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.</p

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

Citation bias and selective focus on positive findings in the literature on the serotonin transporter gene (5-HTTLPR), life stress and depression

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

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 (PMS) or premenstrual dysphoric disorder (PMDD) 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 (PROSPERO registration number CRD42020205510). DATA SOURCES: We searched Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Web of Science, PsycINFO, Emcare, and EMBASE from inception to June 3rd, 2021. STUDY ELIGIBILITY: All randomized clinical trials that evaluated efficacy of combined oral contraceptives in women with PMS or PMDD were considered eligible for inclusion in the present 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, nine eligible trials were included that studied 1205 women with PMS or PMDD (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 SMD [95%CrI], 0.41 [0.17, 0.67]), but not premenstrual depressive symptoms specifically (SMD [95%CrI], 0.22 [-0.06, 0.47]). However, none of the combined oral contraceptives were more effective than each other in reducing premenstrual depressive symptoms and overall premenstrual symptomatology. CONCLUSIONS: Combined oral contraceptives may improve overall premenstrual symptomatology in women with PMS or PMDD, but not premenstrual depressive symptoms. There is no evidence for one combined oral contraceptive being more efficacious than any other

Dynamics of Parasite Clearance in Cutaneous Leishmaniasis Patients Treated with Miltefosine

Parasite loads were quantified in repeated skin biopsies from lesions of 2 patients with Old-World cutaneous leishmaniasis (CL) caused by Leishmania major and L. infantum during and after treatment with miltefosine. Miltefosine induced a rapid therapeutic effect on both infections with an initial decline of parasites of ∼1 log/week for the L. major infection. These observations illustrate the usability of quantifying parasite loads in skin lesions as a pharmacodynamic measure and quantitative descriptor of drug effect for CL supporting clinical assessment

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

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.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.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  = 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 = 14.5; P

Proof-of-concept of a data-driven approach to estimate the associations of comorbid mental and physical disorders with global health-related disability

Objective: The standard method of generating disorder-specific disability scores has lay raters make rankings between pairs of disorders based on brief disorder vignettes. This method introduces bias due to differential rater knowledge of disorders and inability to disentangle the disability due to disorders from the disability due to comorbidities. Methods: We propose an alternative, data-driven, method of generating disorder-specific disability scores that assesses disorders in a sample of individuals either from population medical registry data or population survey self-reports and uses Generalized Random Forests(GRF) to predict global (rather than disorder-specific) disability assessed by clinician ratings or by survey respondent self-reports. This method also provides a principled basis for studying patterns and predictors of heterogeneity in disorder-specific disability. We illustrate this method by analyzing data for 16 disorders assessed in the World Mental Health Surveys(n=53,645).Results: Adjustments for comorbidity decreased estimates of disorder-specific disability substantially. Estimates were generally somewhat higher with GRF than conventional multivariable regression models. Heterogeneity was nonsignificant. Conclusions: The results show clearly that the proposed approach is practical, and that adjustment is needed for comorbidities to obtain accurate estimates of disorder-specific disability. Expansion to a wider range of disorders would likely find more evidence for heterogeneity

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

A many-analysts approach to the relation between religiosity and well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N = 10, 535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported beta = 0.120). For the second research question, this was the case for 65% of the teams (median reported beta = 0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates.</p

Cell-Autonomous Alterations in Dendritic Arbor Morphology and Connectivity Induced by Overexpression of MeCP2 in Xenopus Central Neurons In Vivo

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