find that the loss of efficacy over time is likely explained by biases such as the novelty bias or by variations of expectancy effects. CONCLUSION:The seeming lack of clinically meaningful efficacy of fluoxetine for the treatment of pediatric depression needs to be considered by those who develop treatment recommendations as well as by patients and clinicians. The biases we observed are not only relevant in the evaluation of fluoxetine and other antidepressants for pediatric depression, but also for any new treatment.

Background:The STAR*D trial is the most influential study of sequential antidepressant treatment strategies. However, major STAR*D publications deviated from the protocol-defined analytic plan. Prior re-analyses found lower cumulative remission rates than STAR*D publications reported, sustained remission rates of only 3.1 to 8.4% at 12 months, and high rates of treatment-emergent suicidal ideation (TESI) during medication-switch therapy. A similar reanalysis is warranted for STAR*D's augmentation study in which citalopram was augmented with sustained-release bupropion or buspirone. Methods:We reanalyzed STAR*D's patient-level augmentation dataset with fidelity to the original protocol or relevant STAR*D publications where the protocol did not prespecify an analytic plan. Results:This reanalysis identified 124 patients (21.9% of enrolled subjects) who were inappropriately included in the original STAR*D analysis, including 54 who were in protocol-defined remission before starting augmentation therapy. Remission rates as defined in the protocol were lower than reported in the original publication for bupropion SR (25.0% vs 29.7%) and buspirone (25.8% vs. 30.1%). Using a secondary definition of remission, bupropion SR's rate was significantly lower than reported in original publications (29.2% vs. 39.0%). Sustained remission through 12 months was low (4.9-12.5%). TESI rates were significantly higher for buspirone (13.9%) than bupropion SR (3.6%) augmentation. Conclusion:Compared with the original STAR*D publication, our reanalysis identified inflated remission rates, low sustained remission, and marked differences in TESI risk between augmentation strategies. These findings suggest that both treatments offer lower acute and sustained benefit than is widely understood, with buspirone associated with more TESI.

Background: Previous ecological studies reported that increasing antidepressant prescriptions were associated with decreasing suicide rates. Aim: To determine whether antidepressant prescription prevalence is negatively associated with suicide rates (i.e., as antidepressant prescribing increases, suicide rates decrease) between 1999 and 2020. Method: The study protocol was pre-registered on the Open Science Framework (https://osf.io/978sk/). Publicly available data from the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiological Research (CDC WONDER) and Medical Expenditure Panel Survey (MEPS) were used. Results: Overall, both the antidepressant prescription prevalence and the suicide rate were increasing from 1990 to 2020 in the United States. Positive trends for both outcomes were also evident when analyses were stratified according to sex and/or race/ethnicity. Pearson's correlation analyses consistently found positive associations between antidepressant prescription prevalence and suicide rates. Limitations: Trends and their associations were examined at the population level. The results cannot clarify the causal nature of the association observed. Conclusion: The results of our analysis consistently demonstrated positive trends for both antidepressant prescription prevalence and suicide rates over time as well as positive associations between them. These findings update those from previous studies and are at odds with the notion that, at a population level, more antidepressant prescriptions would lead to lower suicide rates. However, it needs to be acknowledged that ecological studies provide insufficient evidence to infer causality.