Clinical characteristics indexing genetic differences in bipolar disorder - a systematic review.

Bipolar disorder is a heterogenous condition with a varied clinical presentation. While progress has been made in identifying genetic variants associated with bipolar disorder, most common genetic variants have not yet been identified. More detailed phenotyping (beyond diagnosis) may increase the chance of finding genetic variants. Our aim therefore was to identify clinical characteristics that index genetic differences in bipolar disorder.We performed a systematic review of all genome-wide molecular genetic, family, and twin studies investigating familial/genetic influences on the clinical characteristics of bipolar disorder. We performed an electronic database search of PubMed and PsycInfo until October 2022. We reviewed title/abstracts of 2693 unique records and full texts of 391 reports, identifying 445 relevant analyses from 142 different reports. These reports described 199 analyses from family studies, 183 analyses from molecular genetic studies and 63 analyses from other types of studies. We summarized the overall evidence per phenotype considering study quality, power, and number of studies.We found moderate to strong evidence for a positive association of age at onset, subtype (bipolar I versus bipolar II), psychotic symptoms and manic symptoms with familial/genetic risk of bipolar disorder. Sex was not associated with overall genetic risk but could indicate qualitative genetic differences. Assessment of genetically relevant clinical characteristics of patients with bipolar disorder can be used to increase the phenotypic and genetic homogeneity of the sample in future genetic studies, which may yield more power, increase specificity, and improve understanding of the genetic architecture of bipolar disorder.

Commentary: The evidence base regarding the long-term effects of childhood mental disorder treatments needs to be strengthened - reply to Dekkers et al. (2023).

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.

Clinical characteristics indexing genetic differences in schizophrenia: a systematic review.

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.

Editorial Perspective: Are treatments for childhood mental disorders helpful in the long run? An overview of systematic reviews.

Mental disorders may have severe consequences for individuals across their entire lifespan, especially when they start in childhood. Effective treatments (both psychosocial and pharmacological) exist for the short-term treatment of common mental disorders in young people. These could, at least theoretically, prevent future problems, including recurrence of the disorder, development of comorbidity, or problems in functioning. However, little is known about the actual effects of these treatments in the long run. In the current editorial perspective, we consider the available evidence for the long-term (i.e., ≥2 years) effectiveness and safety of treatments for attention deficit hyperactivity disorder, behavior disorders, and anxiety and depressive disorders for children between 6 and 12 years old. After providing an overview of the literature, we reflect on two key issues, namely, methodological difficulties in establishing long-term treatment effects, and the risk-benefit ratio of treatments for common childhood mental disorders. In addition, we discuss future research possibilities, clinical implications, and other approaches, specifically whole-of-society-actions that could potentially reduce the burden of common childhood mental disorders.

Statistical power in clinical trials of interventions for mood, anxiety, and psychotic disorders.

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 (ESMA). 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 ESMA: 0.23 [0.09-0.58]), only reaching conventionally acceptable levels (80%) for SMD = 0.80. Median power to detect the ESMA 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.

Increased risks for mental disorders among LGB individuals: cross-national evidence from the World Mental Health Surveys.

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.

Patterns and correlates of patient-reported helpfulness of treatment for common mental and substance use disorders in the WHO World Mental Health Surveys.

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.

Selective publication of antidepressant trials and its influence on apparent efficacy: Updated comparisons and meta-analyses of newer versus older trials.

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.

Transdiagnostic development of internalizing psychopathology throughout the life course up to age 45: a World Mental Health Surveys report.

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.

Previous disorders and depression outcomes in individuals with 12-month major depressive disorder in the World Mental Health surveys.

AIMS: Major depressive disorder (MDD) is characterised by a recurrent course and high comorbidity rates. A lifespan perspective may therefore provide important information regarding health outcomes. The aim of the present study is to examine mental disorders that preceded 12-month MDD diagnosis and the impact of these disorders on depression outcomes. METHODS: Data came from 29 cross-sectional community epidemiological surveys of adults in 27 countries (n = 80 190). The Composite International Diagnostic Interview (CIDI) was used to assess 12-month MDD and lifetime DSM-IV disorders with onset prior to the respondent's age at interview. Disorders were grouped into depressive distress disorders, non-depressive distress disorders, fear disorders and externalising disorders. Depression outcomes included 12-month suicidality, days out of role and impairment in role functioning. RESULTS: Among respondents with 12-month MDD, 94.9% (s.e. = 0.4) had at least one prior disorder (including previous MDD), and 64.6% (s.e. = 0.9) had at least one prior, non-MDD disorder. Previous non-depressive distress, fear and externalising disorders, but not depressive distress disorders, predicted higher impairment (OR = 1.4-1.6) and suicidality (OR = 1.5-2.5), after adjustment for sociodemographic variables. Further adjustment for MDD characteristics weakened, but did not eliminate, these associations. Associations were largely driven by current comorbidities, but both remitted and current externalising disorders predicted suicidality among respondents with 12-month MDD. CONCLUSIONS: These results illustrate the importance of careful psychiatric history taking regarding current anxiety disorders and lifetime externalising disorders in individuals with MDD.

Comparing the evidential strength for psychotropic drugs: a Bayesian meta-analysis.

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. BFBMA). Strength of evidence and trialling varied between drugs. Median evidential strength was extreme for ADHD medication (BFBMA = 1820.4), moderate for antipsychotics (BFBMA = 365.4), and considerably lower and more frequently classified as weak or moderate for antidepressants for depression (BFBMA = 94.2) and anxiety (BFBMA = 49.8). Varying median effect sizes (ESschizophrenia = 0.45, ESdepression = 0.30, ESanxiety = 0.37, ESADHD = 0.72), sample sizes (Nschizophrenia = 324, Ndepression = 218, Nanxiety = 254, NADHD = 189.5), and numbers of trials (kschizophrenia = 3, kdepression = 5.5, kanxiety = 3, kADHD = 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.

Efficacy of combined oral contraceptives for depressive symptoms and overall symptomatology in premenstrual syndrome: pairwise and network meta-analysis of randomized trials.

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.

Rethinking remdesivir for COVID-19: A Bayesian reanalysis of trial findings.

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.

Hormonal contraceptive use and depressive symptoms: systematic review and network meta-analysis of randomised trials.

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.

Perceived helpfulness of treatment for specific phobia: Findings from the World Mental Health Surveys.

BACKGROUND: Although randomized trials show that specific phobia treatments can be effective, it is unclear whether patients experience treatment as helpful in clinical practice. We investigated this issue by assessing perceived treatment helpfulness for specific phobia in a cross-national epidemiological survey. METHODS: Cross-sectional population-based WHO World Mental Health (WMH) surveys in 24 countries (n=112,507) assessed lifetime specific phobia. Respondents who met lifetime criteria were asked whether they ever received treatment they considered helpful and the number of professionals seen up to the time of receiving helpful treatment. Discrete-event survival analysis was used to calculate conditional-cumulative probabilities of obtaining helpful treatment across number of professionals seen and of persisting in help-seeking after prior unhelpful treatment. RESULTS: 23.0% of respondents reported receiving helpful treatment from the first professional seen, whereas cumulative probability of receiving helpful treatment was 85.7% after seeing up to 9 professionals. However, only 14.7% of patients persisted in seeing up to 9 professionals, resulting in the proportion of patients ever receiving helpful treatment (47.5%) being much lower than it could have been with persistence in help-seeking. Few predictors were found either of perceived helpfulness or of persistence in help-seeking after earlier unhelpful treatments. LIMITATIONS: Retrospective recall and lack of information about either types of treatments received or objective symptomatic improvements limit results. CONCLUSIONS: Despite these limitations, results suggest that helpfulness of specific phobia treatment could be increased, perhaps substantially, by increasing patient persistence in help-seeking after earlier unhelpful treatments. Improved understanding is needed of barriers to help-seeking persistence.

Mental, behavioral and neurodevelopmental disorders in the ICD-11: an international perspective on key changes and controversies.

An update of the chapter on Mental, Behavioral and Neurodevelopmental Disorders in the International Classification of Diseases and Related Health Problems (ICD) is of great interest around the world. The recent approval of the 11th Revision of the ICD (ICD-11) by the World Health Organization (WHO) raises broad questions about the status of nosology of mental disorders as a whole as well as more focused questions regarding changes to the diagnostic guidelines for specific conditions and the implications of these changes for practice and research. This Forum brings together a broad range of experts to reflect on key changes and controversies in the ICD-11 classification of mental disorders. Taken together, there is consensus that the WHO's focus on global applicability and clinical utility in developing the diagnostic guidelines for this chapter will maximize the likelihood that it will be adopted by mental health professionals and administrators. This focus is also expected to enhance the application of the guidelines in non-specialist settings and their usefulness for scaling up evidence-based interventions. The new mental disorders classification in ICD-11 and its accompanying diagnostic guidelines therefore represent an important, albeit iterative, advance for the field.

The antidepressant standoff: why it continues and how to resolve it.

BACKGROUND: Antidepressant medications (ADMs) are widely used and long-term use is increasing. Given this extensive use and recommendation of ADMs in guidelines, one would expect ADMs to be universally considered effective. Surprisingly, that is not the case; fierce debate on their benefits and harms continues. This editorial seeks to understand why the controversy continues and how consensus can be achieved. METHODS: 'Position' paper. Critical analysis and synthesis of relevant literature. RESULTS: Advocates point at ADMs impressive effect size (number needed to treat, NNT = 6-8) in acute phase treatment and continuation/maintenance ADM treatment prevention relapse/recurrence in acute phase ADM responders (NNT = 3-4). Critics point at the limited clinically significant surplus value of ADMs relative to placebo and argue that effectiveness is overstated. We identified multiple factors that fuel the controversy: certainty of evidence is low to moderate; modest efficacy on top of strong placebo effects allows critics to focus on small net efficacy and advocates on large gross efficacy; ADM withdrawal symptoms masquerade as relapse/recurrence; lack of association between ADM treatment and long-term outcome in observational databases. Similar problems affect psychological treatments as well, but less so. We recommend four approaches to resolve the controversy: (1) placebo-controlled trials with relevant long-term outcome assessments, (2) inventive analyses of observational databases, (3) patient cohort studies including effect moderators to improve personalized treatment, and (4) psychological treatments as universal first-line treatment step. CONCLUSIONS: Given the public health significance of depression and increased long-term ADM usage, new approaches are needed to resolve the controversy.

A Prescription Trend Analysis of Methylphenidate: Relation to Study Reports on Efficacy.

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.

Childhood generalized specific phobia as an early marker of internalizing psychopathology across the lifespan: results from the World Mental Health Surveys.

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.

A comparison of DSM-5 and DSM-IV agoraphobia in the World Mental Health Surveys.

BACKGROUND: The Diagnostic and Statistical Manual of Mental Disorders, version 5 (DSM-5) definition of agoraphobia (AG) as an independent diagnostic entity makes it timely to re-examine the epidemiology of AG. Study objective was to present representative data on the characteristics of individuals who meet DSM-IV criteria for AG (AG without a history of panic disorder [PD] and PD with AG) but not DSM-5 criteria, DSM-5 but not DSM-IV criteria, or both sets of criteria. METHODS: Population-based surveys from the World Mental Health Survey Initiative including adult respondents (n = 136,357) from 27 countries across the world. The Composite International Diagnostic Interview was used to assess AG and other disorders. RESULTS: Lifetime and 12-month prevalence estimates of DSM-5 AG (1.5% and 1.0%) were comparable to DSM-IV (1.4% and 0.9%). Of respondents meeting criteria in either system, 57.1% met criteria in both, while 24.2% met criteria for DSM-5 only and 18.8% for DSM-IV only. Severe role impairment due to AG was reported by a lower proportion of respondents who met criteria only for DSM-IV AG (30.4%) than those with both DSM-5 and DSM-IV AG (44.0%; χ 21 = 4.7; P = 0.031). The proportion of cases with any comorbidity was lower among respondents who met criteria only for DSM-IV AG (78.7%) than those who met both sets (92.9%; χ 21 = 14.5; P < 0.001). CONCLUSIONS: This first large survey shows that, compared to the DSM-IV, the DSM-5 identifies a substantial group of new cases with AG, while the prevalence rate remains stable at 1.5%. Severity and comorbidity are higher in individuals meeting DSM-5 AG criteria compared with individuals meeting DSM-IV AG criteria only.