Placebo response rates and potential modifiers in double-blind randomized controlled trials of second and newer generation antidepressants for major depressive disorder in children and adolescents: a systematic review and meta-regression analysis

Children and adolescents with major depressive disorder (MDD) appear to be more responsive to placebo than adults in randomized placebo-controlled trials (RCTs) of second and newer generation antidepressants (SNG-AD). Previous meta-analyses obtained conflicting results regarding modifiers. We aimed to conduct a meta-analytical evaluation of placebo response rates based on both clinician-rating and self-rating scales. Based on the most recent and comprehensive study on adult data, we tested whether the placebo response rates in children and adolescents with MDD also increase with study duration and number of study sites. We searched systematically for published RCTs of SNG-AD in children and/or adolescents (last update: September 2017) in public domain electronic databases and additionally for documented studies in clinical trial databases. The log-transformed odds of placebo response were meta-analytically analyzed. The primary and secondary outcomes were placebo response rates at the end of treatment based on clinician-rating and self-rating scales, respectively. To examine the impact of study duration and number of study sites on placebo response rates, we performed simple meta-regression analyses. We selected other potential modifiers of placebo response based on significance in at least one previous pediatric meta-analysis and on theoretical considerations to perform explorative analyses. We applied sensitivity analyses with placebo response rates closest to week 8 to compare our data with those reported for adults. We identified 24 placebo-controlled trials (2229 patients in the placebo arms). The clinician-rated placebo response rates ranged from 22 to 62% with a pooled response rate of 45% (95% CI 41–50%). The number of study sites was a significant modifier in the simple meta-regression analysis [odds ratio (OR) 1.01, 95% CI 1.01–1.02, p = 0.0003, k = 24) with more study sites linked to a higher placebo response. Study duration was not significantly associated with the placebo response rate. The explorative simple analyses revealed that publication year may be an additional modifier. However, in the explorative multivariable analysis including the number of study sites and the publication year only the number of study sites reached a p value ≤ 0.05. The self-rated placebo response rates ranged from 1 to 68% with a pooled response rate of 26% (95% CI 10–54%) (k = 6; n = 396). This meta-analysis confirms a high pooled placebo response rate in children and adolescents based on clinician ratings, which exceeds that observed in the most recent meta-analysis of placebo effects in adults (36%; 95% CI 35–37%) published in 2016. However, and similar to findings in adults, the pooled response rates based on self-ratings were substantially lower. In accordance with previous meta-analyses, we corroborated the number of study sites as significant modifier. In comparison to the recent adult meta-analysis, the substantially lower number of pediatric studies entails a reduced power to detect modifiers. Future studies should provide more precise and homogenous information to support discovery of potential modifiers and consider no-treatment—if ethically permissible—to allow differentiation between placebo and spontaneous remission rates. If these differ, practicing clinicians should facilitate placebo effects as an addition to the verum effect to maximize benefits. Further research is required to explain the discrepant response rates between clinician and self-ratings.     

Purification and properties of virus particles, infectious subviral particles, and cores of bluetongue virus serotypes 1 and 4

Effective purification methods have been developed for virus particles, infectious subviral particles (ISVP), and virus cores of bluetongue virus (BTV) serotypes 1 and 4. The purified particles were analysed by indirect ELISA or PAGE using either silver staining, or fluorography of [35S]methionine-labelled preparations. No significant contamination with host cell proteins, or with the majority of BTV nonstructural proteins was detectable in any of the particle preparations. In addition to the two major outer capsid and five core proteins previously described, the purified virus particles of both serotypes were consistently found to contain small amounts of BTV protein NS2, previously regarded as exclusively nonstructural. This protein could be removed from the particle surface by treatment with a combination of chymotrypsin and sodium N-lauroyl sarcosinate, which also resulted in the cleavage of the larger of the two major outer capsid components (protein VP2). Two of the cleavage products of VP2 and the whole of the other major outer capsid component (protein VP5) formed a modified outer capsid layer in the resultant ISVP. These subviral particles were as or more infectious than the intact virus particles but had lost haemagglutinating activity. The core-associated RNA polymerase remained inactive in ISVP.     

Differentiated thyroid cancer--peculiar morphological and clinical forms

The most common clinical presentation of differentiated thyroid cancer (DTC), consisting of papillary and follicular adenocarcinoma (with their histological variants), is the solitary thyroid nodule. A review of the literature is performed in order to describe particular forms of DTC, in terms of incidence, diagnosis and treatment: occult carcinoma, carcinoma on aberrant thyroid tissue, "functional" thyroid carcinoma and familial non-medullary carcinoma. A particular interest is shown to the coexistence of malignancy with benign thyroid diseases, such as goiter, hyperthyroidism and Hashimoto's thyroiditis, as well as parathyroid adenoma. In conclusion, the authors emphasize that the association of carcinoma with benign thyroid conditions is not rare and it substantiate an aggressive approach in regard to diagnosis and treatment, increasing the indication for surgery and, moreover, for total thyroidectomy.     

The role of lymphadenectomy in the treatment of differentiated thyroid cancer

Papillary and follicular carcinoma represent almost 90% of the thyroid malignancies, being responsible for 70% of the mortality generated by thyroid cancer. Lymph node involvement, far more significant in the papillary form, increases the risk of local recurrence and affects long-term survival. Due to the lack of prospective randomised studies to assess the benefit of lymph node dissection in addition to total thyroidectomy, there is no consensus regarding the need of routine vs elective central compartment lymphadenectomy. Routine lymph node dissection of the central compartment is supported by the argument that it reduces the amount of neoplastic thyroid tissue and, therefore, optimises the effectiveness of radioiodine in DTC patients. Moreover, it provides an accurate staging by the detailed histopathological analysis and allows an optimal postoperative thyroid scanning. No additional morbidity of central lymphadenectomy is reported, compared to total thyroidectomy alone, if performed by a specialised surgeon. However, reinterventions for recurrence in the central compartment, carry a significantly higher risk of recurrent nerve and parathyroids damage. Unlike central compartment, it is generally agreed that lymphadenectomy of the lateral neck, as modified radical neck dissection, is employed when there is evidence of neoplastic lymph node involvement, wether macroscopic, imaging or by pathological data.     

External Assessment of the GEMA2009 Recommendations by a Multidisciplinary Expert Panel on Asthma

ObjectivesTo assess the level of agreement on the GEMA 2009 clinical recommendations by a Spanish expert panel on asthma.Materials and methodsThe study was divided into four stages: 1) establishment of a 9 member scientific committee (GEMA authors) for selection of GEMA recommendations to use in the survey; 2) formation of a panel of 74 professionals with expertise in this field (pulmonologists, allergists, family doctors, ear, nose and throat and paediatric specialists); 3) Delphi survey in two rounds, sent by mail, with intermediate processing of opinions and a report to the panel members; and 4) analysis and discussion of results for the Scientific Committee.ResultsSeventy four participants completed the two rounds of survey. During the first round, a consensus was reached in 49 out of 56 questions analysed. Following discussion by the panel, the consensus was increased to a total of 53 items in the survey. With respect to the remaining questions, Insufficient consensus was obtained on the rest of the questions, due to differing views between sub-specialists, or lack of criteria by most of the experts.ConclusionsThe external analysis by asthma experts from different specialities showed a high level of professional agreement with the GEMA 2009 recommendations in Spain (96.5 %). The disagreement shown in three recommendations reflect the lack of a high level evidence. These issues represent areas of interest for future research.     

Borderline Personality Disorder and Psychosis: A Review

Early views of borderline personality disorder (BPD) were based on the idea that patients with this pathology were “on the border” of psychosis. However, more recent studies have not supported this view, although they have found evidence of a malevolent interpersonal evaluation and a significant proportion of BPD patients showing psychotic symptoms. For example, in one study, 24% of BPD patients reported severe psychotic symptoms and about 75% had dissociative experiences and paranoid ideation. Thus, we start with an overview regarding the prevalence of psychotic symptoms in BPD patients. Furthermore, we report findings of studies investigating the role of comorbidity (eg, post-traumatic stress disorder) in the severity and frequency of psychotic symptoms in BPD patients. We then present results of genetic and neurobiological studies comparing BPD patients with patients with schizophrenia or nonschizophrenic psychotic disorders. In conclusion, this review reveals that psychotic symptoms in BPD patients may not predict the development of a psychotic disorder but are often permanent and severe and need careful consideration by clinicians. Therefore, adequate diagnosis and treatment of psychotic symptoms in BPD patients is emphasized.