Efficacy of a dilemma-focused intervention for unipolar depression: study protocol for a multicenter randomized controlled trial

Background Depression is one of the more severe and serious health problems because of its morbidity, disabling effects and for its societal and economic burden. Despite the variety of existing pharmacological and psychological treatments, most of the cases evolve with only partial remission, relapse and recurrence. Cognitive models have contributed significantly to the understanding of unipolar depression and its psychological treatment. However, success is only partial and many authors affirm the need to improve those models and also the treatment programs derived from them. One of the issues that requires further elaboration is the difficulty these patients experience in responding to treatment and in maintaining therapeutic gains across time without relapse or recurrence. Our research group has been working on the notion of cognitive conflict viewed as personal dilemmas according to personal construct theory. We use a novel method for identifying those conflicts using the repertory grid technique (RGT). Preliminary results with depressive patients show that about 90% of them have one or more of those conflicts. This fact might explain the blockage and the difficult progress of these patients, especially the more severe and/or chronic. These results justify the need for specific interventions focused on the resolution of these internal conflicts. This study aims to empirically test the hypothesis that an intervention focused on the dilemma(s) specifically detected for each patient will enhance the efficacy of cognitive behavioral therapy (CBT) for depression. Design A therapy manual for a dilemma-focused intervention will be tested using a randomized clinical trial by comparing the outcome of two treatment conditions: combined group CBT (eight, 2-hour weekly sessions) plus individual dilemma-focused therapy (eight, 1-hour weekly sessions) and CBT alone (eight, 2-hour group weekly sessions plus eight, 1-hour individual weekly sessions). Method Participants are patients aged over 18 years meeting diagnostic criteria for major depressive disorder or dysthymic disorder, with a score of 19 or above on the Beck depression inventory, second edition (BDI-II) and presenting at least one cognitive conflict (implicative dilemma or dilemmatic construct) as assessed using the RGT. The BDI-II is the primary outcome measure, collected at baseline, at the end of therapy, and at 3- and 12-month follow-up; other secondary measures are also used. Discussion We expect that adding a dilemma-focused intervention to CBT will increase the efficacy of one of the more prestigious therapies for depression, thus resulting in a significant contribution to the psychological treatment of depression. Trial registration ISRCTN92443999; ClinicalTrials.gov Identifier: NCT01542957.

Usefulness of betalactam therapy for community-acquired pneumonia in the era of drug-resistant Streptococcus pneumoniae: a randomized study of amoxicillin-clavulanate and ceftriaxone

Empirical antibiotic therapy of community-acquired pneumonia (CAP) has been complicated by the worldwide emergence of penicillin resistance among Streptococcus pneumoniae. The impact of this resistance on the outcome of patients hospitalized for CAP, empirically treated with betalactams, has not been evaluated in a randomized study. We conducted a prospective, randomized trial to assess the efficacy of amoxicillin-clavulanate (2 g/200 mg/8 hr) and ceftriaxone (1 g/24 hr) in a cohort of patients hospitalized for moderate-to-severe CAP. Three-hundred seventy-eight patients were randomized to receive amoxicillin-clavulanate (184 patients) or ceftriaxone (194 patients). Efficacy was assessed on Day 2, after completion of therapy and at long term follow-up. There were no significant differences in outcomes between treatment groups, both in intention-to-treat and per-protocol analysis. Overall mortality was 10.3% for amoxicillin-clavulanate and 8.8% for ceftriaxone (NS). There were 116 evaluable patients with proven pneumococcal pneumonia. Rates of high-level penicillin resistance (MIC of penicillin ≥2 µg/mL) were similar in the two groups (8.2 and 10.2%). Clinical efficacy at the end of therapy was 90.6% for amoxicillin-clavulanate and 88.9% for ceftriaxone (95% C.I. of the difference: -9.3 to +12.7%). No differences in outcomes were attributable to differences in penicillin susceptibility of pneumococcal strains. Sequential i.v./oral amoxicillin-clavulanate and parenteral ceftriaxone were equally safe and effective for the empirical treatment of acute bacterial pneumonia, including penicillin and cephalosporin-resistant pneumococcal pneumonia. The use of appropriate betalactams in patients with penumococcal pneumonia and in the overall CAP population, is reliable at the current level of resistance

Experimental study of clinafloxacin alone and in combination in the treatment of ciprofloxacin-susceptible and -resistant pneumococcal meningitis

The increasing incidence of ciprofloxacin resistance in Streptococcus pneumoniae may limit the efficacy of the new quinolones in difficult-to-treat infections such as meningitis. The aim of the present study was to determine the efficacy of clinafloxacin alone and in combination with teicoplanin and rifampin in the therapy of ciprofloxacin-susceptible and ciprofloxacin-resistant pneumococcal meningitis in rabbits. When used against a penicillin-resistant ciprofloxacin-susceptible strain (Clinafloxacin MIC 0.12 μg/ml), clinafloxacin at a dose of 20 mg/kg per day b.i.d. decreased bacterial concentration by -5.10 log cfu/ml at 24 hr. Combinations did not improve activity. The same clinafloxacin schedule against a penicillin- and ciprofloxacin-resistant strain (Clinafloxacin MIC 0.5 μg/ml) was totally ineffective. Our data suggest that a moderate decrease in quinolone susceptibility, as indicated by the detection of any degree of ciprofloxacin resistance, may render these antibiotics unsuitable for the management of pneumococcal meningitis

A germination study of herbicide-resistant field poppies in Spain

Field poppy, Papaver rhoeas L., is a very common weed in winter cereals in North-Eastern Spain. Its control is becoming difficult due to expanding herbicide resistance. To control field poppies there are alternative strategies such as non-chemical control that take into account the weed emergence period. However, there is a lack of knowledge of P. rhoeas emergence patterns in semi-arid conditions. Thus, here we conducted pot experiments on the emergence of P. rhoeas. We aimed to describe the emergence period and to quantify the emergence of a susceptible and of a herbicide-resistant P. rhoeas population at two locations in Catalonia, Spain, from 1998 to 2001 and until 2004 at one of them. Therefore, pots containing seeds of both populations were established at the two locations and emergence was recorded monthly. We studied the origin of the population, the sowing location, the effect of cultivation and the sowing year. First, we found that the main emergence peaks in our experiments occurred in autumn, accounting for between 65.7 and 98.5% of the annual emergence from October to December, and only little emergence was recorded in spring. This emergence pattern is different from those found in the literature corresponding to Northern European countries, where in some cases main flushes occur only in autumn, in spring and winter or only in spring. The emergence was mainly affected by cultivation, but the effect of light stimulus was observed several months later. As a consequence, cultivation should be done in early autumn, promoting emergence during the whole autumn and winter so that emerged seedlings can be controlled before sowing a spring crop. Second, most experiments showed that the emergence was significantly higher in the first autumn than in the following seasons, e.g. 4.1% emergence in the first year and only 2.1, 2.3, 0.5 and 0.6% new emergence at one of the locations for the second, third, fourth and fifth years. Thus, after having a severe P. rhoeas infestation causing a big seed rain, emergence should be stimulated by autumn cultivation in the following season and seedlings controlled by trying to deplete the soil seed bank as much as possible. Despite the fact that emergence will be staggered throughout several years and that there was a significant relationship between rainfall and emergence, so that dry years will cause a smaller emergence rate of the weed, these findings define a cultural management strategy to reduce P. rhoeas infestations and to contribute to integrated weed management strategies combining it with other tools.

Cultural control of herbicide-resistant Lolium rigidum Gaud. populations in winter cereal in Northeastern Spain

Lolium rigidum Gaud. is one of the most common weed species in winter cereals in Northeastern Spain. Herbicide resistance has been growing since the mid 90's and exclusive herbicide use is not enough in many cases, so that it is necessary to combine as many control tools as possible. Six field trials have been conducted during the cropping seasons 2001-02, 2002-03 and 2003-04 on winter cereal infested with herbicide resistant L. rigidum in Northeastern Spain testing different cultural control strategies. Sowing delay was conducted at five fields, mouldboard ploughing at four fields, the combination of sowing delay and ploughing at two fields, increasing the cereal sowing density and combined with sowing delay at one field. Sowing delay was confirmed to have an irregular efficacy depending on the L. rigidum emergence during the delay period. In the trials, weed emergence was reduced up to 88% in the best case but there was no effect in two cases. Ploughing had a more constant efficacy and reduced weed emergence between 50 and 80% although stoniness impeded in one occasion a correct soil inversion causing a very low efficacy. Increasing the cereal sowing rate did not reduce the weed population. The combination of the different methods did not increase significantly the individual efficacy, and one method was clearly more effective than the other, depending on the trial. In fields with high L. rigidum density, these methods are not effective enough and need to be combined with other methods, which are discussed in the text.

Isolation and characterization of Saccharomyces cerevisiae mutants resistant to aculeacin A

Aculeacin A is a lipopeptide that inhibits ,B-glucan synthesis in yeasts. A number of Saccharomyces cerevisiae mutants resistant to this antibiotic were isolated, and four loci (ACRI, ACR2, ACR3, and ACR4) whose products are involved in the sensitivity to aculeacin A of yeast ceils were defined. Mutants containing mutations in the four loci were also resistant to echinocandin B, another member of this lipopeptide family of antibiotics. In contrast, acri, acr3, and acr4 mutants were resistant to papulacandin B (an antibiotic containing a disaccharide linked to two fatty acid chains that also inhibits P-glucan synthesis), but acr2 mutants were susceptible'to this antibiotic. This result defines common and specific steps in the entry and action of aculeacin A and papulacandin B. The analysis of double mutants revealed an epistatic effect of the acr2 mutation on the other three mutations. Cell walls of the four different mutants did not show significant alterations in composition with respect to the parental strain, and in vitro glucan synthase activity was also unaffected. However, cell surface hydrophobicity in three of the mutants was considerably decreased with respect to the parental strain.

Ultra-Deep Pyrosequencing Detects Conserved Genomic Sites and Quantifies Linkage of Drug-Resistant Amino Acid Changes in the Hepatitis B Virus Genome

Selection of amino acid substitutions associated with resistance to nucleos(t)ide-analog (NA) therapy in the hepatitis B virus (HBV) reverse transcriptase (RT) and their combination in a single viral genome complicates treatment of chronic HBV infection and may affect the overlapping surface coding region. In this study, the variability of an overlapping polymerase-surface region, critical for NA resistance, is investigated before treatment and under antiviral therapy, with assessment of NA-resistant amino acid changes simultaneously occurring in the same genome (linkage analysis) and their influence on the surface coding region.

Efficacy of modern antipsychotics in placebo-controlled trials in bipolar depression: a meta-analysis.

Randomized, controlled trials have demonstrated efficacy for second-generation antipsychotics in the treatment of acute mania in bipolar disorder. Despite depression being considered the hallmark of bipolar disorder, there are no published systematic reviews or meta-analyses to evaluate the efficacy of modern atypical antipsychotics in bipolar depression. We systematically reviewed published or registered randomized, double-blind, placebo-controlled trials (RCTs) of modern antipsychotics in adult bipolar I and/or II depressive patients (DSM-IV criteria). Efficacy outcomes were assessed based on changes in the Montgomery-Asberg Depression Rating Scale (MADRS) during an 8-wk period. Data were combined through meta-analysis using risk ratio as an effect size with a 95% confidence interval (95% CI) and with a level of statistical significance of 5% (p<0.05). We identified five RCTs; four involved antipsychotic monotherapy and one addressed both monotherapy and combination with an antidepressant. The two quetiapine trials analysed the safety and efficacy of two doses: 300 and 600 mg/d. The only olanzapine trial assessed olanzapine monotherapy within a range of 5-20 mg/d and olanzapine-fluoxetine combination within a range of 5-20 mg/d and 6-12 mg/d, respectively. The two aripiprazole placebo-controlled trials assessed doses of 5-30 mg/d. Quetiapine and olanzapine trials (3/5, 60%) demonstrated superiority over placebo (p<0.001). Only 2/5 (40%) (both aripiprazole trials) failed in the primary efficacy measure after the first 6 wk. Some modern antipsychotics (quetiapine and olanzapine) have demonstrated efficacy in bipolar depressive patients from week 1 onwards. Rapid onset of action seems to be a common feature of atypical antipsychotics in bipolar depression. Comment in The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface controlEfficacy of modern antipsychotics in placebo-controlled trials in bipolar depression: a meta-analysis--results to be interpreted with caution.

Cost-effectiveness of a community pharmacist intervention in patients with depression: a randomized controlled trial (PRODEFAR study)

Background: Non-adherence to antidepressants generates higher costs for the treatment of depression. Little is known about the cost-effectiveness of pharmacist's interventions aimed at improving adherence to antidepressants. The study aimed to evaluate the cost-effectiveness of a community pharmacist intervention in comparison with usual care in depressed patients initiating treatment with antidepressants in primary care. Methods: Patients were recruited by general practitioners and randomized to community pharmacist intervention (87) that received an educational intervention and usual care (92). Adherence to antidepressants, clinical symptoms, Quality-Adjusted Life-Years (QALYs), use of healthcare services and productivity losses were measured at baseline, 3 and 6 months. Results: There were no significant differences between groups in costs or effects. From a societal perspective, the incremental cost-effectiveness ratio (ICER) for the community pharmacist intervention compared with usual care was 1,866 for extra adherent patient and 9,872 per extra QALY. In terms of remission of depressive symptoms, the usual care dominated the community pharmacist intervention. If willingness to pay (WTP) is 30,000 per extra adherent patient, remission of symptoms or QALYs, the probability of the community pharmacist intervention being cost-effective was 0.71, 0.46 and 0.75, respectively (societal perspective). From a healthcare perspective, the probability of the community pharmacist intervention being cost-effective in terms of adherence, QALYs and remission was of 0.71, 0.76 and 0.46, respectively, if WTP is 30,000. Conclusion: A brief community pharmacist intervention addressed to depressed patients initiating antidepressant treatment showed a probability of being cost-effective of 0.71 and 0.75 in terms of improvement of adherence and QALYs, respectively, when compared to usual care. Regular implementation of the community pharmacist intervention is not recommended.

Evaluation of a pharmacist intervention on patients initiating pharmacological treatment for depression: a randomized controlled superiority trial

Major depression is associated with high burden, disability and costs. Non-adherence limits the effectiveness of antidepressants. Community pharmacists (CP) are in a privileged position to help patients cope with antidepressant treatment. The aim of the study was to evaluate the impact of a CP intervention on primary care patients who had initiated antidepressant treatment. Newly diagnosed primary care patients were randomised to usual care (UC) (92) or pharmacist intervention (87). Patients were followed up at 6 months and evaluated three times (Baseline, and at 3 and 6 months). Outcome measurements included clinical severity of depression (PHQ-9), health-related quality of life (HRQOL) (Euroqol-5D) and satisfaction with pharmacy care. Adherence was continuously registered from the computerised pharmacy records. Non-adherence was defined as refilling less than 80% of doses or having a medication-free gap of more than 1 month. Patients in the intervention group were more likely to remain adherent at 3 and 6 months follow-up but the difference was not statistically significant. Patients in the intervention group showed greater statistically significant improvement in HRQOL compared with UC patients both in the main analysis and PP analyses. No statistically significant differences were observed in clinical symptoms or satisfaction with the pharmacy service. The results of our study indicate that a brief intervention in community pharmacies does not improve depressed patients' adherence or clinical symptoms. This intervention helped patients to improve their HRQOL, which is an overall measure of patient status.

Synaptic depression and slow oscillatory activity in a biophysical network model of the cerebral cortex

Short-term synaptic depression (STD) is a form of synaptic plasticity that has a large impact on network computations. Experimental results suggest that STD is modulated by cortical activity, decreasing with activity in the network and increasing during silent states. Here, we explored different activity-modulation protocols in a biophysical network model for which the model displayed less STD when the network was active than when it was silent, in agreement with experimental results. Furthermore, we studied how trains of synaptic potentials had lesser decay during periods of activity (UP states) than during silent periods (DOWN states), providing new experimental predictions. We next tackled the inverse question of what is the impact of modifying STD parameters on the emergent activity of the network, a question difficult to answer experimentally. We found that synaptic depression of cortical connections had a critical role to determine the regime of rhythmic cortical activity. While low STD resulted in an emergent rhythmic activity with short UP states and long DOWN states, increasing STD resulted in longer and more frequent UP states interleaved with short silent periods. A still higher synaptic depression set the network into a non-oscillatory firing regime where DOWN states no longer occurred. The speed of propagation of UP states along the network was not found to be modulated by STD during the oscillatory regime; it remained relatively stable over a range of values of STD. Overall, we found that the mutual interactions between synaptic depression and ongoing network activity are critical to determine the mechanisms that modulate cortical emergent patterns.