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Background: Major depressive disorder (MDD) is common and often has sub-optimal response to treatment. Difficult-to-treat depression (DTD) is a new concept that describes ‘depression that continues to cause significant burden despite usual treatment efforts’. Aims: To identify patients with likely DTD in UK secondary care and examine demographic, disease and treatment data as compared with ‘non-DTD’ MDD patients. Methods: Anonymised electronic health records (EHRs) of five specialist mental health National Health Service (NHS) Trusts in the United Kingdom were analysed using a natural language processing model. Data on disease characteristics, comorbidities and treatment histories were extracted from structured fields and using natural language algorithms from unstructured fields. Patients with MDD aged ⩾18 years were included in the analysis; those with presumed DTD were identified on the basis of MDD history (duration and recurrence) and number of treatments prescribed. Results: In a sample of 28,184 patients with MDD, 19% met criteria for DTD. Compared to the non-DTD group, patients with DTD were more likely to have severe depression, suicidal ideation, and comorbid psychiatric and/or physical illness, as well as higher rates of hospitalisation. They were also more likely to be in receipt of unemployment and sickness/disability benefits. More intensive treatment strategies were used in the DTD group, including higher rates of combination therapy, augmentation, psychotherapy and electroconvulsive therapy. Conclusion: This study demonstrates the feasibility of identifying patients with probable DTD from EHRs and highlights the increased burden associated with MDD in these patients.

Background In difficult-to-treat depression (DTD) the outcome metrics historically used to evaluate treatment effectiveness may be suboptimal. Metrics based on remission status and on single end-point (SEP) assessment may be problematic given infrequent symptom remission, temporal instability, and poor durability of benefit in DTD. Methods Self-report and clinician assessment of depression symptom severity were regularly obtained over a 2-year period in a chronic and highly treatment-resistant registry sample (N = 406) receiving treatment as usual, with or without vagus nerve stimulation. Twenty alternative metrics for characterizing symptomatic improvement were evaluated, contrasting SEP metrics with integrative (INT) metrics that aggregated information over time. Metrics were compared in effect size and discriminating power when contrasting groups that did (N = 153) and did not (N = 253) achieve a threshold level of improvement in end-point quality-of-life (QoL) scores, and in their association with continuous QoL scores. Results Metrics based on remission status had smaller effect size and poorer discrimination of the binary QoL outcome and weaker associations with the continuous end-point QoL scores than metrics based on partial response or response. The metrics with the strongest performance characteristics were the SEP measure of percentage change in symptom severity and the INT metric quantifying the proportion of the observation period in partial response or better. Both metrics contributed independent variance when predicting end-point QoL scores. Conclusions Revision is needed in the metrics used to quantify symptomatic change in DTD with consideration of INT time-based measures as primary or secondary outcomes. Metrics based on remission status may not be useful.

Background: Treatment-resistant depression (TRD) has a profound cost to patients and healthcare services worldwide. Pharmacological augmentation is one therapeutic option for TRD, with lithium and quetiapine currently recommended as first-line agents. Patient opinions about pharmacological augmentation may affect treatment outcomes, yet these have not been systematically explored. Aims: This study aimed to qualitatively assess patient experiences of lithium and quetiapine augmentation. Methods: Semi-structured interviews were conducted with 32 patients from the ongoing lithium versus quetiapine open-label trial comparing these augmentation agents in patients with TRD. Interviews were audio recorded, transcribed and a thematic analysis was used to assess patient opinions of each agent. Results: Four main themes were generated from the thematic analysis: ‘Initial concerns’, ‘Experience of side effects’, ‘Perception of treatment efficacy’ and ‘Positive perception of treatment monitoring’. Patient accounts indicated a predominantly positive experience of lithium and quetiapine augmentation. Greater apprehension about side effects was reported for lithium prior to treatment initiation, but greater experience of negative side effects was reported for quetiapine. Clinical monitoring was perceived positively. Conclusion: Patient accounts suggested treatment augmentation with lithium or quetiapine was acceptable and helpful for most patients. However, anticipation and experiences of adverse side effects may prevent some patients from benefitting from these treatments.

Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.

Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of 'difficult-to-treat depression' (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments. ispartof: PSYCHOLOGICAL MEDICINE vol:52 issue:3 pages:419-432 ispartof: location:England status: published

Bipolar and psychotic disorders are relatively common and likely to have a significant impact on quality of life and functioning which, in the context of elite sport, includes a potential negative impact on sporting performance. For this narrative review article, the literature on bipolar and psychotic disorders in elite athletes was comprehensively searched, and little empirical research was found. A diagnosis of bipolar or psychotic disorders may be challenging in elite athletes because of complicating factors related to the modifying role of exercise and potential precipitating impact of substance use. Medications used to treat bipolar and psychotic disorders may have side effects particularly problematic for elite athletes. Future research should be tailored to the specific characteristics and needs of elite athletes and to the sporting context in which the disorders may arise. Specifically, further research is needed on the prevalence and incidence of these conditions in elite athletes and the impact of both the disorders and their treatments on sporting performance.

BACKGROUND Depression is a substantial health and economic burden. In approximately one-third of patients, depression is resistant to first-line treatment; therefore, it is essential to find alternative treatments. Transcranial magnetic stimulation (TMS) is a neuromodulatory treatment involving the application of magnetic pulses to the brain that is approved in the United Kingdom and the United States in treatment-resistant depression. This trial aims to compare the clinical effectiveness, cost-effectiveness, and mechanism of action of standard treatment repetitive TMS (rTMS) targeted at the F3 electroencephalogram site with a newer treatment—a type of TMS called theta burst stimulation (TBS) targeted based on measures of functional brain connectivity. This protocol outlines brain imaging acquisition and analysis for the Brain Imaging Guided Transcranial Magnetic Stimulation in Depression (BRIGhTMIND) study trial that is used to create personalized TMS targets and answer the proposed mechanistic hypotheses. OBJECTIVE The aims of the imaging arm of the BRIGhTMIND study are to identify functional and neurochemical brain signatures indexing the treatment mechanisms of rTMS and connectivity-guided intermittent theta burst TMS and to identify imaging-based markers predicting response to treatment. METHODS The study is a randomized double-blind controlled trial with 1:1 allocation to either 20 sessions of TBS or standard rTMS. Multimodal magnetic resonance imaging (MRI) is acquired for each participant at baseline (before TMS treatment) with T1-weighted and task-free functional MRI during rest used to estimate TMS targets. For participants enrolled in the mechanistic substudy, additional diffusion-weighted sequences are acquired at baseline and at posttreatment follow-up 16 weeks after treatment randomization. Core data sets of T1-weighted and task-free functional MRI during rest are acquired for all participants and are used to estimate TMS targets. Additional sequences of arterial spin labeling, magnetic resonance spectroscopy, and diffusion-weighted images are acquired depending on the recruitment site for mechanistic evaluation. Standard rTMS treatment is targeted at the F3 electrode site over the left dorsolateral prefrontal cortex, whereas TBS treatment is guided using the coordinate of peak effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. Both treatment targets benefit from the level of MRI guidance, but only TBS is provided with precision targeting based on functional brain connectivity. RESULTS Recruitment began in January 2019 and is ongoing. Data collection is expected to continue until January 2023. CONCLUSIONS This trial will determine the impact of precision MRI guidance on rTMS treatment and assess the neural mechanisms underlying this treatment in treatment-resistant depressed patients. CLINICALTRIAL ISRCTN Registry ISRCTN19674644; https://www.isrctn.com/ISRCTN19674644 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/31925

Background Treatment Resistant Bipolar Depression (TRBD) is a major contributor to the burden of disease associated with Bipolar Disorder (BD). Treatment options for people experiencing bipolar depression are limited to three interventions listed by National Institute for Health and Care: lamotrigine, quetiapine and olanzapine, of which the latter two are often not well tolerated. The majority of depressed people with BD are therefore prescribed antidepressants despite limited efficacy. This demonstrates an unmet need for additional interventions. Pramipexole has been shown to improve mood symptoms in animal models of depression, in people with Parkinson’s Disease and two proof of principle trials of pramipexole for people with BD who are currently depressed. Methods The PAX-BD study, funded by the United Kingdom (UK) National Institute for Health Research, aims to extend previous findings by assessing the efficacy, safety and health economic impact of pramipexole in addition to mood stabilisers for patients with TRBD. A randomised, double-blind, placebo controlled design is conducted in a naturalistic UK National Health Service setting. An internal pilot study to examine feasibility and acceptability of the study design is included. Participants with TRBD are screened from National Health Service secondary care services in up to 40 mental health trusts in the UK, with the aim of recruiting approximately 414 participants into a pre-randomisation phase to achieve a target of 290 randomised participants. Primary safety and efficacy measures are at 12 weeks following randomisation, with follow up of participants to 52 weeks. The primary outcome is depressive symptoms as measured by Quick Inventory for Depressive Symptomatology – Self Report. Secondary outcomes include changes in anxiety, manic symptoms, tolerability, acceptability, quality of life and cost-effectiveness. Outcome measures are collected remotely using self-report tools implemented online, and observer-rated assessments conducted via telephone. ANCOVA will be used to examine the difference in rating scale scores between treatment arms, and dependent on compliance in completion of weekly self-report measures. A mixed effects linear regression model may also be used to account for repeated measures. Trial registration ISRCTN72151939. Registered on 28 August 2019, http://www.isrctn.com/ISRCTN72151939 Protocol Version: 04-FEB-2021, Version 9.0.

OBJECTIVES Electroconvulsive therapy (ECT) is a mainstay in both acute and long-term management of difficult-to-treat depression. However, frequent acute courses of ECT or prolonged maintenance ECT treatment may increase adverse-effect burden and/or reduce patient acceptability. Therefore, we investigated the effectiveness of adjunctive vagus nerve stimulation (VNS) therapy as an alternative strategy for long-term maintenance treatment in ECT-responsive patients. METHODS This retrospective chart review identified maintenance ECT patients with unipolar (n = 5) and bipolar depression (n = 5) from 2 large hospital systems who had a history of ECT response, but the patients had significant residual incapacitating symptoms or increasing concerns regarding the burden associated with ECT and opted to receive adjunctive VNS therapy. The patients were followed for 2 years after VNS implantation. Response and remission were defined as Clinical Global Impression-Severity scale scores of ≤2 and 1, respectively, obtained at 1- and 2-year postimplantation compared with just before VNS implantation. RESULTS One-year postimplantation, 6 of 10 had responded of which 5 met remission criteria. All 10 patients benefited from adjunctive VNS therapy with either fewer hospitalizations and/or ECT sessions. Seven of 10 stopped maintenance ECT by the end of year 1; an additional patient stopped maintenance ECT by year 2. No patients required an acute course of ECT during the 2-year follow-up. There was a statistically significant reduction (P < 0.0001) in mean (SD) Clinical Global Impression-Severity scale scores between baseline (5.4 [0.51]) and the 1-year postimplantation (2.1 [1.37]) time points, and between baseline and the 2-year postimplantation (2.3 [1.16]) time points, whereas no difference existed between the 1- and 2-year postimplantation time points. CONCLUSIONS Vagus nerve stimulation therapy may be a useful maintenance strategy in patients with difficult-to-treat depression receiving maintenance ECT.

Background Individuals with treatment-resistant depression (TRD) experience a high burden of illness. Current guidelines recommend a stepped care approach for treating depression, but the extent to which best-practice care pathways are adhered to is unclear. Aims To explore the extent and nature of ‘treatment gaps’ (non-adherence to stepped care pathways) experienced by a sample of patients with established TRD (non-response to two or more adequate treatments in the current depressive episode) across three cities in the UK. Method Five treatment gaps were considered and compared with guidelines, in a cross-sectional retrospective analysis: delay to receiving treatment, lack of access to psychological therapies, delays to medication changes, delays to adjunctive (pharmacological augmentation) treatment and lack of access to secondary care. We additionally explored participant characteristics associated with the extent of treatment gaps experienced. Results Of 178 patients with TRD, 47% had been in the current depressive episode for >1 year before initiating antidepressants; 53% had received adequate psychological therapy. A total of 47 and 51% had remained on an unsuccessful first and second antidepressant trial respectively for >16 weeks, and 24 and 27% for >1 year before medication switch, respectively. Further, 54% had tried three or more antidepressant medications within their episode, and only 11% had received adjunctive treatment. Conclusions There appears to be a considerable difference between treatment guidelines for depression and the reality of care received by people with TRD. Future research examining representative samples of patients could determine recommendations for optimising care pathways, and ultimately outcomes, for individuals with this illness.

We are heartened that our consensus statement1 on difficult-to-treat depression has provoked robust debate. As pointed out by Lisa Cosgrove and colleagues,2 our proposed definition and model of care for difficult-to-treat depression is not derived from a systematic review or a Delphi technique. The term difficult-to-treat depression had previously been proposed to address semantic and conceptual issues with the so-called treatment-resistant depression model, for patients where achieving sustained remission proves elusive.3 We aimed to extend the discussion regarding this proposal, focusing on practical clinical advice. As the concept of difficult-to-treat depression is new, there is no literature to systematically review. The literature around the management of so-called treatment-resistant depression has been reviewed on many occasions, but this literature was only of partial relevance to our aims. Not only is there no universally accepted definition of treatment-resistant depression, but those that are used rarely if ever take into account psychotherapeutic or neurostimulatory treatments, or how to account for differential efficacy among treatments.4, 5 At the core of the proposed difficult-to-treat depression model is the importance of taking a holistic approach and considering all treatment options available. A systematic review of all treatments for depression was not practical. As a result, our consensus was based on the culmination of extensive discussion and deliberation among 15 international experts in the management of depression from across three continents, and the national guidelines for the treatment of depression from the countries represented. Rather than through a Delphi technique, we arrived at a consensus through many iterative reviews of the manuscript until all 15 contributors were comfortable with all the statements being discussed. However, we wish to clarify two key points that we feel Cosgrove and colleagues might have misunderstood.

The structure of stakeholder networks impacts the ability for environmental governance to fulfil core functions: share information; agree on problem framing and actions; and resolve conflict. Managing pest and disease incursions presents particular challenges. Rapid coordination of action is needed in times of crisis, but any hope of success during crisis requires a foundation of ongoing communication and surveillance. Recent Australian strategic planning for marine biosecurity identified the critical role of an independent national marine pest network in providing ongoing communication. We surveyed stakeholders in the existing marine pest network to map how they share information. Constructing a multilevel, directed network, with 304 organizations and 12 policy forums, we applied statistical network theory to identify which subnetwork configuration patterns were present more or less than by chance. We mapped configurations against how they shape the network's propensity for information sharing. What we found was a marine pest network with a predisposition for bridging; evidence of hubs for both provision and receiving of information; and organizations reporting greater levels of information provision to others compared to receiving information. Our assessment is that the network is well structured for top-down information provision, but that a more sustainable network will require attention to building two-way communication particularly with community groups.

BackgroundAs uncertainty remains about whether clinical response influences cognitive function after electroconvulsive therapy (ECT) for depression, we examined the effect of remission status on cognitive function in depressed patients 4 months after a course of ECT.MethodA secondary analysis was undertaken on participants completing a randomised controlled trial of ketamine augmentation of ECT for depression who were categorised by remission status (MADRS ⩽10 v. >10) 4 months after ECT. Cognition was assessed with self-rated memory and neuropsychological tests of anterograde verbal and visual memory, autobiographical memory, verbal fluency and working memory. Patients were assessed through the study, healthy controls on a single occasion, and compared using analysis of variance.ResultsAt 4-month follow-up, remitted patients (N = 18) had a mean MADRS depression score of 3.8 (95% CI 2.2–5.4) compared with 27.2 (23.0–31.5) in non-remitted patients (N = 19), with no significant baseline differences between the two groups. Patients were impaired on all cognitive measures at baseline. There was no deterioration, with some measures improving, 4-months after ECT, at which time remitted patients had significantly improved self-rated memory, anterograde verbal memory and category verbal fluency compared with those remaining depressed. Self-rated memory correlated with category fluency and autobiographical memory at follow-up.ConclusionsWe found no evidence of persistent impairment of cognition after ECT. Achieving remission improved subjective memory and verbal memory recall, but other aspects of cognitive function were not influenced by remission status. Self-rated memory may be useful to monitor the effects of ECT on longer-term memory.

A number of effective maintenance medication options exist for bipolar disorder (BD) and these are regarded as the foundation of long-term treatment in BD. However, nonadherence to medication is common in BD. For example, a large data base study in the United States of America (USA) showed that approximately half of patients with BD were nonadherent with lithium and maintenance medications over a 12 month period. Such nonadherence carries a high risk of relapse due to the recurrent nature of the illness and the fact that abrupt cessation of treatment, particularly lithium, may cause rebound depression and mania. Indeed, medication nonadherence in BD is associated with significantly increased risks of relapse, recurrence, hospitalization and suicide attempts and a decreased likelihood of achieving remission and recovery, as well as with higher overall treatment costs. Factors associated with nonadherence include adverse effects of medication, complex medication regimens, negative patient attitudes to medication, poor insight, rapid-cycling BD, comorbid substance misuse and a poor therapeutic alliance. Clinicians should routinely enquire about nonadherence in a nonjudgmental fashion. Potential steps to improve adherence include simple pragmatic strategies related to prescribing including shared decision-making, psychoeducation with a clear focus on adherence, reminders (traditional and digital), potentially using a depot rather than an oral antipsychotic, managing comorbid substance misuse and improving therapeutic alliance. Financial incentives have been shown to improve adherence to depot antipsychotics, but this approach raises ethical issues and its long-term effectiveness is unknown. Often a combination of approaches will be required. The strategies that are adopted need to be patient specific, reflecting that nonadherence has no single cause, and chosen by the patient and clinician working together.

Summary Background The use of electroconvulsive therapy (ECT) is limited by concerns about its cognitive adverse effects. Preliminary evidence suggests that administering the glutamate antagonist ketamine with ECT might alleviate cognitive adverse effects and accelerate symptomatic improvement; we tested this in a randomised trial of low-dose ketamine. Methods In this multicentre, randomised, parallel-group study in 11 ECT suites serving inpatient and outpatient care settings in seven National Health Service trusts in the North of England, we recruited severely depressed patients, who were diagnosed as having unipolar or bipolar depressive episodes defined as moderate or severe by DSM-IV criteria, aged at least 18 years, and were able and willing to provide written consent to participate in the study. Patients were randomly assigned (1:1) to ketamine (0·5 mg/kg intravenous bolus) or saline adjunctive to the anaesthetic for the duration of their ECT course. Patients and assessment and ECT treatment teams were masked to treatment allocation, although anaesthetists administering the study medication were not. We analysed the primary outcome, Hopkins Verbal Learning Test-Revised delayed verbal recall (HVLT-R-DR) after four ECT treatments, using a Gaussian repeated measures model in all patients receiving the first ECT treatment. In the same population, safety was assessed by adverse effect monitoring. This trial was registered with International Standard Randomised Controlled Trial Number, number ISRCTN14689382. Findings Between early December, 2012, and mid-June, 2015, 628 patients were screened for eligibility, of whom 79 were randomly assigned to treatment (40 in the ketamine group vs 39 in the saline group). Ketamine (mean 5·17, SD 2·92), when compared with saline (5·54, 3·42), had no benefit on the primary outcome (HVLT-R-DR; difference in means −0·43 [95% CI −1·73 to 0·87]). 15 (45%) of 33 ketamine-treated patients compared with 10 (27%) of 37 patients receiving saline experienced at least one adverse event which included two (6%) of 33 patients who had ketamine-attributable transient psychological effects. Psychiatric adverse events were the most common in both groups (six [27%] of 22 adverse events in the ketamine group vs seven [54%] of 13 in the saline group). Interpretation No evidence of benefit for ketamine was found although the sample size used was small; however, the results excluded greater than a small to moderate benefit with 95% confidence. The results do not support the use of adjunctive low-dose ketamine in routine ECT treatment. Funding National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme, an MRC and NIHR partnership.

Governance of the environment and natural resources involves interests of multiple stakeholders at different scales. In community-based forest management, organisations outside of communities play important roles in achieving multiple social and ecological objectives. How and when these organisations play a role in the community-based forest management process remains a key question. We applied social network analysis to a case study in Indonesian Borneo to better understand the evolution of interactions between organisational actors, and with communities. NGOs featured most prominently in initiating the permit process, implementing management, and providing other support activities, while also being well-connected to donors and government actors. The network configurations indicated significant cooperation among organisations when initiating the community forest process, while bridging between village and organisational levels characterised all stages of the community forest process. While community-based forest management often evokes images of grassroots efforts and broad local capacity to manage forests, reality shows a more dynamic and heterogeneous picture and broader involvement of different actor types and motivations in Indonesia. These findings can be applied to other countries implementing and expanding their decentralised forest policies.

Background: Reduced frontal cortex metabolism and blood flow in depression may be associated with low mood and cognitive impairment. Further reduction has been reported during a course of electroconvulsive therapy but it is not known if this relates to mood and cognitive changes caused by electroconvulsive therapy. Aims: The purpose of this study was to investigate frontal function while undertaking cognitive tasks in depressed patients compared with healthy controls, and following electroconvulsive therapy in patients. Methods: We measured frontal haemodynamic responses to a category verbal fluency task and a working memory N-back task using portable functional near infra-red spectroscopy (fNIRS) in 51 healthy controls and 18 severely depressed patients, 12 of whom were retested after the fourth treatment of a course of electroconvulsive therapy. Mood was assessed using the Montgomery Åsberg Depression Rating Scale and cognitive function using category Verbal Fluency from the Controlled Oral Word Association Test and Digit Span backwards. Results: Compared to healthy controls, depressed patients had bilaterally lower frontal oxyhaemoglobin responses to the cognitive tasks, although this was only significant for the N-Back task where performance correlated inversely with depression severity in patients. After four electroconvulsive therapy treatments oxyhaemoglobin responses were further reduced during the Verbal Fluency task but the changes did not correlate with mood or cognitive changes. Discussion: Our results confirmed a now extensive literature showing impaired frontal fNIRS oxyhaemoglobin responses to cognitive tasks in depression, and showed for the first time that these are further reduced during a course of electroconvulsive therapy. Further research is needed to investigate the biology and clinical utility of frontal fNIRS in psychiatric patients.

Summary Background Many patients with major depressive disorder have treatment-resistant depression, defined as no adequate response to two consecutive courses of antidepressants. Some evidence suggests that antiglucocorticoid augmentation of antidepressants might be efficacious in patients with major depressive disorder. We aimed to test the proof of concept of metyrapone for the augmentation of serotonergic antidepressants in the clinically relevant population of patients with treatment-resistant depression. Methods This double-blind, randomised, placebo-controlled trial recruited patients from seven UK National Health Service (NHS) Mental Health Trusts from three areas (northeast England, northwest England, and the Leeds and Bradford area). Eligible patients were aged 18–65 years with treatment-resistant depression (Hamilton Depression Rating Scale 17-item score of ≥18 and a Massachusetts General Hospital Treatment-Resistant Depression staging score of 2–10) and taking a single-agent or combination antidepressant treatment that included a serotonergic drug. Patients were randomly assigned (1:1) through a centralised web-based system to metyrapone (500 mg twice daily) or placebo, in addition to their existing antidepressant regimen, for 21 days. Permuted block randomisation was done with a block size of two or four, stratified by centre and primary or secondary care setting. The primary outcome was improvement in Montgomery-Asberg Depression Rating Scale (MADRS) score 5 weeks after randomisation, analysed in the modified intention-to-treat population of all randomly assigned patients that completed the MADRS assessment at week 5. The study has an International Standard Randomised Controlled Trial Number (ISRCTN45338259) and is registered with the EU Clinical Trial register, number 2009-015165-31. Findings Between Feb 8, 2011, and Dec 10, 2012, 165 patients were recruited and randomly assigned (83 to metyrapone and 82 to placebo), with 143 (87%) completing the primary outcome assessment (69 [83%] in the metyrapone and 74 [90%] in the placebo group). At 5 weeks, MADRS score did not significantly differ between groups (21·7 points [95% CI 19·2–24·4] in the metyrapone group vs 22·6 points [20·1–24·8] in the placebo group; adjusted mean difference of −0·51 points [95% CI −3·48 to 2·46]; p=0·74). 12 serious adverse events were reported in four (5%) of 83 patients in the metyrapone group and six (7%) of 82 patients in the placebo group, none of which were related to study treatment. 134 adverse events occurred in 58 (70%) patients in the metyrapone group compared with 95 events in 45 (55%) patients in the placebo group, of which 11 (8%) events in the metyrapone group and four (4%) in the placebo group were judged by principle investigators at the time of occurrence to be probably related to the study drug. Interpretation Metyrapone augmentation of antidepressants is not efficacious in a broadly representative population of patients with treatment-resistant depression within the NHS and therefore is not an option for patients with treatment-resistant depression in routine clinical practice at this time. Further research is needed to clarify if such augmentation might benefit subpopulations with demonstrable hypothalamic–pituitary–adrenal axis abnormalities. Funding Efficacy and Mechanism Evaluation (EME) programme, a UK Medical Research Council and National Institute for Health Research partnership.

The distribution of risk of coastal inundation, and the potential benefits of adapting to protect against inundation, vary greatly both within and between coastal communities. This diversity is a result of physical factors, such as the risk of storm surge, sea level rise projections, and the topography of the landscape, as well as socio-economic factors, such as the level of development, and the capacity within the community to adapt. Despite this strong local variation, various communities share common characteristics that constrain or enable different adaptation options in different situations. Understanding these drivers is likely to be important in engaging coastal communities in the discussion around adaptation and may provide new insights into which adaptation options are suitable for each of our at-risk coastal communities. We performed a property-level analysis of 6 suburb-sized case studies distributed along the coast of Queensland, Australia. We assessed the potential economic costs of inundation events now and in the future under sea level rise projections, and the potential avoided costs following adaptation to protect against inundation. We went beyond this to estimate the distribution of risk in each community and compared the potential costs of adaptation with the capacity of the community to pay for their implementation. We used these insights to propose a typology of coastal communities based on their exposure to total inundation risk, the distribution of that risk within the community, and their capacity to adapt.

In delivering public policy, governments worldwide increasingly partner with diverse sets of stakeholders. This spreads commercial risk, but particularly where agendas diverge, introduces new risks related to trust in relationships. The “risk hypothesis” distinguishes between networks for “cooperation” problems, where partners have high individual payoffs for uncooperative behaviors, and “coordination” problems, where partners subscribe to a common goal and uncooperative behaviors are less rewarding. We used mixed-methods to study networks of local and state government, developers, and consultants that center on joint-venture partnerships for developing new urban, residential projects. Statistical network methods showed that within the mix of partners involved in development projects, only state governments displayed structural patterns associated with solving “cooperation” problems (rather than coordination). In other words, the patterns of state government interactions showed they are most exposed to risky relationships. In contrast to the state governments’ apparent exposure to risk, qualitative data showed they are not only well trusted but also overall the partnership networks reported very low levels of conflict. By exploring the distribution of “cooperation” and “coordination,” we identified which stakeholders perceived most risk. In our case, how the state governments’ structure interactions in response to risky relationships leads to an overall network characterized by trust.

Episodic memory is a complex memory system which allows recall and mental re-experience of previous episodes from one's own life. Real-life episodic memories are about events in their spatiotemporal context and are typically visuospatial, rather than verbal. Yet often, tests of episodic memory use verbal material to be recalled (word lists, stories). The Real-World What-Where-When memory test requires participants to hide a total of 16 different objects in 16 different locations over two temporal occasions, 2 h apart. Another two hours later, they are then asked to recall which objects (What) they had hidden in which locations (Where) and on which of the two occasions (When). In addition to counting the number of correctly recalled complete what-where-when combinations, this task can also be used to test real-world spatial memory and object memory. This task is sensitive to normal cognitive aging, and correlates well with performance on other episodic memory tasks, while at the same time providing more ecological validity and being cheap and easy to run.

BackgroundElectroconvulsive therapy (ECT) is the most effective acute treatment for severe depression, but there are concerns about its adverse cognitive effects. ECT may impair cognition through stimulation of glutamate receptors, and preliminary evidence has suggested that ketamine, a glutamate antagonist, may alleviate these effects. Ketamine has been shown to have a rapid, but temporary, antidepressant effect after a single infusion.ObjectiveTo determine the efficacy and safety of adjunctive low-dose ketamine to reduce cognitive impairments caused by ECT and, secondarily, to improve symptomatic outcome.DesignMulticentre, two-arm, parallel-group, patient-randomised, placebo-controlled superiority trial.SettingEleven ECT suites based in seven NHS trusts in the north of England.ParticipantsSeverely depressed hospitalised patients or outpatients who received ECT as part of their usual clinical care.InterventionsPatients were randomised to ketamine (0.5 mg/kg) or saline as an adjunct to their anaesthetic for their ECT course in a 1 : 1 ratio.Main outcome measuresThe primary outcome was delayed verbal recall on the Hopkins Verbal Learning Task – Revised (HVLT-R) after four ECT treatments (mid-ECT), analysed using a Gaussian repeated measures model. Secondary outcomes included autobiographical, working and visual memory and verbal fluency, symptoms and quality of life; assessments occurred at mid-ECT, end of treatment and 1 and 4 months after the last ECT. Neuropsychological function was compared with that of healthy control subjects and a functional near-infrared spectroscopy (fNIRS) substudy investigated prefrontal cortex function. A patient survey of study participation was carried out.ResultsSeventy-nine severely depressed patients were randomised to ketamine (0.5 mg/kg) or saline as an adjunct to their anaesthetic for their ECT course; the modified intention-to-treat sample included 70 patients. Compared with saline, adjunctive ketamine had no significant effect on HVLT-R delayed recall [treatment effect difference –0.43, 95% confidence interval (CI) –1.73 to 0.87], other neuropsychological outcomes, improvement in depression [difference in Montgomery–Åsberg Depression Rating Scale (MADRS) score of 0.44, 95% CI –1.03 to 1.91], the number of ECT treatments to remission (MADRS score of ≤ 10: 0.83, 95% CI –3.2 to 4.9), anxiety symptoms or quality of life. By the end of ECT treatment, 37% (saline 35%, ketamine 39%) of patients had remitted. Tolerability was similar in the two treatment arms; two patients had isolated transient psychological effects attributable to ketamine. Preliminary fNIRS analysis found that patients had blunted prefrontal cortical haemodynamic responses compared with control subjects during a verbal fluency task at baseline; this was further diminished at mid-ECT without modulation by ketamine. Greater haemodynamic responsivity to ECT appeared to be associated with a better clinical response. The majority of patients surveyed reported a positive experience of study participation.ConclusionsThe results of the study do not support the use of adjunctive ketamine in routine ECT treatment in the NHS. Although no evidence of benefit was found for ketamine, moderate benefits or harms cannot be excluded, as recruitment was Trial registrationCurrent Controlled Trials ISRCTN14689382.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

This paper takes inspiration from the field of bio-mimicry to suggest what a plant biosecurity system might look like if it was modelled on the human immune system. We suggest structural and institutional changes to current biosecurity systems that would facilitate adaptive preparation and response policies, focusing particularly on the Australian plant biosecurity system. By improving information exchanges, interpretation and managing overlapping complementary response capabilities of this system, novel policies emerge that increase resilience to harmful weeds, pests and diseases. This is achieved by adding an element of flexibility in invasion response to cope with different circumstances and contexts, rather than a 'one size fits all' approach. While we find bio-mimicry to be a potentially useful system design tool, there are key differences between the immune and biosecurity systems that the analogy makes clear. Perhaps the most important of these stems from the inability of immune systems to imagine future threats. (C) 2014 Elsevier Ltd. All rights reserved. (Less)

Large-scale conservation requires the involvement of numerous stakeholders to plan for and implement a range of activities across multiple scales. Establishing and sustaining the effective collaborations necessary to achieve this is a key challenge. Utilizing data from a large-scale conservation initiative in the south west of Australia we characterize the interactions between stakeholders as a social network. We employ a novel network theoretical approach to assess the different forms of collaboration, including cross-scale collaboration. We find that the social network predisposes cross-scale collaboration for invasive animal control, an action where coordination of activities is necessary. We find that for revegetation activities there is little evidence of collaboration across scales, but this could be fostered by a subset of stakeholders acting in a “scale-bridging” role. Addressing this will likely improve the effectiveness of revegetation efforts and the outcomes of the broader conservation initiative.

Rangelands encompass 30–40% of Earth's land surface and support 1 to 2 billion people. Their predominant use is extensive livestock production by pastoralists and ranchers. But rangelands are characterized by ecological, economic, and political marginality, and higher value, more intensive land uses are impinging on rangelands around the world. Earth Stewardship of rangelands must address both livestock management and the broader socioecological dynamics that promote land-use changes, fragmentation, and degradation. We identify specific gradients on which human–rangeland systems can be arrayed, including issues of variability, adaptation to disturbance, commercialization, land-use change, land-tenure security, and effective governance, and we illustrate the gradients' interactions and effects in sites worldwide. The result is a synthetic framework to help in understanding how rangeland Earth Stewardship can be achieved in the face of marginality, globalization, and climate change.