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Tranexamic acid (TXA) is commonly used in upper and lower limb arthroplasty to limit blood loss and postoperative hematoma formation. The role of TXA in rotator cuff repair (RCR) surgery is less defined. This trial assessed the effect of preoperative TXA on early postoperative pain scores.A randomized double-blind trail was conducted in 89 patients undergoing RCR. Patients were randomized to either 2 g of intravenous TXA or placebo at induction. The primary outcome was visual analog scale (VAS)-pain score at day 3 postoperation, with secondary outcomes including VAS-pain, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), and Constant scores at 2, 8, 24, and 52 weeks.There was no significant difference in VAS-pain scores between groups at day 3 postoperation. Pain scores were significantly better in the TXA group at 8 weeks. There was no difference between groups at any time point in the ASES or Constant score. The TXA group had improved motion at 6 months with a reduced rate of secondary adhesive capsulitis.TXA did not improve postoperative pain scores after RCR, however, patients who received the intervention demonstrated greater range of motion at 6 months with lower rates of secondary adhesive capsulitis.

Late-life depression (LLD) has been linked to increased likelihood of subsequent dementia, although mechanisms responsible for this association remain largely unknown. One feature frequently observed in both LLD and dementia is elevated levels of plasma inflammatory markers. PRODE (Prognosis of Depression in the Elderly) is a prospective naturalistic study of patients with LLD (N=152; aged 60+). Patients were followed up for 3 years; follow-up data was available for 138 patients, and 36 (26.1%) developed dementia by year 3. Plasma inflammatory markers data were available for 136 patients at baseline for the following range of cytokines and chemokines: IL-1β, IL-1ra, IL-6, IL-10, IL-17a, IL-18, IL-33, TNFα, CD40L, IFN-γ, CCL-2 and CCL-4. Levels of plasma inflammatory markers were compared between 136 LLD patients and healthy controls (n=103), using first multiple linear regression (inflammatory markers as outcome) with stepwise adjustment, and then binary logistic regression with depression status (LLD vs controls) as outcome. Further, we explored whether inflammatory markers and clinical characteristics of LLD (age of onset, course) predicted progression from LLD to dementia using Cox regression. Levels of IL-1ra, IFN-γ, CCL-2, CCL-4 and IL-17a were significantly higher in LLD patients compared to controls. However, none of the inflammatory markers predicted progression from LLD to dementia. Among clinical features, only poor response to treatment significantly predicted higher risk of progression to dementia. In summary, this study replicated previous findings of an increase in inflammatory markers in LLD but did not find evidence they had increased risk of developing future dementia.

IntroductionObstructive sleep apnoea (OSA) is a multisystem, debilitating, chronic disorder of breathing during sleep, resulting in a relatively consistent pattern of cognitive deficits. More recently, it has been argued that those cognitive deficits, especially in middle-aged patients, may be driven by cardiovascular and metabolic comorbidities, rather than by distinct OSA-processes, such as are for example ensuing nocturnal intermittent hypoxaemia, oxidative stress, neuroinflammation, and sleep fragmentation.MethodsThus, we undertook to define cognitive performance in a group of 27 middle-aged male patients with untreated OSA, who had no concomitant comorbidities, compared with seven matched controls (AHI mean ± S.D.: 1.9 ± 1.4 events/h; mean age 34.0 ± 9.3 years; mean BMI 23.8 ± 2.3 kg/m2). Of the 27 patients, 16 had mild OSA (AHI mean ± S.D.:11.7 ± 4.0 events/h; mean age 42.6 ± 8.2 years; mean BMI 26.7 ± 4.1 kg/m2), and 11 severe OSA (AHI 41.8 ± 20.7 events/h; age: 46.9 ± 10.9 years, BMI: 28.0 ± 3.2 kg/m2).ResultsIn our patient cohort, we demonstrate poorer executive-functioning, visuospatial memory, and deficits in vigilance sustained attention, psychomotor and impulse control. Remarkably, we also report, for the first time, effects on social cognition in this group of male, middle-aged OSA patients.ConclusionOur findings suggest that distinct, OSA-driven processes may be sufficient for cognitive changes to occur as early as in middle age, in otherwise healthy individuals.

SUMMARYThis review highlights some of the recent advances in the psychopharmacology of major depressive disorder (MDD). We synthesise evidence on emerging pharmacological therapies targeting the serotonergic system, before exploring several novel treatment targets: the glutamatergic system, the GABAergic system and inflammation. When describing new treatment avenues, we examine the evidence base and how far these new treatments are from routine practice.

Importance: Major depressive disorder (MDD) is a heterogeneous clinical syndrome with widespread subtle neuroanatomical correlates. Identifying neuroimaging-based biomarkers might aid in defining the disease-related dimensions that characterize MDD and predict treatment response. Objective: To investigate the neuroanatomical dimensions that characterize MDD and predict treatment response to selective serotonin reuptake inhibitor (SSRI) antidepressant or placebo. Design: Big data consortium (COORDINATE-MDD) sharing raw MRI data in first episode and recurrent MDD, deep clinical phenotyping, and state-of-the art machine learning analysis, involving harmonization of multi-center MRI data and the application of semi-supervised machine learning clustering, HYDRA, to regional brain volumes. Setting: International, multi-center, community-based MDD and healthy controls. Participants: International sample (N=1384), consisting of medication-free, first episode and recurrent MDD individuals (N=685) in a current depressive episode of moderate to severe intensity, that is not treatment resistant depression, and healthy controls (N=699). Prospective longitudinal treatment response data were available in a subset of MDD individuals (N=359 MDD). Treatments were SSRI antidepressant medication (escitalopram, citalopram, sertraline) or placebo. Treatment duration was 6-8 weeks, and symptom severity was measured by clinician-rated scales. Main outcomes: First episode and recurrent MDD is optimally characterized by two neuroanatomical dimensions, which show distinct treatment effects to placebo and SSRI antidepressant medications. Results: Dimension 1 is characterized by preserved gray and white matter (N=290 MDD), whereas Dimension 2 is characterized by widespread subtle reductions in gray and white matter (N=395 MDD) relative to healthy controls. There are no significant differences in age of onset, years of illness, number of episodes, or duration of current episode between dimensions, but there is a significant dimension by treatment response interaction effect. Dimension 1 shows a significant decrease in depressive symptoms following treatment with SSRI medication (51.1%) but limited changes following placebo (28.6%), whereas Dimension 2 shows a comparable improvement to either SSRI (46.9%) or placebo (42.2%) (β=-18.3, 95% CI (-0.34 to -0.2), p=0.03). Conclusions and Relevance: Neuroimaging-based markers may aid in characterizing the MDD dimensions that predict treatment response. In an iterative process, we can characterize the disease-based dimensions that comprise MDD.

• Background: Major Depression represents a pressing challenge for health care. In England, Increasing Access to Psychological Therapies (IAPT) services provide evidence-based psychological therapies in a stepped care approach to patients with depression. While introduction of these services has successfully increased access to therapy, estimates suggest that about 50 percent of depressed patients who have come to the end of the IAPT pathway still show significant levels of symptoms. This study will investigate whether Mindfulness-Based Cognitive Therapy (MBCT), a group intervention combining training in mindfulness meditation and elements from cognitive therapy, can have beneficial effects in depressed patients who have not responded to high-intensity therapy in IAPT. It will seek to establish the effectiveness and cost-effectiveness of MBCT as compared to the treatment these patients would usually receive. • Methods: In a 2-arm randomised controlled trial, patients who currently meet criteria for Major Depressive Disorder and who have not sufficiently responded to at least 12 sessions of IAPT high-intensity therapy will be allocated, at a ratio of 1:1, to receive either MBCT (in addition to treatment as usual [TAU]) or continue with TAU only. Assessments will take place at baseline, 10-weeks and 34-weeks post-randomisation. The primary outcome will be reduction in depression symptomatology 34 weeks post-randomisation as assessed using the Public Health Questionnaire-9 (PHQ-9). Secondary outcomes will include depressive symptomatology at 10-weeks post-randomisation and other clinical outcomes measured at 10-week and 34-week follow-up, along with a series of binarized outcomes to indicate clinically significant and reliable change. Evaluations of cost-effectiveness will be based on assessments of service use costs collected using the Adult Service Use Schedule and health utilities derived from the EQ-5D. • Discussion: This trial will add to the evidence-base for the use of MBCT in depressed treatment non-responders. It will constitute the first trial to test MBCT following non-response to psychological therapy, with results providing a direct estimate of efficacy within the IAPT pathway. As such, its results will offer an important basis for decisions regarding the adoption of MBCT for non-responders within IAPT. • Trial registration: ClinicalTrials.gov NCT05236959, 11.02.2022; ISRCTN: 17755571, 02.02.2021

Bipolar disorder is heterogeneous in phenomenology, illness trajectory, and response to treatment. Despite evidence for the efficacy of multimodal-ity interventions, the majority of persons affected by this disorder do not achieve and sustain full syndromal recovery. It is eagerly anticipated that combining datasets across various information sources (e.g., hierarchical "multi-omic" measures, electronic health records), analyzed using advanced computational methods (e.g., machine learning), will inform future diagnosis and treatment selection. In the interim, identifying clinically meaningful subgroups of persons with the disorder having differential response to specific treatments at point-of-care is an empirical priority. This paper endeavours to synthesize salient domains in the clinical characterization of the adult patient with bipolar disorder, with the overarching aim to improve health outcomes by informing patient management and treatment considerations. Extant data indicate that characterizing select domains in bipolar disorder provides actionable information and guides shared decision making. For example, it is robustly established that the presence of mixed features - especially during depressive episodes - and of physical and psychiatric comorbidities informs illness trajectory, response to treatment, and suicide risk. In addition, early environmental exposures (e.g., sexual and physical abuse, emotional neglect) are highly associated with more complicated illness presentations, inviting the need for developmentally-oriented and integrated treatment approaches. There have been significant advances in validating subtypes of bipolar disorder (e.g., bipolar I vs. II disorder), particularly in regard to pharmacological interventions. As with other severe mental disorders, social functioning, interpersonal/family relationships and internalized stigma are domains highly relevant to relapse risk, health outcomes, and quality of life. The elevated standardized mortality ratio for completed suicide and suicidal behaviour in bipolar disorder invites the need for characterization of this domain in all patients. The framework of this paper is to describe all the above salient domains, providing a synthesis of extant literature and recommendations for decision support tools and clinical metrics that can be implemented at point-of-care.

ObjectivesTo develop and probe the first computerised decision-support tool to provide antidepressant treatment guidance to general practitioners (GPs) in UK primary care.DesignA parallel group, cluster-randomised controlled feasibility trial, where individual participants were blind to treatment allocation.SettingSouth London NHS GP practices.ParticipantsTen practices and eighteen patients with treatment-resistant current major depressive disorder.InterventionsPractices were randomised to two treatment arms: (a) treatment-as-usual, (b) computerised decision support tool.ResultsTen GP practices participated in the trial, which was within our target range (8–20). However, practice and patient recruitment were slower than anticipated and only 18 of 86 intended patients were recruited. This was due to fewer than expected patients being eligible for the study, as well as disruption resulting from the COVID-19 pandemic. Only one patient was lost to follow-up. There were no serious or medically important adverse events during the trial. GPs in the decision tool arm indicated moderate support for the tool. A minority of patients fully engaged with the mobile app-based tracking of symptoms, medication adherence and side effects.ConclusionsOverall, feasibility was not shown in the current study and the following modifications would be needed to attempt to overcome the limitations found: (a) inclusion of patients who have only tried one Selective Serotonin Reuptake Inhibitor, rather than two, to improve recruitment and pragmatic relevance of the study; (b) approaching community pharmacists to implement tool recommendations rather than GPs; (c) further funding to directly interface between the decision support tool and self-reported symptom app; (d) increasing the geographic reach by not requiring detailed diagnostic assessments and replacing this with supported remote self-report.Trial registration numberNCT03628027.

Zinc transporter 3 (ZnT3) has been implicated in the aetiopathology of schizophrenia. In this pilot study, we tested the hypothesis that the presence of a minor allele of two variants in the gene encoding ZnT3 (SLC30A3) affects brain glutamate and cognitive activity in patients with schizophrenia and bipolar affective disorder. Fifteen patients with schizophrenia (SCZ), 15 with bipolar affective disorder type 2 (BD), and 14 healthy volunteers (HV) were genotyped for two SLC30A3 single nucleotide polymorphisms (rs11126936 and rs11126929). They also underwent structural and functional MRI (n-back) imaging as well as static (PRESS) and functional magnetic resonance spectroscopy (n-back) on a 3 Tesla MRI system. SCZ with at least one copy of the minor allele showed reductions in dorsal anterior cingulate cortex glutamate during the n-back task, whereas SCZ without the minor allele showed an increase in glutamate. BD with the minor allele had reduced glutamate in the anterior cingulate cortex (p < 0.05). There was no effect of SLC30A3 genotype on BOLD activation during n-back or on cortical brain volume. This study supports the further investigation of SLC30A3 and its role in glutamatergic neurotransmission and in the neuropathology of mental illness.

Background: Psilocybin-containing mushrooms are used for recreational, spiritual, self-development and therapeutic purposes. However, physiologically relatively nontoxic, adverse reactions are occasionally reported. Aims: This study investigated the 12-month prevalence and nature of magic mushroom-related adverse reactions resulting in emergency medical treatment seeking in a global sample of people reporting magic mushroom use. Methods: We use data from the 2017 Global Drug Survey – a large anonymous online survey on patterns of drug use conducted between November 2016 and January 2017. Results: Out of 9233 past year magic mushroom users, 19 (0.2%) reported having sought emergency medical treatment, with a per-event risk estimate of 0.06%. Young age was the only predictor associated with higher risk of emergency medical presentations. The most common symptoms were psychological, namely anxiety/panic and paranoia/suspiciousness. Poor ‘mindset’, poor ‘setting’ and mixing substances were most reported reasons for incidents. All but one respondent returned back to normality within 24 h. Conclusions: The results confirm psilocybin mushrooms are a relatively safe drug, with serious incidents rare and short lasting. Providing harm-reduction information likely plays a key role in preventing adverse effects. More research is needed to examine the detailed circumstances and predictors of adverse reactions including rarer physiological reactions.

N-Arylindoles are transformed into dihydroacridines in a new type of rearrangement, through heating with triethylsilane and potassium tert-butoxide. Studies indicate that the pathway involves (i) the formation of indole radical anions followed by fragmentation of the indole C2–N bond, and (ii) a ring-closing reaction that follows a potassium-ion dependent hydrogen atom transfer step. Unexpected behaviors of ‘radical-trap’ substrates prove very helpful in framing the proposed mechanism., N-Arylindoles are transformed into dihydroacridines in a new type of rearrangement, through heating with triethylsilane and potassium tert-butoxide.

SummaryThere are many structural problems facing the UK at present, from a weakened National Health Service to deeply ingrained inequality. These challenges extend through society to clinical practice and have an impact on current mental health research, which was in a perilous state even before the coronavirus pandemic hit. In this editorial, a group of psychiatric researchers who currently sit on the Academic Faculty of the Royal College of Psychiatrists and represent the breadth of research in mental health from across the UK discuss the challenges faced in academic mental health research. They reflect on the need for additional investment in the specialty and ask whether this is a turning point for the future of mental health research.

ObjectivesTo test the hypothesis that people with concurrent diagnosis of epilepsy and psychogenic nonepileptic seizures (PNES) are at increased risk of attempting suicide as compared to people with epilepsy or PNES alone. To report on suicide rates.MethodsRetrospective cohort study from the UK largest tertiary mental health care provider, with linked nationwide admission and mortality data from the Hospital Episode Statistics and Office for National Statistics. Participants were 2460 people with a primary or secondary diagnosis of epilepsy, PNES or concurrent epilepsy and PNES attending between 1 January 2007 and 18 June 2021. The primary outcome was a first hospital admission for suicide attempt (International Classification of Diseases, version 10 X60–X84).Results9% of participants had at least one suicide attempt-related hospital admission. For people with concurrent diagnosis of epilepsy and PNES, the odds for suicide attempt-related admissions were 2.52 times the odds of people with epilepsy alone (OR 0.40; 95% CI 0.21 to 0.79; p=0.01). Odds were comparable between people with concurrent diagnosis and people with PNES alone (OR 0.75; 95% CI 0.41 to 1.48; p=0.40). Post hoc analyses revealed that the odds of people with PNES alone were 1.93 times the odds of people with epilepsy alone (OR 0.52; 95% CI 0.38 to 0.70; pConclusionsPeople with concurrent diagnosis of epilepsy and PNES or PNES alone have significantly increased odds of hospitalisation due to suicide attempt as compared to people with epilepsy alone (152% and 93% increase, respectively). These findings have direct implications for the clinical management of suicide risk in people with epilepsy.