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Background: It is important to know predictors of long-term course over time of suicidal thoughts and ideation in depressed older persons., Methods: In this study, 378 depressed older persons were interviewed at baseline, and after 2 and 6 years to evaluate the presence of depressive disorder. The Inventory of Depressive Symptomatology (IDS) was administered every 6 months for 6 years. Latent Class Growth Analysis was performed on the IDS item on suicidal ideation to identify subgroups with different trajectories., Results: Five subgroups with suicidal ideation trajectories were identified: 1) severe, transient (10.9 %), 2) severe, persisting (8.0 %), 3) mild, but increasing (14.9 %), 4) moderate, persisting (35.6 %), and 5) no thoughts (30.6 %). Mixed model analysis showed that trajectories were related to 6-year course of depressive symptoms. Yet, suicidal ideation or thoughts of loss of meaning of life were still present in 22.7 % and 17.4 % of those who remitted after 2 and 6 years. Independent of baseline depressive symptom severity, loneliness, childhood trauma, history of suicidal ideation or attempt, openness to experience, earlier age of depression onset, anxiety symptom severity and worse mastery predicted worse trajectories., Limitations: 47 % dropped out at 6-years follow-up, we did not distinguish between thoughts of death and suicide, we did not assess death by suicide., Conclusions: Although trajectories of suicidal ideation and thoughts of loss of meaning of life were strongly related to the course of depression severity, they also appear after remission. Clinicians should be vigilant for suicidal ideation or death wish, even after remission of depression., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: To quantify the strength of statistical evidence of randomized controlled trials (RCTs) for novel cancer drugs approved by the Food and Drug Administration in the last 2 decades., Study Design and Setting: We used data on overall survival (OS), progression-free survival, and tumor response for novel cancer drugs approved for the first time by the Food and Drug Administration between January 2000 and December 2020. We assessed strength of statistical evidence by calculating Bayes factors (BFs) for all available endpoints, and we pooled evidence using Bayesian fixed-effect meta-analysis for indications approved based on 2 RCTs. Strength of statistical evidence was compared among endpoints, approval pathways, lines of treatment, and types of cancer., Results: We analysed the available data from 82 RCTs corresponding to 68 indications supported by a single RCT and 7 indications supported by 2 RCTs. Median strength of statistical evidence was ambiguous for OS (BF = 1.9; interquartile range [IQR] 0.5-14.5), and strong for progression-free survival (BF = 24,767.8; IQR 109.0-7.3 × 10 6 ) and tumor response (BF = 113.9; IQR 3.0-547,100). Overall, 44 indications (58.7%) were approved without clear statistical evidence for OS improvements and 7 indications (9.3%) were approved without statistical evidence for improvements on any endpoint. Strength of statistical evidence was lower for accelerated approval compared to nonaccelerated approval across all 3 endpoints. No meaningful differences were observed for line of treatment and cancer type. This analysis is limited to statistical evidence. We did not consider nonstatistical factors (eg, risk of bias, quality of the evidence)., Conclusion: BFs offer novel insights into the strength of statistical evidence underlying cancer drug approvals. Most novel cancer drugs lack strong statistical evidence that they improve OS, and a few lack statistical evidence for efficacy altogether. These cases require a transparent and clear explanation. When evidence is ambiguous, additional postmarketing trials could reduce uncertainty., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Medicine regulators need to judge whether a drug's favorable effects outweigh its unfavorable effects based on a dossier submitted by an applicant, such as a pharmaceutical company. Because scientific knowledge is inherently uncertain, regulators also need to judge the credibility of these effects by identifying and evaluating uncertainties. We performed an ethnographic study of assessment procedures at the Dutch Medicines Evaluation Board (MEB) and describe how regulators evaluate the credibility of an applicant's claims about the benefits and risks of a drug in practice. Our analysis shows that regulators use an investigative approach, which illustrates the effort required to identify uncertainties. Moreover, we show that regulators' expectations about the presentation, the design, and the results of studies can shape how they perceive a medicine's dossier. We highlight the importance of regulatory experience and expertise in the identification and evaluation of uncertainties. In light of our observations, we provide two recommendations to reduce avoidable uncertainty: less reliance on evidence generated by the applicant; and better communication about, and enforcement of, regulatory frameworks toward drug developers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hoek, Brenninkmeijer, de Vries, Meijer and van Ravenzwaaij.)

In their reply to our editorial (Journal of Child Psychology and Psychiatry, 2023, 64, 464), Dekkers et al. (Journal of Child Psychology and Psychiatry, 2023, 64, 470) argue that treatment is the best choice for children with mental disorders because there is 'sound evidence' that interventions are effective, also in the long term. We agree that there is sound evidence for treatment effectiveness in the short-term and there is some evidence for longer-term effects of certain specific treatments, such as behavioral parent training in children with behavioral disorders, as acknowledged in our editorial. However, we strongly disagree that there is sound evidence for long-term effectiveness., (© 2023 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Background: Previous research has suggested that statistical power is suboptimal in many biomedical disciplines, but it is unclear whether power is better in trials for particular interventions, disorders, or outcome types. We therefore performed a detailed examination of power in trials of psychotherapy, pharmacotherapy, and complementary and alternative medicine (CAM) for mood, anxiety, and psychotic disorders., Methods: We extracted data from the Cochrane Database of Systematic Reviews (Mental Health). We focused on continuous efficacy outcomes and estimated power to detect predetermined effect sizes (standardized mean difference [SMD] = 0.20-0.80, primary SMD = 0.40) and meta-analytic effect sizes (ES MA ). We performed meta-regression to estimate the influence of including underpowered studies in meta-analyses., Results: We included 256 reviews with 10 686 meta-analyses and 47 384 studies. Statistical power for continuous efficacy outcomes was very low across intervention and disorder types (overall median [IQR] power for SMD = 0.40: 0.32 [0.19-0.54]; for ES MA : 0.23 [0.09-0.58]), only reaching conventionally acceptable levels (80%) for SMD = 0.80. Median power to detect the ES MA was higher in treatment-as-usual (TAU)/waitlist-controlled (0.49-0.63) or placebo-controlled (0.12-0.38) trials than in trials comparing active treatments (0.07-0.13). Adequately-powered studies produced smaller effect sizes than underpowered studies ( B = -0.06, p ⩽ 0.001)., Conclusions: Power to detect both predetermined and meta-analytic effect sizes in psychiatric trials was low across all interventions and disorders examined. Consistent with the presence of reporting bias, underpowered studies produced larger effect sizes than adequately-powered studies. These results emphasize the need to increase sample sizes and to reduce reporting bias against studies reporting null results to improve the reliability of the published literature.

Genome-wide studies are among the best available tools for identifying etiologic processes underlying psychiatric disorders such as schizophrenia. However, it is widely recognized that disorder heterogeneity may limit genetic insights. Identifying phenotypes indexing genetic differences among patients with non-affective psychotic disorder will improve genome-wide studies of these disorders. The present study systematically reviews existing literature to identify phenotypes that index genetic differences among patients with schizophrenia and related disorders. We systematically reviewed family-based studies and genome-wide molecular-genetic studies investigating whether phenotypic variation in patients with non-affective psychotic disorders (according to DSM or equivalent systems) was associated with genome-wide genetic variation (PROSPERO number CRD42019136169). An electronic database search of PubMed, EMBASE, and PsycINFO from inception until 17 May 2019 resulted in 4347 published records. These records included a total of 813 relevant analyses from 264 articles. Two independent raters assessed the quality of all analyses based on methodologic rigor and power. We found moderate to strong evidence for a positive association between genetic/familial risk for non-affective psychosis and four phenotypes: early age of onset, negative/deficit symptoms, chronicity, and functional impairment. Female patients also tended to have more affected relatives. Severity of positive symptoms was not associated with genetic/familial risk for schizophrenia. We suggest that phenotypes with the most evidence for reflecting genetic difference in participating patients should be measured in future large-scale genetic studies of schizophrenia to improve power to discover causal variants and to facilitate discovery of modifying genetic variants., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Lesbian, gay, and bisexual (LGB) individuals, and LB women specifically, have an increased risk for psychiatric morbidity, theorized to result from stigma-based discrimination. To date, no study has investigated the mental health disparities between LGB and heterosexual AQ1individuals in a large cross-national population-based comparison. The current study addresses this gap by examining differences between LGB and heterosexual participants in 13 cross-national surveys, and by exploring whether these disparities were associated with country-level LGBT acceptance. Since lower social support has been suggested as a mediator of sexual orientation-based differences in psychiatric morbidity, our secondary aim was to examine whether mental health disparities were partially explained by general social support from family and friends., Methods: Twelve-month prevalence of DSM-IV anxiety, mood, eating, disruptive behavior, and substance disorders was assessed with the WHO Composite International Diagnostic Interview in a general population sample across 13 countries as part of the World Mental Health Surveys. Participants were 46,889 adults (19,887 males; 807 LGB-identified)., Results: Male and female LGB participants were more likely to report any 12-month disorder (OR 2.2, p < 0.001 and OR 2.7, p < 0.001, respectively) and most individual disorders than heterosexual participants. We found no evidence for an association between country-level LGBT acceptance and rates of psychiatric morbidity between LGB and heterosexualAQ2 participants. However, among LB women, the increased risk for mental disorders was partially explained by lower general openness with family, although most of the increased risk remained unexplained., Conclusion: These results provide cross-national evidence for an association between sexual minority status and psychiatric morbidity, and highlight that for women, but not men, this association was partially mediated by perceived openness with family. Future research into individual-level and cross-national sexual minority stressors is needed., (© 2022. The Author(s).)

Background: Depressive and anxiety disorders are highly comorbid, which has been theorized to be due to an underlying internalizing vulnerability. We aimed to identify groups of participants with differing vulnerabilities by examining the course of internalizing psychopathology up to age 45., Methods: We used data from 24158 participants (aged 45+) in 23 population-based cross-sectional World Mental Health Surveys. Internalizing disorders were assessed with the Composite International Diagnostic Interview (CIDI). We applied latent class growth analysis (LCGA) and investigated the characteristics of identified classes using logistic or linear regression., Results: The best-fitting LCGA solution identified eight classes: a healthy class (81.9%), three childhood-onset classes with mild (3.7%), moderate (2.0%), or severe (1.1%) internalizing comorbidity, two puberty-onset classes with mild (4.0%) or moderate (1.4%) comorbidity, and two adult-onset classes with mild comorbidity (2.7% and 3.2%). The childhood-onset severe class had particularly unfavorable sociodemographic outcomes compared to the healthy class, with increased risks of being never or previously married (OR = 2.2 and 2.0, p < 0.001), not being employed (OR = 3.5, p < 0.001), and having a low/low-average income (OR = 2.2, p < 0.001). Moderate or severe ( v . mild) comorbidity was associated with 12-month internalizing disorders (OR = 1.9 and 4.8, p < 0.001), disability (B = 1.1-2.3, p < 0.001), and suicidal ideation (OR = 4.2, p < 0.001 for severe comorbidity only). Adult ( v . childhood) onset was associated with lower rates of 12-month internalizing disorders (OR = 0.2, p < 0.001)., Conclusions: We identified eight transdiagnostic trajectories of internalizing psychopathology. Unfavorable outcomes were concentrated in the 1% of participants with childhood onset and severe comorbidity. Early identification of this group may offer opportunities for preventive interventions.

Patient-reported helpfulness of treatment is an important indicator of quality in patient-centered care. We examined its pathways and predictors among respondents to household surveys who reported ever receiving treatment for major depression, generalized anxiety disorder, social phobia, specific phobia, post-traumatic stress disorder, bipolar disorder, or alcohol use disorder. Data came from 30 community epidemiological surveys - 17 in high-income countries (HICs) and 13 in low- and middle-income countries (LMICs) - carried out as part of the World Health Organization (WHO)'s World Mental Health (WMH) Surveys. Respondents were asked whether treatment of each disorder was ever helpful and, if so, the number of professionals seen before receiving helpful treatment. Across all surveys and diagnostic categories, 26.1% of patients (N=10,035) reported being helped by the very first professional they saw. Persisting to a second professional after a first unhelpful treatment brought the cumulative probability of receiving helpful treatment to 51.2%. If patients persisted with up through eight professionals, the cumulative probability rose to 90.6%. However, only an estimated 22.8% of patients would have persisted in seeing these many professionals after repeatedly receiving treatments they considered not helpful. Although the proportion of individuals with disorders who sought treatment was higher and they were more persistent in HICs than LMICs, proportional helpfulness among treated cases was no different between HICs and LMICs. A wide range of predictors of perceived treatment helpfulness were found, some of them consistent across diagnostic categories and others unique to specific disorders. These results provide novel information about patient evaluations of treatment across diagnoses and countries varying in income level, and suggest that a critical issue in improving the quality of care for mental disorders should be fostering persistence in professional help-seeking if earlier treatments are not helpful., (© 2022 World Psychiatric Association.)

Background: Valid assessment of drug efficacy and safety requires an evidence base free of reporting bias. Using trial reports in Food and Drug Administration (FDA) drug approval packages as a gold standard, we previously found that the published literature inflated the apparent efficacy of antidepressant drugs. The objective of the current study was to determine whether this has improved with recently approved drugs., Methods and Findings: Using medical and statistical reviews in FDA drug approval packages, we identified 30 Phase II/III double-blind placebo-controlled acute monotherapy trials, involving 13,747 patients, of desvenlafaxine, vilazodone, levomilnacipran, and vortioxetine; we then identified corresponding published reports. We compared the data from this newer cohort of antidepressants (approved February 2008 to September 2013) with the previously published dataset on 74 trials of 12 older antidepressants (approved December 1987 to August 2002). Using logistic regression, we examined the effects of trial outcome and trial cohort (newer versus older) on transparent reporting (whether published and FDA conclusions agreed). Among newer antidepressants, transparent publication occurred more with positive (15/15 = 100%) than negative (7/15 = 47%) trials (OR 35.1, CI95% 1.8 to 693). Controlling for trial outcome, transparent publication occurred more with newer than older trials (OR 6.6, CI95% 1.6 to 26.4). Within negative trials, transparent reporting increased from 11% to 47%. We also conducted and contrasted FDA- and journal-based meta-analyses. For newer antidepressants, FDA-based effect size (ESFDA) was 0.24 (CI95% 0.18 to 0.30), while journal-based effect size (ESJournals) was 0.29 (CI95% 0.23 to 0.36). Thus, effect size inflation, presumably due to reporting bias, was 0.05, less than for older antidepressants (0.10). Limitations of this study include a small number of trials and drugs-belonging to a single class-and a focus on efficacy (versus safety)., Conclusions: Reporting bias persists but appears to have diminished for newer, compared to older, antidepressants. Continued efforts are needed to further improve transparency in the scientific literature., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: ET previously worked as a Medical Officer for the US Food and Drug Administration (FDA) and reviewed applications submitted by pharmaceutical companies to determine they should be approved for US marketing. He has no financial interest in any pharmaceutical products, approved or otherwise. AC is supported by the National Institute for Health Research (NIHR) Oxford Cognitive Health Clinical Research Facility, by an NIHR Research Professorship (grant RP-2017-08-ST2-006), by the NIHR Oxford and Thames Valley Applied Research Collaboration and by the NIHR Oxford Health Biomedical Research Centre (grant BRC-1215-20005). He has received research and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation and Angelini Pharma, outside the submitted work. TAF reports grants and personal fees from Mitsubishi-Tanabe, personal fees from MSD, grants and personal fees from Shionogi, outside the submitted work; in addition, he has a patent 2020-548587 concerning smartphone CBT apps pending, and intellectual properties for Kokoro-app licensed to Mitsubishi-Tanabe. GS has received fees paid to the University of Bern for participating in a meeting as real-world evidence and metaanalysis expert from Biogen and Merck. YV has no competing interests.

Objective: Combined oral contraceptives are often considered a treatment option for women with premenstrual syndrome or premenstrual dysphoric disorder also seeking contraception, but evidence for this treatment is scarce. We aimed to determine (1) the level of evidence for the efficacy of combined oral contraceptives in managing premenstrual depressive symptoms and overall premenstrual symptomatology and (2) the comparative efficacy of combined oral contraceptives (the International Prospective Register of Systematic Reviews registration number CRD42020205510)., Data Sources: We searched Cochrane Central Register of Controlled Trials, PubMed, Web of Science, PsycINFO, EMCare, and Embase from inception to June 3, 2021., Study Eligibility Criteria: All randomized clinical trials that evaluated the efficacy of combined oral contraceptives in women with premenstrual syndrome or premenstrual dysphoric disorder were considered eligible for inclusion in this meta-analysis., Study Appraisal and Synthesis Methods: A random effect Bayesian pairwise and network meta-analysis was conducted with change in premenstrual depressive symptoms and overall premenstrual symptomatology between baseline and 3 cycles as outcome. Certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach., Results: Of 3664 records, 9 eligible trials were included that studied 1205 women with premenstrual syndrome or premenstrual dysphoric disorder (mean age per study range, 24.6-36.5 years). The pairwise meta-analysis revealed that combined oral contraceptives were more efficacious than placebo in treating overall premenstrual symptomatology (standardized mean difference, 0.41; 95% credible interval, 0.17-0.67), but not premenstrual depressive symptoms specifically (standardized mean difference, 0.22; 95% credible interval, -0.06 to 0.47). However, none of the combined oral contraceptives were more effective than each other in reducing premenstrual depressive symptoms and overall premenstrual symptomatology., Conclusion: Combined oral contraceptives may improve overall premenstrual symptomatology in women with premenstrual syndrome or premenstrual dysphoric disorder, but not premenstrual depressive symptoms. There is no evidence for one combined oral contraceptive being more efficacious than any other., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Approval and prescription of psychotropic drugs should be informed by the strength of evidence for efficacy. Using a Bayesian framework, we examined (1) whether psychotropic drugs are supported by substantial evidence (at the time of approval by the Food and Drug Administration), and (2) whether there are systematic differences across drug groups. Data from short-term, placebo-controlled phase II/III clinical trials for 15 antipsychotics, 16 antidepressants for depression, nine antidepressants for anxiety, and 20 drugs for attention deficit hyperactivity disorder (ADHD) were extracted from FDA reviews. Bayesian model-averaged meta-analysis was performed and strength of evidence was quantified (i.e. BF BMA ). Strength of evidence and trialling varied between drugs. Median evidential strength was extreme for ADHD medication ( BF BMA = 1820.4), moderate for antipsychotics ( BF BMA = 365.4), and considerably lower and more frequently classified as weak or moderate for antidepressants for depression ( BF BMA = 94.2) and anxiety ( BF BMA = 49.8). Varying median effect sizes ( ES schizophrenia = 0.45, ES depression = 0.30, ES anxiety = 0.37, ES ADHD = 0.72), sample sizes ( N schizophrenia = 324, N depression = 218, N anxiety = 254, N ADHD = 189.5), and numbers of trials ( k schizophrenia = 3, k depression = 5.5, k anxiety = 3, k ADHD = 2) might account for differences. Although most drugs were supported by strong evidence at the time of approval, some only had moderate or ambiguous evidence. These results show the need for more systematic quantification and classification of statistical evidence for psychotropic drugs. Evidential strength should be communicated transparently and clearly towards clinical decision makers.

Background: Following testing in clinical trials, the use of remdesivir for treatment of COVID-19 has been authorized for use in parts of the world, including the USA and Europe. Early authorizations were largely based on results from two clinical trials. A third study published by Wang et al. was underpowered and deemed inconclusive. Although regulators have shown an interest in interpreting the Wang et al. study, under a frequentist framework it is difficult to determine if the non-significant finding was caused by a lack of power or by the absence of an effect. Bayesian hypothesis testing does allow for quantification of evidence in favor of the absence of an effect., Findings: Results of our Bayesian reanalysis of the three trials show ambiguous evidence for the primary outcome of clinical improvement and moderate evidence against the secondary outcome of decreased mortality rate. Additional analyses of three studies published after initial marketing approval support these findings., Conclusions: We recommend that regulatory bodies take all available evidence into account for endorsement decisions. A Bayesian approach can be beneficial, in particular in case of statistically non-significant results. This is especially pressing when limited clinical efficacy data is available., Competing Interests: The authors have declared that no competing interests exist.

Background: Observational studies suggest that hormonal contraceptive use may increase depressive symptoms in women, but it is unclear whether the effect is causal., Aims: To quantitatively examine the evidence from randomised clinical trials for the link between hormonal contraceptive use and depressive symptoms., Method: We performed a systematic review and network meta-analysis of randomised clinical trials comparing women randomised to any form of a hormonal contraceptive with women randomised to any other form of a (non-)hormonal contraceptive or placebo. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Web of Science, PsycINFO, EMCare and EMBASE, from inception to 1 May 2020. Certainty of the evidence was assessed with the Grading of Recommendations Assessment, Development and Evaluation approach. A random-effect Bayesian network meta-analysis was conducted, with change in depressive symptoms between baseline and three cycles as outcome., Results: This review identified 3492 records, of which 14 trials were eligible and 12 could be included in the network meta-analysis. These trials included 5833 participants (mean age per study range: 16.8-32.4 years) and compared 10 different interventions. Compared with placebo, hormonal contraceptive use did not cause worsening of depressive symptoms (standardised mean difference: median, -0.04; range, -0.17 [95% credible interval -0.46 to 0.13] to 0.13 [95% credible interval -0.28 to 0.56])., Conclusions: This study suggests that hormonal contraceptive use does not lead to an increase in depressive symptoms in adult women. Future studies should include first-time users, to confirm the results in young women.

Aims: Epidemiological studies indicate that individuals with one type of mental disorder have an increased risk of subsequently developing other types of mental disorders. This study aimed to undertake a comprehensive analysis of pair-wise lifetime comorbidity across a range of common mental disorders based on a diverse range of population-based surveys., Methods: The WHO World Mental Health (WMH) surveys assessed 145 990 adult respondents from 27 countries. Based on retrospectively-reported age-of-onset for 24 DSM-IV mental disorders, associations were examined between all 548 logically possible temporally-ordered disorder pairs. Overall and time-dependent hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Absolute risks were estimated using the product-limit method. Estimates were generated separately for men and women., Results: Each prior lifetime mental disorder was associated with an increased risk of subsequent first onset of each other disorder. The median HR was 12.1 (mean = 14.4; range 5.2-110.8, interquartile range = 6.0-19.4). The HRs were most prominent between closely-related mental disorder types and in the first 1-2 years after the onset of the prior disorder. Although HRs declined with time since prior disorder, significantly elevated risk of subsequent comorbidity persisted for at least 15 years. Appreciable absolute risks of secondary disorders were found over time for many pairs., Conclusions: Survey data from a range of sites confirms that comorbidity between mental disorders is common. Understanding the risks of temporally secondary disorders may help design practical programs for primary prevention of secondary disorders.

Aims: Intermittent explosive disorder (IED) is characterised by impulsive anger attacks that vary greatly across individuals in severity and consequence. Understanding IED subtypes has been limited by lack of large, general population datasets including assessment of IED. Using the 17-country World Mental Health surveys dataset, this study examined whether behavioural subtypes of IED are associated with differing patterns of comorbidity, suicidality and functional impairment., Methods: IED was assessed using the Composite International Diagnostic Interview in the World Mental Health surveys (n = 45 266). Five behavioural subtypes were created based on type of anger attack. Logistic regression assessed association of these subtypes with lifetime comorbidity, lifetime suicidality and 12-month functional impairment., Results: The lifetime prevalence of IED in all countries was 0.8% (s.e.: 0.0). The two subtypes involving anger attacks that harmed people ('hurt people only' and 'destroy property and hurt people'), collectively comprising 73% of those with IED, were characterised by high rates of externalising comorbid disorders. The remaining three subtypes involving anger attacks that destroyed property only, destroyed property and threatened people, and threatened people only, were characterised by higher rates of internalising than externalising comorbid disorders. Suicidal behaviour did not vary across the five behavioural subtypes but was higher among those with (v. those without) comorbid disorders, and among those who perpetrated more violent assaults., Conclusions: The most common IED behavioural subtypes in these general population samples are associated with high rates of externalising disorders. This contrasts with the findings from clinical studies of IED, which observe a preponderance of internalising disorder comorbidity. This disparity in findings across population and clinical studies, together with the marked heterogeneity that characterises the diagnostic entity of IED, suggests that it is a disorder that requires much greater research.

Use of methylphenidate in children has increased substantially, despite conflicting evidence regarding efficacy. In this study, prescription data were analyzed in relation to the publication of new evidence regarding efficacy. Incidence rates and prescribed doses of methylphenidate increased, with a decline during the last few years. Duration of use is still increasing. In half of the cases, starting dosages are higher than recommended in guidelines. There was little evidence that publication of new evidence directly influenced the use of methylphenidate. Recent and critical study findings should receive more attention to contribute to the development and use of treatment guidelines for ADHD and evidence-based methylphenidate use.

Aims: Mental disorders are associated with lower subjective social status (SSS), but a more nuanced understanding of this relationship is needed. We examined the influence of disorder age of onset and recency on SSS and studied whether mental disorders are also associated with the discrepancy between actual and desired SSS., Method: Data are from the baseline and second wave of the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2). Mental disorders were assessed with the Composite International Diagnostic Interview (CIDI 3.0), while both actual and desired SSS were assessed with a ten-rung ladder. Linear regression was used to examine the association between mental disorders and SSS., Results: Of 5303 participants, 2237 had a lifetime mental disorder at baseline. These participants reported significantly lower actual SSS (6.28) at follow-up than healthy participants (6.66, B = -0.38 [95% CI -0.48 to -0.27], p < 0.001) and a significantly greater actual-desired SSS discrepancy (1.14 v. 1.05 after controlling for actual SSS, B = 0.09 [0.01-0.17], p = 0.024). Lower age of onset of the first mental disorder was marginally significantly associated with lower actual SSS (B = 0.006 [0.000-0.012], p = 0.046). More recent disorders were also associated with lower actual SSS (B = 0.015 [0.005-0.026], p = 0.005), such that participants whose disorder remitted ⩾6 years before baseline were statistically indistinguishable from healthy participants., Conclusions: Lifetime mental disorders are associated with lower actual SSS and a slightly greater discrepancy between actual and desired SSS. However, people with mental disorders in (long-term) remission have a similar social status as healthy participants.

Background: Previous studies on reporting bias generally examined whether trials were published in stand-alone publications. In this study, we investigated whether pooled-trials publications constitute a specific form of reporting bias. We assessed whether negative trials were more likely to be exclusively published in pooled-trials publications than positive trials and examined the research questions, individual trial results, and conclusions presented in these articles., Methods: Data from a cohort of 105 randomized controlled trials of 16 antidepressants were extracted from earlier publications and the corresponding Food and Drug Administration (FDA) reviews. A systematic literature search was conducted to identify pooled-trials publications., Results: We found 107 pooled-trials publications that reported results of 23 (72%) of 32 trials not published in stand-alone publications. Only two (3.8%) of 54 positive trials were published exclusively in pooled-trials publications, compared with 21 (41.1%) of 51 negative trials (p < 0.001). Thirteen (12%) of 107 publications had as primary aim to present data on the trial's primary research question (drug efficacy compared with placebo). Only four of these publications, reporting on five (22%) trials, presented individual efficacy data for the primary research question. Additionally, only five (5%) of 107 pooled-trials publications had a negative conclusion., Conclusions: Compared with positive trials, negative trials of antidepressants for depression were much more likely to be reported exclusively in pooled-trials publications. Pooled-trials publications flood the evidence base with often-redundant articles that, instead of addressing the original primary research question, present (positive) results on secondary questions. Therefore, pooled-trials publications distort the apparent risk-benefit profile of antidepressants.

Background: Specific phobia (SP) is a relatively common disorder associated with high levels of psychiatric comorbidity. Because of its early onset, SP may be a useful early marker of internalizing psychopathology, especially if generalized to multiple situations. This study aimed to evaluate the association of childhood generalized SP with comorbid internalizing disorders., Methods: We conducted retrospective analyses of the cross-sectional population-based World Mental Health Surveys using the Composite International Diagnostic Interview. Outcomes were lifetime prevalence, age of onset, and persistence of internalizing disorders; past-month disability; lifetime suicidality; and 12-month serious mental illness. Logistic and linear regressions were used to assess the association of these outcomes with the number of subtypes of childhood-onset (< 13 years) SP., Results: Among 123,628 respondents from 25 countries, retrospectively reported prevalence of childhood SP was 5.9%, 56% of whom reported one, 25% two, 10% three, and 8% four or more subtypes. Lifetime prevalence of internalizing disorders increased from 18.2% among those without childhood SP to 46.3% among those with one and 75.6% those with 4+ subtypes (OR = 2.4, 95% CI 2.3-2.5, p < 0.001). Twelve-month persistence of lifetime internalizing comorbidity at interview increased from 47.9% among those without childhood SP to 59.0% and 79.1% among those with 1 and 4+ subtypes (OR = 1.4, 95% CI 1.4-1.5, p < 0.001). Respondents with 4+ subtypes also reported significantly more disability (3.5 days out of role in the past month) than those without childhood SP (1.1 days) or with only 1 subtype (1.8 days) (B = 0.56, SE 0.06, p < 0.001) and a much higher rate of lifetime suicide attempts (16.8%) than those without childhood SP (2.0%) or with only 1 subtype (6.5%) (OR = 1.7, 95% CI 1.7-1.8, p < 0.001)., Conclusions: This large international study shows that childhood-onset generalized SP is related to adverse outcomes in the internalizing domain throughout the life course. Comorbidity, persistence, and severity of internalizing disorders all increased with the number of childhood SP subtypes. Although our study cannot establish whether SP is causally associated with these poor outcomes or whether other factors, such as a shared underlying vulnerability, explain the association, our findings clearly show that childhood generalized SP identifies an important target group for early intervention.

Background: Improvement in depression within the first 2 weeks of antidepressant treatment predicts good outcomes, but non-improvers can still respond or remit, whereas improvers often do not.AimsWe aimed to investigate whether early improvement of individual depressive symptoms better predicts response or remission., Method: We obtained individual patient data of 30 trials comprising 2184 placebo-treated and 6058 antidepressant-treated participants. Primary outcome was week 6 response; secondary outcomes were week 6 remission and week 12 response and remission. We compared models that only included improvement in total score by week 2 (total improvement model) with models that also included improvement in individual symptoms., Results: For week 6 response, the area under the receiver operating characteristic curve and negative and positive predictive values of the total improvement model were 0.73, 0.67 and 0.74 compared with 0.77, 0.70 and 0.71 for the item improvement model. Model performance decreased for week 12 outcomes. Of predicted non-responders, 29% actually did respond by week 6 and 43% by week 12, which was decreased from the baseline (overall) probabilities of 51% by week 6 and 69% by week 12. In post hoc analyses with continuous rather than dichotomous early improvement, including individual items did not enhance model performance., Conclusions: Examining individual symptoms adds little to the predictive ability of early improvement. Additionally, early non-improvement does not rule out response or remission, particularly after 12 rather than 6 weeks. Therefore, our findings suggest that routinely adapting pharmacological treatment because of limited early improvement would often be premature.Declaration of interestNone.

Background: Antidepressants remain controversial, partly due to allegations that disappointing results were buried and because of their modest average efficacy.
AIM: To investigate bias in the antidepressant literature and the possibilities for predicting which patients with depression or anxiety do receive significant benefits from antidepressants.
METHOD: We investigated bias by comparing information from the US Food and Drug Administration with the published literature. To predict response, we used patient data from randomized trials.
RESULTS: Of all studies on depression or anxiety, 50% and 72% were positive, compared to 95% and 96% of all published studies. Safety outcomes were poorly reported in published articles and unpublished studies were often 'bundled' into pooled-trials publications with positive conclusions. We found an association between severity and antidepressant efficacy for some, but not all, anxiety disorders; previous research has found inconsistent evidence for this association for depression. Furthermore, patients with depression that showed early improvement were more likely to attain a good response, irrespective of which symptoms improved.
CONCLUSION: These results demonstrate the severe impact of bias on the antidepressant literature. Severity and early improvement predicted a good response, but more information is needed to improve predictions. The increased accessibility of individual patient data will hopefully soon enable further progress in this area.

Background: It has been suggested that antidepressant benefits are smaller for mild than severe depression. Because antidepressants are also used for anxiety disorders, obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD), we examined the influence of severity for these disorders., Methods: We used individual patient data of eight trials (3,430 participants) for generalized anxiety disorder (GAD); four trials (1,195 participants) for social anxiety disorder (SAD); four trials (1,132 participants) for OCD; three trials (1,071 participants) for PTSD; and 10 trials (2,151 participants) for panic disorder (PD). Mixed-effects models were used to investigate an interaction between severity and treatment group., Results: For GAD and PD, severity moderated antidepressant efficacy. The antidepressant-placebo difference was 1.4 (95% CI: 0.4-2.5; SMD: 0.21) Hamilton Anxiety Rating Scale (HAM-A) points for participants with mild GAD (baseline HAM-A = 10), increasing to 4.0 (3.4-4.6; SMD: 0.45) or greater for severely ill participants (HAM-A ≥ 30). For PD, the difference was 0.4 (0.3-0.6) panic attacks/2 weeks for participants with 10 panic attacks/2 weeks at baseline, increasing to 4.7 (3.0-6.4) for participants with 40. For SAD, OCD, and PTSD, no interaction was found. Across severity levels, the differences were 16.1 (12.9-19.3; SMD: 0.59) Liebowitz Social Anxiety Scale points, 3.4 (2.5-4.4, SMD: 0.39) Yale-Brown Obsessive-Compulsive Scale points, and 10.3 (6.9-13.6; SMD: 0.41) Clinician-Administered PTSD Scale points., Conclusions: Antidepressants are equally effective across severity levels for SAD, OCD, and PTSD. For GAD and PD, however, benefits are small at low severity, and the benefit-risk ratio may be unfavorable for these patients., (© 2018 Wiley Periodicals, Inc.)

The Dutch guideline for the treatment of depression in young people recommends initiating antidepressant treatment with fluoxetine, as the evidence for its efficacy is strongest and the risk of suicidality may be lower than with other antidepressants. Furthermore, low starting doses are recommended. We aimed to determine whether antidepressant prescriptions are in accord with guidelines. A cohort of young people aged between 6 and 17 at the time of antidepressant initiation was selected from IABD, a Dutch pharmacy prescription database. The percentage of prescriptions for each antidepressant was determined. Starting and maintenance doses were determined and compared with recommendations for citalopram, fluoxetine, fluvoxamine, and sertraline. During the study period, 2942 patients initiated antidepressant treatment. The proportion of these young people who were prescribed fluoxetine increased from 10.1 % in 1994-2003 to 19.7 % in 2010-2014. However, the most commonly prescribed antidepressants were paroxetine in 1994-2003 and citalopram in 2004-2014. The median starting and maintenance doses were ≤0.5 DDD/day for tricyclic antidepressants and 0.5-1 DDD/day for SSRIs and other antidepressants. Starting doses were guideline-concordant 58 % of the time for children, 31 % for preteens, and 16 % for teens. Sixty percent of teens were prescribed an adult starting dose. In conclusion, guideline adherence was poor. Physicians preferred citalopram over fluoxetine, in contrast to the recommendations. Furthermore, although children were prescribed a low starting dose relatively frequently, teens were often prescribed an adult starting dose. These results suggest that dedicated effort may be necessary to improve guideline adherence., Competing Interests: Compliance with ethical standards Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest. Ethical statement This study made use of de-identified patient data. Ethical approval was not required.

Previous research has shown that reporting bias has inflated the apparent efficacy of antidepressants. We investigated whether apparent safety was also affected. We included 133 trials, involving 31,296 patients, of second-generation antidepressants for the treatment of major depressive disorder (MDD) or anxiety disorders, obtained from Food and Drug Administration (FDA) reviews. We extracted data on overall discontinuation, discontinuation due to adverse events, and serious adverse events (SAEs). Meta-analysis was used to compare discontinuation rates between FDA reviews and matching journal articles, while SAEs were compared qualitatively. The odds ratio for overall discontinuation, comparing drug to placebo, was 1.0 for both sources, while that for discontinuation due to adverse events was 2.4 for both sources. Seventy-seven of 97 (79%) journal articles provided incomplete information on SAEs; sixty-one (63%) articles made no mention of SAEs at all. Of 21 articles which could be compared to the FDA, only 6 (29%) had full reporting without discrepancies. Nine (43%) articles reported a discrepant number of SAEs. Descriptions were absent or discrepant in 6 (29%) additional articles, even for important SAEs such as suicide attempts. In conclusion, reporting bias has not affected average discontinuation rates over trials. However, SAE reporting is not only very poor, with over half of articles failing to discuss SAEs altogether, but discrepancies between the FDA and articles were common and often led to a more favorable drug-placebo comparison. These findings suggest that journal articles are an unreliable source of data on SAEs in antidepressant trials., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

Background: Caspi et al.'s 2003 report that 5-HTTLPR genotype moderates the influence of life stress on depression has been highly influential but remains contentious. We examined whether the evidence base for the 5-HTTLPR-stress interaction has been distorted by citation bias and a selective focus on positive findings., Method: A total of 73 primary studies were coded for study outcomes and focus on positive findings in the abstract. Citation rates were compared between studies with positive and negative results, both within this network of primary studies and in Web of Science. In addition, the impact of focus on citation rates was examined., Results: In all, 24 (33%) studies were coded as positive, but these received 48% of within-network and 68% of Web of Science citations. The 38 (52%) negative studies received 42 and 23% of citations, respectively, while the 11 (15%) unclear studies received 10 and 9%. Of the negative studies, the 16 studies without a positive focus (42%) received 47% of within-network citations and 32% of Web of Science citations, while the 13 (34%) studies with a positive focus received 39 and 51%, respectively, and the nine (24%) studies with a partially positive focus received 14 and 17%., Conclusions: Negative studies received fewer citations than positive studies. Furthermore, over half of the negative studies had a (partially) positive focus, and Web of Science citation rates were higher for these studies. Thus, discussion of the 5-HTTLPR-stress interaction is more positive than warranted. This study exemplifies how evidence-base-distorting mechanisms undermine the authenticity of research findings.

Background: Antidepressants are established first-line treatments for anxiety disorders, but it is not clear whether they are equally effective across the severity range., Aims: To examine the influence of baseline severity of anxiety on antidepressant efficacy for generalised anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD) and panic disorder., Method: Fifty-six trials of second-generation antidepressants for the short-term treatment of an anxiety disorder were included. Baseline and change scores were extracted for placebo and treatment groups in each trial. Mixed effects meta-regression was used to investigate the effects of treatment group, baseline severity and their interaction., Results: Increased baseline severity did not predict greater improvement in drug groups compared with placebo groups. Standardised regression coefficients of the interaction term between baseline severity and treatment group were 0.04 (95% CI -0.13 to 0.20, P = 0.65) for GAD, -0.06 (95% CI -0.20 to 0.09, P = 0.43) for SAD, 0.04 (95% CI -0.07 to 0.16, P = 0.46) for OCD, 0.16 (95% CI -0.22 to 0.53, P = 0.37) for PTSD and 0.002 (95% CI -0.10 to 0.10, P = 0.96) for panic disorder. For OCD, baseline severity did predict improvement in both placebo and drug groups equally (β = 0.11, 95% CI 0.05 to 0.17, P = 0.001)., Conclusions: No relationship between baseline severity and drug-placebo difference was found for anxiety disorders. These results suggest that if the efficacy of antidepressants is considered clinically relevant, they may be prescribed to patients with anxiety regardless of symptom severity., (© The Royal College of Psychiatrists 2016.)

Objective: To examine if Dutch physicians adhere to the national guidelines on the treatment of depression in children and adolescents., Design: Retrospective database research., Method: Data on children and adolescents aged between 6 and 17 years were selected from the IADB, a Dutch database of filled prescriptions. We examined whether children and adolescents were prescribed fluoxetine as recommended by the guideline, and whether the starting dose was in accordance with the guideline., Results: Of 2942 children and adolescents in whom antidepressant treatment was initiated, the proportion prescribed fluoxetine increased from 10.1% in 1994-2003 to 19.7% in 2010-2014. However, paroxetine (1994-2003) and citalopram (2004-2014) were the most frequently prescribed antidepressants. Starting doses were guideline-concordant in 58% of children, 31% of preadolescents and 16% of adolescents. Sixty percent of all adolescents were prescribed an adult starting dose., Conclusion: Guideline adherence was poor. In contrast to the guidelines, physicians preferred citalopram to fluoxetine in children and adolescents with depression. Furthermore, adolescents often received an adult starting dose. These results suggest that dedicated effort is necessary to improve guideline adherence.

Importance: Studies have shown that the scientific literature has overestimated the efficacy of antidepressants for depression, but other indications for these drugs have not been considered., Objective: To examine reporting biases in double-blind, placebo-controlled trials on the pharmacologic treatment of anxiety disorders and quantify the extent to which these biases inflate estimates of drug efficacy., Data Sources and Study Selection: We included reviews obtained from the US Food and Drug Administration (FDA) for premarketing trials of 9 second-generation antidepressants in the treatment of anxiety disorders. A systematic search for matching publications (until December 19, 2012) was performed using PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials., Data Extraction and Synthesis: Double data extraction was performed for the FDA reviews and the journal articles. The Hedges g value was calculated as the measure of effect size., Main Outcomes and Measures: Reporting bias was examined and classified as study publication bias, outcome reporting bias, or spin (abstract conclusion not consistent with published results on primary end point). Separate meta-analyses were conducted for the 2 sources, and the effect of publication status on the effect estimates was examined using meta-regression., Results: The findings of 41 of the 57 trials (72%) were positive according to the FDA, but 43 of the 45 published article conclusions (96%) were positive (P < .001). Trials that the FDA determined as positive were 5 times more likely to be published in agreement with that determination compared with trials determined as not positive (risk ratio, 5.20; 95% CI, 1.87 to 14.45; P < .001). We found evidence for study publication bias (P < .001), outcome reporting bias (P = .02), and spin (P = .02). The pooled effect size based on the published literature (Hedges g, 0.38; 95% CI, 0.33 to 0.42; P < .001) was 15% higher than the effect size based on the FDA data (Hedges g, 0.33; 95% CI, 0.29 to 0.38; P < .001), but this difference was not statistically significant (β = 0.04; 95% CI, -0.02 to 0.10; P = .18)., Conclusions and Relevance: Various reporting biases were present for trials on the efficacy of FDA-approved second-generation antidepressants for anxiety disorders. Although these biases did not significantly inflate estimates of drug efficacy, reporting biases led to significant increases in the number of positive findings in the literature.

Methyl CpG binding protein-2 (MeCP2) is an essential epigenetic regulator in human brain development. Mutations in the MeCP2 gene have been linked to Rett syndrome, a severe X-linked progressive neurodevelopmental disorder, and one of the most common causes of mental retardation in females. MeCP2 duplication and triplication have also been found to affect brain development, indicating that both loss of function and gain in MeCP2 dosage lead to similar neurological phenotypes. Here, we used the Xenopus laevis visual system as an in vivo model to examine the consequence of increased MeCP2 expression during the morphological maturation of individual central neurons in an otherwise intact brain. Single-cell overexpression of wild-type human MeCP2 was combined with time-lapse confocal microscopy imaging to study dynamic mechanisms by which MeCP2 influences tectal neuron dendritic arborization. Analysis of neurons co-expressing DsRed2 demonstrates that MeCP2 overexpression specifically interfered with dendritic elaboration, decreasing the rates of branch addition and elimination over a 48 hour observation period. Moreover, dynamic analysis of neurons co-expressing wt-hMeCP2 and PSD95-GFP revealed that even though neurons expressing wt-hMeCP2 possessed significantly fewer dendrites and simpler morphologies than control neurons at the same developmental stage, postsynaptic site density in wt-hMeCP2-expressing neurons was similar to controls and increased at a rate higher than controls. Together, our in vivo studies support an early, cell-autonomous role for MeCP2 during the morphological differentiation of neurons and indicate that perturbations in MeCP2 gene dosage result in deficits in dendritic arborization that can be compensated, at least in part, by synaptic connectivity changes.