Probiotics as adjunctive treatment in major depressive disorder: estimates of treatment effect and underlying mechanisms from a double-blind placebo-controlled randomised pilot trial

AimsDespite considerable preclinical evidence, clinical trials assessing the effects of probiotics on individuals with major depressive disorder (MDD) are scarce. This study aimed to provide further evidence of the acceptability, tolerability and putative efficacy of probiotics in this patient group and to improve our understanding of the underlying mechanisms of action.MethodsThis double-blind randomised placebo-controlled pilot and mechanistic trial investigated the effects of an 8-week adjunctive multi-strain probiotic intervention in adults with MDD taking antidepressants. Psychiatric data and stool and blood samples were collected at baseline, week 4 and week 8. A computer-based emotion recognition task was also administered. Stool samples from 25 matched healthy controls were also obtained.Results49 participants, randomised to probiotic (n = 24) or placebo (n = 25), were included in intent-to-treat analyses. Standardised effect sizes (SES) from linear mixed models demonstrated that the probiotic group attained greater improvements in depressive (HAMD week 4: SES [95%CI] = 0.70[0.01, 0.98]; IDS week 8: SES [95%CI] = 0.64 [0.03, 0.87]) and anxiety symptoms (HAMA week 4: SES [95%CI] = 0.67 [0.00, 0.95]; week 8: SES [95%CI] = 0.79 [0.06, 1.05]), compared to the placebo group. Attrition was 8% (n = 3 placebo, n = 1 probiotic), adherence was 97.2% and there were no serious adverse reactions. The probiotic modified the composition of the faecal microbiota by normalising richness and diversity towards healthy control levels. The probiotic also increased levels of specific taxa, including Bacillaceae (FDR p ConclusionCompared to placebo, the probiotic group had greater improvement in depressive and anxiety scores, from as early as 4 weeks. The acceptability, tolerability and estimated effect sizes on key clinical outcomes are promising and encourage further investigation of this probiotic as add-on treatment in MDD. The beneficial effects of probiotics in this patient group may be partially mediated by modification of the composition of the gut microbiota and improvement of affective biases, inherent to depressive disorders.</p

Family tree and ancestrey inference: is there a need for a `generational' consent?

Background: Genealogical research and ancestry testing are popular recreational activities but little is known about the impact of the use of these services on clients’ biological and social families. Ancestry databases are being enriched with self-reported data and data from deoxyribonucleic acid (DNA) analyses, but also are being linked to other direct-to-consumer genetic testing and research databases. As both family history data and DNA can provide information on more than just the individual, we asked whether companies, as a part of the consent process, were informing clients, and through them clients’ relatives, of the potential implications of the use and linkage of their personal data. Methods: We used content analysis to analyse publically-available consent and informational materials provided to potential clients of ancestry and direct-to-consumer genetic testing companies to determine what consent is required, what risks associated with participation were highlighted, and whether the consent or notification of third parties was suggested or required. Results: We identified four categories of companies providing: 1) services based only on self-reported data, such as personal or family history; 2) services based only on DNA provided by the client; 3) services using both; and 4) services using both that also have a research component. The amount of information provided on the potential issues varied significantly across the categories of companies. ‘Traditional’ ancestry companies showed the greatest awareness of the implications for family members, while companies only asking for DNA focused solely on the client. While in some cases companies included text recommending clients inform their relatives, showing they recognised the issues, often it was located within lengthy terms and conditions or privacy statements that may not be read by potential clients. Conclusions: We recommend that companies should make it clearer that clients should inform third parties about their plans to participate, that third parties’ data will be provided to companies, and that that data will be linked to other databases, thus raising privacy and issues on use of data. We also suggest investigating whether a ‘generational consent’ should be created that would include more than just the individual in decisions about participating in genetic investigations

Targeted Cks1 overexpression is not sufficient to induce B cell lymphoproliferation or lymphoma.

<p>Data from two experiments (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037433#pone-0037433-g002" target="_blank">Figure 2</a>) are combined. One experiment with 2×10⁶ transplanted cells and an infection rate of 15% (n = 4 or 5 recipient mice) and one with 1×10⁶ cells and an infection rate of 45% (n = 2 or 3 recipient mice). <b>A</b>, Flow cytometric analysis of the percentage of GFP-positive B cells. Leucocytes were gated on B220+ cells. The analysis shows a divergence in the groups, some animals loose GFP positivity in the B cell compartment over time irrespective of the transduction efficiency. <b>B</b>, Left panel: Flow cytometric results of the bone marrow (BM) and spleen (S) for GFP positivity (of all cells, after lysis of erythrocytes). Right panel: percentage of GFP-positive cells in the B220 compartment of bone marrow (BM) and spleen (S). The analysis was performed on the day of indisposition and sacrifice. <b>C</b>, Representative images of flow cytometric analysis of GFP-positive B cells in the bone marrow. The genetic group is indicated. <b>D</b>, Survival of the <i>CD19-Cre;Stop-Cks1-GFP</i> group (median: 444 days) was identical to the survival of the <i>CD19-Cre;Stop-GFP</i> group (median: 391 days). All mice died from irradiation induced reasons but not B cell lymphoma.</p

Cks1 regulates proliferation in oncogene-induced AML by suppressing p27^Kip1.

<p><b>A</b>, 5-FU-mobilized bone morrow from mice of the indicated genotype was infected with <i>Myc-GFP</i> virus and 2×10⁶ GFP-positive cells were transplanted with an infection rate of about 40% into lethally irradiated recipients. Immunoblot analysis of the indicated proteins was performed 3 weeks after transplantation. <b>B</b>, Flow cytometric anti-BrdU staining of GFP-positive Gr1/CD11b-positive bone marrow cells. 1 mg BrdU/g body weight was intraperitoneally injected 12 hours before bone marrow harvest. The bars represent the mean ± standard deviation of n = 3 or 5 individual mice per genotype. <b>C</b>, Survival curve of mice transplanted with <i>Myc-GFP</i>-infected bone marrow of the indicated <i>Cks1</i> and <i>p27^Kip1</i> genotype. All mice died from AML. The median survival is not significantly different between the genotypes.</p

Ubiquitous Cks1 overexpression in the bone marrow is not sufficient to induce myeloproliferative disease or leukemia.

<p>4×10⁶ GFP-positive cells were transplanted with an infection rate of 30%. <b>A</b>, Cks1 mRNA levels in the indicated bone marrow subsets of transplanted mice were analyzed by realtime PCR at day 160 after transplantation. Shown is the relative expression of Cks1 as compared to the B cell expression of the GFP mice as a control sample set at 1. <i>GFP</i> group: n = 2; <i>Cks1-GFP</i> group: n = 3. The bars represent the mean relative expression ± standard deviation. realtime PCR was performed in duplicates. <b>B</b>, Immunoblot analysis of the bone marrow of transplanted mice on the day of indisposition and sacrifice. <b>C</b>, The left panel shows the GFP positivity of the bone marrow (BM) and spleen (S). The three right panels show the percentages of B-, T- and myeloid cells. <b>D</b>, Representative flow cytometric dot blot images of the myeloid cell compartment of <i>GFP</i>, <i>Cks1-GFP</i> and <i>Myc-GFP</i> animals on the day of their sacrifice. <b>E</b>, Survival analysis of lethally irradiated recipient mice that were transplanted with <i>GFP</i>, <i>Cks1-GFP</i> or <i>Myc-GFP</i> infected bone marrow. None of the <i>GFP</i> or <i>Cks1-GFP</i> mice died of leukemia, while all <i>Myc-GFP</i> mice succumbed to AML. Median survival: <i>GFP</i> group, 469 days; <i>Cks1-GFP</i> group, 541.5 days; <i>Myc-GFP</i> group, 52 days. Only the survival of <i>Myc-GFP</i> group is significantly different from the other groups.</p