Discrepancies from registered protocols and spin occurred frequently in randomized psychotherapy trials:A meta-epidemiologic study

Objectives: This study aimed to investigate the relationship between trial registration, trial discrepancy from registered protocol, and spin in nonpharmacological trials. Study Design and Setting: Recent psychotherapy trials on depression (2015-2018) were analyzed regarding their registration status and its relationship to discrepancies between registered and published primary outcomes and to spin (discrepancy between the nonsignificant finding in a study and an overly beneficial interpretation of the effect of the treatment). Results: A total of 196 trials were identified, of which 78 (40%) had been registered prospectively and 56 (29%) had been registered retrospectively. In 102 (76%) of 134 registered trials, discrepancies between trial and protocol were present. Of 72 trials with a nonsignif-icant difference between treatments for the primary outcome, 68 trials (94%) showed spin. Discrepancies from protocol were less frequent in prospectively than in retrospectively registered trials (odds ratio5 0.19; 95% confidence interval [CI]: 0.07-0.52), but regarding the amount of spin, there was no difference between prospectively and retrospectively registered trials (rb=0.12; 95% CI: -0.41 to 0.19) or between registered and unregistered trials (rb=0.22, 95% CI -0.49 to 0.08). Conclusion: Protocol discrepancies and spin have a high prevalence in psychotherapy outcome research. The results show no relation between registration and spin, but prospective registration may prevent discrepancies from protocol

BDNF Plasma Levels and BDNF Exon IV Promoter Methylation as Predictors for Antidepressant Treatment Response

Major problems of current antidepressant pharmacotherapy are insufficient response rates and difficulties in response prediction. We recently provided preliminary evidence in a small study that patients with major depressive disorder (MDD) with a hypomethylation of the CpG-87 site of the promoter IV region of the brain-derived neurotrophic factor (BDNF) gene are less likely to benefit from antidepressants. Here, we aimed at replicating this finding in a secondary analysis of 561 MDD patients (mean age 40.0 ± 11.9 years, 56% female) included into the Early Medication Change study (EMC). We measured BDNF exon IV promoter and p11 gene methylation at Baseline (BL) as well as BDNF-plasma-levels (pBDNF) at BL and day 14 and related them to treatment outcome. Although we were not able to replicate the predictor function of hypomethylation of the BDNF exon IV promoter, a subgroup of patients with severe depression (Hamilton Depression Rating Scale [HAMD-17] ≥ 25) (n = 199) and hypermethylation at CpG-87 of the BDNF exon IV promoter had significantly higher remission rates than patients without a methylation (p = 0.032). We also found that 421 (75%) of 561 patients showed an early improvement (≥ 20% HAMD-17 reduction after 2 weeks), which was associated with a 4.24-fold increased likelihood to remit at study end compared to the 140 patients without early improvement. However, specificity of response prediction of early improvement was low (34%) and false positive rate high (66%). The combination of early improvement with a pBDNF increase between BL and day 14, however, increased the specificity of response prediction from 34 to 76%, and the combination with methylation of the CpG-87 site of the BDNF exon IV promoter from 34 to 62%. Thus, the combined markers reduced false positives rates from 66 to 24% and 38%, respectively. Methylation at other sites or p11 promoter methylation failed to increase specificity of early improvement prediction. In sum, the results add to previous findings that BDNF, BDNF promoter methylation and the combination of clinical and biological markers may be interesting candidates for therapy response prediction which has to be confirmed in further studies.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT00974155, identifier: NCT0097415

Conflicts of Interest in Medicine. A Systematic Review of Published and Scientifically evaluated Curricula

Objective: Conflicts of interests resulting from interactions with pharmaceutical companies are pervasive in medicine and can result in an undue influence on physicians’ decision-making. The objective of this systematic review is to analyze published and scientifically evaluated curricula for medical students and residents regarding such conflicts of interest. We begin by describing the covered topics and teaching methods; afterwards we analyze the quality of the curricula using the published data on their evaluations and comparing the content with content recommended for such curricula.Methods: We searched Pubmed, PsycInfo, EMBASE, OECD, WISO, SOWI and googlescholar up to and including the 5th of September 2016. Publications describing curricula for residents or medical students on the topic of conflicts of interest in medicine and evaluating them for their effects on the participants’ learning were included. We analyzed the covered topics and the teaching methods used and compared them with recommendations by the American Medical Students’ Association (AMSA) and Health Action International (HAI). Results: The literature search resulted in 20 publications that fulfilled our search criteria. In five trials, a control group was used, in no trial the participants were randomized to intervention or control group. 16/20 published curricula primarily covered marketing strategies by pharmaceutical companies, especially the interaction with pharmaceutical sales representatives (PSRs). Most curricula only covered a limited number of topics recommended by AMSA/HAI. The most frequent teaching method was a group discussion, which was used in 18/20 curricula; all curricula used at least one interactive teaching method. The evaluation of the curricula was heterogeneous in results as well as design. Some publications described a change of attitudes toward a stronger skepticism regarding interactions with pharmaceutical companies. Four publications described improved knowledge, one publication described a change in behavior toward a reduction of the acceptance of gifts.Conclusion: The trials conducted to this date regarding curricula on conflicts of interests are methodologically flawed and the described curricula lack important topics beyond marketing strategies of pharmaceutical companies. In addition, there are no data so far on the sustainability of the courses’ effects on participants’ behavior. It is therefore necessary to develop a model curriculum that covers a broader variety of topics and to evaluate it using a well thought-out methodology to create a foundation for the further improvement of teaching conflicts of interest in medicine

Development of a checklist for evaluating psychiatric reports

Abstract Background Performing a psychiatric interview and documenting the recorded findings in the form of a brief psychiatric report is one of the main learning goals in the psychiatric curriculum for medical students. However, observing and assessing students‘ reports is time consuming and there are no objective assessment tools at hand. Thus, we applied an integrative approach for designing a checklist that evaluates clinical performance, as a tool for the assessment of a psychiatric report. Methods A systematic review of the literature yielded no objective instrument for assessing the quality of written reports of psychiatric interviews. We used a 4-step mixed-methods approach to design a checklist as an assessment tool for psychiatric reports: 1. Development of a draft checklist, using literature research and focus group interviews; 2. Pilot testing and subsequent group discussion about modifications resulting from the pilot testing; 3. Creating a scoring system; 4. Testing for interrater-reliability, internal consistency and validity. Results The final checklist consisted of 36 items with a Cronbach’s alpha of 0.833. Selectivity of items ranged between 0.080 and 0.796. After rater-training, an interrater-reliability of 0.96 (ICC) was achieved. Conclusions Our approach, which integrated published evidence and the knowledge of domain experts, resulted in a reliable and valid checklist. It offers an objective instrument to measure the ability to document psychiatric interviews. It facilitates a transparent assessment of students’ learning goals with the goal of structural alignment of learning goals and assessment. We discuss ways it may additionally be used to measure the ability to perform a psychiatric interview and supplement other assessment formats

Predictors of the effectiveness of an early medication change strategy in patients with major depressive disorder

Abstract Background Patients with Major Depressive Disorder (MDD) who are non-improvers after two weeks of antidepressant treatment have a high risk of treatment failure. Recently, we did not find differences in outcomes in non-improvers randomized to an early medication change (EMC) strategy compared to treatment as usual (TAU). This secondary analysis investigated possible predictors of higher remission rates in the EMC strategy. Methods Of 192 non-improvers (i.e. decrease of ≤20% on the HAMD-17 depression scale) after a two-week treatment with escitalopram, n = 97 were randomized to EMC (immediate switch to high doses of venlafaxine XR) and n = 95 to TAU (continued escitalopram until day 28 with non-responders switched to venlafaxine XR). We first analyzed patient characteristics, psychopathological features and subtypes of MDD by logistic regression analyses as possible predictors of remission rates. In a second investigation, we analyzed the predictors, which showed a significant association in the first analysis before Bonferroni-Holm correction by chi-squared tests separated for treatment groups. All analyses were corrected by Bonferroni-Holm method. Results The first analyses yielded no statistically significant results after correction for multiple testing. In the second analyses, however, patients with prior medication at study entry showed higher remission rates in EMC than in TAU (24.2% versus 8.6%, p = 0.017; Bonferroni-Holm corrected significance level: p = 0.025.). Furthermore, patients with a recurrent course of MDD benefited less from treatment as usual (p = 0.009; Bonferroni-Holm corrected significance level: p = 0.025). Age, sex, age of onset, psychiatric or somatic comorbidities, and other subtypes of MDD did not predict remission rates. Conclusions Although in our first analysis we found statistically non-significant results, the second analysis showed significant differences in remission rates between patients with or without previous medication and in patients with recurrent MDD or the first depressive episode. It would therefore be valuable to examine in larger and prospective studies whether remission rates can be increased by quick escalation of treatment in certain subgroups of patients. Promising subgroups to be tested are patients who were previously medicated, and who show a recurrent course of MDD. Trial registration clinicaltrials.gov Identifier: NCT00974155. Registered at the 10th of September 2009. Retrospectively registered

Plasma brain-derived neurotrophic factor (pBDNF) and executive dysfunctions in patients with major depressive disorder

<p><b>Objectives:</b> Executive dysfunctions are frequently seen in patients with major depressive disorder (MDD) and normalise in many cases during effective antidepressant therapy. This study investigated whether a normalisation of executive dysfunctions during antidepressant treatment correlates with or can be predicted by clinical parameters or levels of brain-derived neurotrophic factor (BDNF).</p> <p><b>Methods:</b> In 110 MDD patients with executive dysfunctions (percentile <16), executive functions and plasma BDNF levels were analysed at baseline, and days 14 and 56 of an antidepressant treatment. BDNF exon IV and P11 methylation status was studied at baseline.</p> <p><b>Results:</b> Eighty patients (73%) experienced a normalisation of executive dysfunctions, while 30 (27%) suffered from persistent dysfunctions until day 56. Patients with persistent dysfunctions had significantly higher HAMD scores at days 14 and 56, and lower plasma BDNF levels at each time point than patients with a normalisation of dysfunctions (<i>F</i>₁= 10.18; <i>P</i> = 0.002). This was seen for verbal fluency, but not processing speed. BDNF exon IV and p11 promoter methylation was not associated with test performance.</p> <p><b>Conclusions:</b> Our results corroborate a concomitant amelioration of executive dysfunctions with successful antidepressant therapy and support a role of BDNF in the neural mechanisms underlying the normalisation of executive dysfunctions in MDD.</p> <p><b>ClinicalTrials.gov number:</b> NCT00974155; EudraCT: 2008-008280-96</p