Pharmacological treatment approaches to difficult-to-treat depression

In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial of almost 3000 patients with depression in the United States, 50% responded to the initial trial of a selective serotonin reuptake inhibitor antidepressant, but only a third achieved remission (nil or minimal depressive symptoms). The final remission rate, even after four potential treatment steps, was only 70%. This finding reflects the reality of clinical practice and highlights the need to employ the best available evidence in the management of people with complex depression. Before adopting a pharmacological strategy for a patient with difficult-to-treat depression, general clinical issues (such as missed psychiatric diagnoses, unresolved psychological issues and treatment non-adherence) should be considered. While there is no strong evidence for the order of implementing evidence-based pharmacological strategies for difficult-to-treat depression, we recommend: i) increase antidepressant dose; ii) switch to different antidepressant; iii) augment with a non-antidepressant agent; and iv) combine antidepressants. Sometimes it may be more appropriate to consider augmentation before switching antidepressants. The use of psychological interventions or other physical treatments such as electroconvulsive therapy should be considered at each step in management

Society issues, painkiller solutions, dependence and sustainable agriculture

Mahatma Gandhi listed seven blunders of humanity: Wealth without work, Pleasure without conscience, Commerce without morality, Worship without sacrifice, Politics without principles, Knowledge without character, and Science without humanity. Here I tackle three major issues, climate change, financial crisis and nation security, to disclose weak points of current remedies, and to propose sustainable solutions. Global warming and the unexpected financial crisis will undoubtedly impact all nations. Treating those two critical issues solely by painkiller solutions will fail because only adverse consequences are healed, not their causes. Therefore all sources of issues must be treated at the same time by enhancing collaboration between politicians and scientists. Furthermore, the adverse consequences of globalisation of markets for energy, food and other goods have been overlooked, thus deeply weakening the security of society structures in the event of major breakdowns. Therefore dependence among people, organisations and nations must be redesigned and adapted to take into account ecological, social and security impacts. Solving climate, financial and security issues can be done by using tools and principles developed by agronomists because agronomy integrates mechanisms occurring at various space and time levels. Agriculture is also a central driver for solving most society issues because society has been founded by agriculture, and agriculture is the activity that provides food, renewable energies and materials to humans. I present a to-do list summarising the major practices, principles and benefits of sustainable agriculture based on about 100 recently-published review articles. The practices are agroforestry, allelopathy, aquaculture, beneficial microorganisms and insects, biofertilisation, biofuels, biological control, biological nitrogen fixation, breeding, carbon sequestration, conservation agriculture, crop rotation, cover crops, decision support systems, grass strips, integrated pest management, intercropping, irrigation, mechanical weed control, mulching, no tillage, organic amendments, organic farming, phytoremediation, precision agriculture, seed invigoration, sociology, soil restoration, suicidal germination, terracing, transgenic crops, trap crops, and urban agriculture

Change in Negative Affective Bias following a Single Ketamine Treatment for Treatment-Resistant Depression

Ketamine has recently emerged as a highly effective new treatment for people with treatment-resistant depression with rapid antidepressant effects. However, these effects are often short lasting, and the potential cognitive mechanisms underlying the therapeutic effects, such as effects on emotional processing bias, remain poorly understood. In the present study, we explored potential changes in emotional and cognitive processing following a single treatment of subcutaneous ketamine in a randomised double-blind controlled study with an active control. Participants with treatment-resistant major depressive disorder (MDD) were recruited from a single site from the Ketamine for Adult Depression Study (KADS Trial) and were randomly assigned to receive racemic ketamine hydrochloride (n=10) or midazolam hydrochloride (n=11) in a 1: 1 ratio. A healthy control sample (n=23) was recruited to attend a single experimental session without any treatment. All MDD participants completed mood ratings and cognitive assessments prior to and one day after a single randomised treatment. The results showed no significant differences in performance changes after treatment across the majority of emotion-related (i.e., Emotional Stroop Task, Affective Go/No-Go Task) and cognitive (Ruff 2 and 7 Selective Attention Test, Controlled Word Association Test) outcome measures. Participants who received ketamine showed a significant improvement in a negative processing bias test (i.e., The Scrambled Sentence Task; Cohen's d=.67, p=.016), which was not significantly associated with improvement in psychological symptoms (r=-.662, p=.074). The results from this exploratory study suggest that a single ketamine treatment may modulate negative affective bias. Limitations to this study included the small sample size and lack of follow-up. Future larger trials are required to confirm this finding

Randomised controlled trial of neurostimulation for symptoms of anorexia nervosa (TRENA study): study protocol

Background: Anorexia nervosa (AN) has amongst the highest mortality rates and the highest treatment costs of any psychiatric disorder. Recently, interest in non-invasive brain stimulation as a novel treatment for AN has grown. These include repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). Methods: This double-blind, randomised sham-controlled trial will compare the relative acceptability and efficacy of tDCS and rTMS in people with AN. 70 participants will be randomised to active or sham tDCS, or active or sham rTMS treatment (2:1:2:1 ratio) over an 8-week treatment period. Participants will receive treatment as usual across the study duration. The primary outcomes are change on the Eating Disorder Examination Questionnaire and treatment acceptability. Secondary outcomes will include change in weight, cognition, mood, interpersonal functioning, and quality of life. Following the 8-week assessment, all participants will have the option of receiving an additional 12 weeks of at-home tDCS. A follow-up assessment will be conducted at 20 weeks post treatment. Discussion: Research into non-invasive brain stimulation as treatments for AN has potential to improve clinical outcomes for patients by comparing the relative efficacy and acceptability of both treatment modalities in the inpatient and at-home setting (i.e., for at-home tDCS) results from this study will provide important information for informing future larger clinical trials of these treatments for AN. Trial registration : ClinicalTrials.gov Identifier: NCT05788042

What we talk about when we talk about "global mindset": managerial cognition in multinational corporations

Recent developments in the global economy and in multinational corporations have placed significant emphasis on the cognitive orientations of managers, giving rise to a number of concepts such as “global mindset” that are presumed to be associated with the effective management of multinational corporations (MNCs). This paper reviews the literature on global mindset and clarifies some of the conceptual confusion surrounding the construct. We identify common themes across writers, suggesting that the majority of studies fall into one of three research perspectives: cultural, strategic, and multidimensional. We also identify two constructs from the social sciences that underlie the perspectives found in the literature: cosmopolitanism and cognitive complexity and use these two constructs to develop an integrative theoretical framework of global mindset. We then provide a critical assessment of the field of global mindset and suggest directions for future theoretical and empirical research

Absence of diabetic retinopathy in a patient who has had diabetes mellitus for 69 years, and inadequate glycemic control: case presentation

The main risk factors for the development and progression of diabetic retinopathy (DR) are chronic hyperglycemia, disease duration and systemic blood pressure. So far chronic hyperglycemia is the strongest evidence concerning the risk of developing DR. However there are some patients with poor metabolic control who never develop this diabetic complication. We present a case of a 73-year-old woman with type 1 diabetes mellitus, diagnosed 69 years ago. The patient is 73 years old, with no evidence of DR, despite poor glycemic control and several risk factors for DR. This case suggests the presence of a possible protection factor, which could be genetic

The Sec1/Munc18 protein Vps45 regulates cellular levels of its SNARE binding partners Tlg2 and Snc2 in Saccharomyces cerevisiae

Intracellular membrane trafficking pathways must be tightly regulated to ensure proper functioning of all eukaryotic cells. Central to membrane trafficking is the formation of specific SNARE (soluble N-ethylmeleimide-sensitive factor attachment protein receptor) complexes between proteins on opposing lipid bilayers. The Sec1/Munc18 (SM) family of proteins play an essential role in SNARE-mediated membrane fusion, and like the SNAREs are conserved through evolution from yeast to humans. The SM protein Vps45 is required for the formation of yeast endosomal SNARE complexes and is thus essential for traffic through the endosomal system. Here we report that, in addition to its role in regulating SNARE complex assembly, Vps45 regulates cellular levels of its SNARE binding partners: the syntaxin Tlg2 and the v-SNARE Snc2: Cells lacking Vps45 have reduced cellular levels of Tlg2 and Snc2; and elevation of Vps45 levels results in concomitant increases in the levels of both Tlg2 and Snc2. As well as regulating traffic through the endosomal system, the Snc v-SNAREs are also required for exocytosis. Unlike most vps mutants, cells lacking Vps45 display multiple growth phenotypes. Here we report that these can be reversed by selectively restoring Snc2 levels in vps45 mutant cells. Our data indicate that as well as functioning as part of the machinery that controls SNARE complex assembly, Vps45 also plays a key role in determining the levels of its cognate SNARE proteins; another key factor in regulation of membrane traffic

Sperm design and variation in the New World blackbirds (Icteridae)

Post-copulatory sexual selection (PCSS) is thought to be one of the evolutionary forces responsible for the rapid and divergent evolution of sperm design. However, whereas in some taxa particular sperm traits are positively associated with PCSS, in other taxa, these relationships are negative, and the causes of these different patterns across taxa are poorly understood. In a comparative study using New World blackbirds (Icteridae), we tested whether sperm design was influenced by the level of PCSS and found significant positive associations with the level of PCSS for all sperm components but head length. Additionally, whereas the absolute length of sperm components increased, their variation declined with the intensity of PCSS, indicating stabilizing selection around an optimal sperm design. Given the diversity of, and strong selection on, sperm design, it seems likely that sperm phenotype may influence sperm velocity within species. However, in contrast to other recent studies of passerine birds, but consistent with several other studies, we found no significant link between sperm design and velocity, using four different species that vary both in sperm design and PCSS. Potential reasons for this discrepancy between studies are discussed

Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal-directed, protocolised resuscitation for emerging septic shock.

BACKGROUND: Early goal-directed therapy (EGDT) is recommended in international guidance for the resuscitation of patients presenting with early septic shock. However, adoption has been limited and uncertainty remains over its clinical effectiveness and cost-effectiveness. OBJECTIVES: The primary objective was to estimate the effect of EGDT compared with usual resuscitation on mortality at 90 days following randomisation and on incremental cost-effectiveness at 1 year. The secondary objectives were to compare EGDT with usual resuscitation for requirement for, and duration of, critical care unit organ support; length of stay in the emergency department (ED), critical care unit and acute hospital; health-related quality of life, resource use and costs at 90 days and at 1 year; all-cause mortality at 28 days, at acute hospital discharge and at 1 year; and estimated lifetime incremental cost-effectiveness. DESIGN: A pragmatic, open, multicentre, parallel-group randomised controlled trial with an integrated economic evaluation. SETTING: Fifty-six NHS hospitals in England. PARTICIPANTS: A total of 1260 patients who presented at EDs with septic shock. INTERVENTIONS: EGDT (n = 630) or usual resuscitation (n = 630). Patients were randomly allocated 1 : 1. MAIN OUTCOME MEASURES: All-cause mortality at 90 days after randomisation and incremental net benefit (at £20,000 per quality-adjusted life-year) at 1 year. RESULTS: Following withdrawals, data on 1243 (EGDT, n = 623; usual resuscitation, n = 620) patients were included in the analysis. By 90 days, 184 (29.5%) in the EGDT and 181 (29.2%) patients in the usual-resuscitation group had died [p = 0.90; absolute risk reduction -0.3%, 95% confidence interval (CI) -5.4 to 4.7; relative risk 1.01, 95% CI 0.85 to 1.20]. Treatment intensity was greater for the EGDT group, indicated by the increased use of intravenous fluids, vasoactive drugs and red blood cell transfusions. Increased treatment intensity was reflected by significantly higher Sequential Organ Failure Assessment scores and more advanced cardiovascular support days in critical care for the EGDT group. At 1 year, the incremental net benefit for EGDT versus usual resuscitation was negative at -£725 (95% CI -£3000 to £1550). The probability that EGDT was more cost-effective than usual resuscitation was below 30%. There were no significant differences in any other secondary outcomes, including health-related quality of life, or adverse events. LIMITATIONS: Recruitment was lower at weekends and out of hours. The intervention could not be blinded. CONCLUSIONS: There was no significant difference in all-cause mortality at 90 days for EGDT compared with usual resuscitation among adults identified with early septic shock presenting to EDs in England. On average, costs were higher in the EGDT group than in the usual-resuscitation group while quality-adjusted life-years were similar in both groups; the probability that it is cost-effective is < 30%. FUTURE WORK: The ProMISe (Protocolised Management In Sepsis) trial completes the planned trio of evaluations of EGDT across the USA, Australasia and England; all have indicated that EGDT is not superior to usual resuscitation. Recognising that each of the three individual, large trials has limited power for evaluating potentially important subgroups, the harmonised approach adopted provides the opportunity to conduct an individual patient data meta-analysis, enhancing both knowledge and generalisability. TRIAL REGISTRATION: Current Controlled Trials ISRCTN36307479. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 97. See the NIHR Journals Library website for further project information

Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation

FUNDING AND DISCLOSURE The research was funded by Wellcome Trust (WT098012) to LKH; and National Institute of Health (DK056731) and the Marilyn H. Vincent Foundation to MGM. The University of Michigan Transgenic Core facility is partially supported by the NIH-funded University of Michigan Center for Gastrointestinal Research (DK034933). The remaining authors declare no conflict of interest. ACKNOWLEDGMENTS We thank Dr Celine Cansell, Ms Raffaella Chianese and the staff of the Medical Research Facility for technical assistance. We thank Dr Vladimir Orduña for the scientific advice and technical assistance.Peer reviewedPublisher PD