Clinical and cost-effectiveness of contingency management for cannabis use in early psychosis: the CIRCLE randomised clinical trial.

BACKGROUND: Cannabis is the most commonly used illicit substance amongst people with psychosis. Continued cannabis use following the onset of psychosis is associated with poorer functional and clinical outcomes. However, finding effective ways of intervening has been very challenging. We examined the clinical and cost-effectiveness of adjunctive contingency management (CM), which involves incentives for abstinence from cannabis use, in people with a recent diagnosis of psychosis. METHODS: CIRCLE was a pragmatic multi-centre randomised controlled trial. Participants were recruited via Early Intervention in Psychosis (EIP) services across the Midlands and South East of England. They had had at least one episode of clinically diagnosed psychosis (affective or non-affective); were aged 18 to 36; reported cannabis use in at least 12 out of the previous 24 weeks; and were not currently receiving treatment for cannabis misuse, or subject to a legal requirement for cannabis testing. Participants were randomised via a secure web-based service 1:1 to either an experimental arm, involving 12 weeks of CM plus a six-session psychoeducation package, or a control arm receiving the psychoeducation package only. The total potential voucher reward in the CM intervention was £240. The primary outcome was time to acute psychiatric care, operationalised as admission to an acute mental health service (including community alternatives to admission). Primary outcome data were collected from patient records at 18 months post-consent by assessors masked to allocation. The trial was registered with the ISRCTN registry, number ISRCTN33576045. RESULTS: Five hundred fifty-one participants were recruited between June 2012 and April 2016. Primary outcome data were obtained for 272 (98%) in the CM (experimental) group and 259 (95%) in the control group. There was no statistically significant difference in time to acute psychiatric care (the primary outcome) (HR 1.03, 95% CI 0.76, 1.40) between groups. By 18 months, 90 (33%) of participants in the CM group, and 85 (30%) of the control groups had been admitted at least once to an acute psychiatric service. Amongst those who had experienced an acute psychiatric admission, the median time to admission was 196 days (IQR 82, 364) in the CM group and 245 days (IQR 99, 382) in the control group. Cost-effectiveness analyses suggest that there is an 81% likelihood that the intervention was cost-effective, mainly resulting from higher mean inpatient costs for the control group compared with the CM group; however, the cost difference between groups was not statistically significant. There were 58 adverse events, 27 in the CM group and 31 in the control group. CONCLUSIONS: Overall, these results suggest that CM is not an effective intervention for improving the time to acute psychiatric admission or reducing cannabis use in psychosis, at least at the level of voucher reward offered.

Treatment of military-related post-traumatic stress disorder: challenges, innovations, and the way forward.

Post-traumatic stress disorder (PTSD) is one of the common mental disorders in military and veteran populations. Considerable research and clinical opinion has been focused on understanding the relationship between PTSD and military service and the implications for prevention, treatment, and management. This paper examines factors associated with the development of PTSD in this population, considers issues relating to engagement in treatment, and discusses the empirical support for best practice evidence-based treatment. The paper goes on to explore the challenges in those areas, with particular reference to treatment engagement and barriers to care, as well as treatment non-response. The final section addresses innovative solutions to these challenges through improvements in agreed terminology and definitions, strategies to increase engagement, early identification approaches, understanding predictors of treatment outcome, and innovations in treatment. Treatment innovations include enhancing existing treatments, emerging non-trauma-focused interventions, novel pharmacotherapy, personalized medicine approaches, advancing functional outcomes, family intervention and support, and attention to physical health.

Evaluation of a community awareness programme to reduce delays in referrals to early intervention services and enhance early detection of psychosis.

BACKGROUND: Reducing treatment delay and coercive pathways to care are accepted aims for Early Intervention Services (EIS) for people experiencing first episode psychosis but how to achieve this is unclear. A one-year community awareness programme was implemented in a London EIS team, targeting staff in non-health service community organisations. The programme comprised psycho-educational workshops and EIS link workers, and offering direct referral routes to EIS. Its feasibility and its impact on duration of untreated psychosis and pathways to EIS were evaluated. METHODS: Evaluation comprised: pre and post questionnaires with workshop participants assessing knowledge and attitudes to psychosis and mental health services; and a comparison of new service users' "service DUP"(time from first psychotic symptom to first contact with EIS) and pathways to care in the intervention year and preceding year. Focus groups sought stakeholders' views regarding the benefits and limitations of the programme and what else might promote help-seeking. RESULTS: 41 workshops at 36 community organisations were attended by 367 staff. 19 follow up workshops were conducted and 16 services were allocated an EIS link worker. Participants' knowledge and attitudes to psychosis and attitudes to mental health services improved significantly following workshops. In the year of the intervention, only 6 of 110 new service users reached EIS directly via community organisations. For all new referrals accepted by EIS, in the intervention year compared to the previous year, there was no difference in mean or median service DUP. A clear impact on pathways to care could not be discerned. Stakeholders suggested that barriers to referral remained. These included: uncertainty about the signs of early psychosis, disengagement by young people when becoming unwell, and worries about stigma or coercive treatment from mental health services. More general, youth focused, mental health services were proposed. CONCLUSIONS: The community awareness programme did not reduce treatment delays for people experiencing first episode psychosis. Further research is needed regarding effective means to reduce duration of untreated psychosis. Although EIS services are guided to promote access through community engagement, this may not be an effective use of their limited resources. TRIAL REGISTRATION: Current Controlled Trial ISRCTN98260910 Registered 19th May 2010.

Ethnic variations in compulsory detention and hospital admission for psychosis across four UK Early Intervention Services.

BackgroundSubstantial ethnic variations have been found in incidence, pathways to care and outcomes in psychosis. It is unknown whether these remain as marked in the presence of specialist Early Intervention Services (EIS) for psychosis. We present the first UK study exploring ethnic differences in compulsory detention and hospitalization rates for EIS patients. We investigated whether the excess rates of compulsory admission for people from Black groups have persisted following nationwide introduction of EIS. We also explored variations in compulsory admission for other ethnic groups, and differences by gender and diagnosis.MethodsFour inner-city London EIS teams gathered data from first-presentation psychosis patients between 2004¿2009 using the MiData audit tool. Clinical, sociodemographic and pathways to care data were recorded regarding adult patients from eight different ethnic groups at entry to EIS and one year later.ResultsBlack African EIS service users had odds of being detained and of being hospitalised three times greater than White British patients, even after adjustment for confounders. This was most marked in Black African women (seven to eight times greater odds than White British women). A post-hoc analysis showed that pathways to care and help-seeking behaviour partially explained these differences.ConclusionThese findings suggest EIS input in its current form has little impact on higher admission and detention rates in certain Black and minority groups. There is a need to tackle these differences and engage patients earlier, focusing on the needs of men and women from the most persistently affected groups.

Mental Health Reform: Design and Implementation of a System to Optimize Outcomes for Veterans and Their Families.

The social, health, and economic burden of mental health problems in the veteran community is heavy. Internationally, the array of services and support available to veterans and their families are extensive but vary in quality, are often disconnected, complex to navigate, and lack clear coordination. This paper describes a conceptual framework to guide the design and implementation of a system of services and supports to optimize the mental health and wellbeing of all veterans and their families. The framework recognizes the diversity of veterans across intersecting identities that uniquely shape experiences of posttraumatic mental health and wellbeing. It brings together several strands of research: the values and principles that should underpin the system; the needs of diverse veterans and their families; challenges in the current services and supports; evidence-based interventions; and principles of effective implementation. Central to the future system design is a next generation stepped model of care that organizes best and next practice interventions in a coherent system, matches service provision to level of need and addresses access and navigation. Practical guidance on implementation provides an aspirational and flexible structure for system evolution, and a template for all stakeholders-individuals, groups, agencies and organizations-to effect system change.

Using an ecological momentary assessment protocol to understand problem anger in veterans.

BACKGROUND AND OBJECTIVES: Problem anger is highly destructive, and is one of the most commonly reported issues in military and veteran populations. The goal of this study was to use ecological momentary assessment (EMA) to explore and characterize moment-to-moment experiences of problem anger in a sample of Australian veterans. METHODS: Sixty veterans with problem anger (measured on the Dimensions of Anger Reactions Scale) completed measures of anger and anger rumination, before and after a 10-day EMA period which assessed the frequency, intensity, and expression of momentary anger experiences. RESULTS: Findings showed that 75% of respondents indicated some level of anger during EMA monitoring. In 25% of cases, anger was reported as severe. Moreover, anger was expressed verbally in 43% of cases, and expressed physically in 27% of cases. While anger fluctuated frequently during the day, more severe anger was more likely to be reported in the late afternoon/early evening. Problem anger symptoms decreased significantly over time, from pre-EMA to post EMA (p < .001). LIMITATIONS: The generalizability of findings is limited to a predominantly male sample, with low levels of risk of harm or violence. The study was also limited in the selection of outcome variables assessed and the lack of a control group; other momentary factors could influence experience of problem anger and provide further explanation of study results. CONCLUSIONS: EMA is a valuable assessment tool for individuals with problem anger, and the potential for EMA as an intervention needs to be explored further.

A Qualitative Study of the Expectations, Experiences, and Perceptions That Underpin Decisions Regarding PTSD Treatment in Help-seeking Veterans.

INTRODUCTION: A range of evidence-based treatments are available for PTSD. However, many veterans with PTSD do not engage in these treatments. Concurrently, various novel PTSD treatments with little or no evidence based are increasingly popular among veterans. This qualitative study explored the expectations, experiences, and perceptions of help-seeking veterans with PTSD to improve understanding of how these veterans make treatment decisions. MATERIALS AND METHODS: Fifteen treatment-seeking veterans with PTSD participated in the study. Participants took part in semi-structured interviews. Data were analyzed using interpretative phenomenological analysis. RESULTS: A number of themes and subthemes emerged from the data, providing a detailed account of the factors that influenced participants' treatment decisions. Most participants were in an acute crisis when they made the initial decision to seek treatment for their PTSD. In choosing a specific treatment, they tended to follow recommendations made by other veterans or health professionals or orders or directions from their superiors, health providers, or employers. Few participants actively considered the scientific evidence supporting different treatments. Participants had a strong preference for treatment provided by or involving other veterans. They reported finding PTSD treatments helpful, although some were not convinced of the value of evidence-based treatments specifically. Many participants reported negative experiences with treatment providers. CONCLUSIONS: These findings will inform strategies to improve engagement of veterans in evidence-based PTSD treatments and advance progress toward veteran-centered care.

Cross-lagged analyses of anger and PTSD symptoms among veterans in treatment.

OBJECTIVE: Anger is a salient feature of posttraumatic mental health which is linked to posttraumatic stress disorder (PTSD) and may have implications for treatment. However, the nature of associations involving anger and PTSD remains unclear. The aim of the present study was to examine bidirectional influences involving anger and International Classification of Diseases (ICD)-11 PTSD symptom clusters over time among treatment-seeking veterans. METHOD: Current or ex-serving members (n = 742; 92.4% male) who participated in an accredited outpatient PTSD treatment program were administered measures of PTSD symptoms (PTSD checklist for Diagnostic and Statistical Manual of Mental Disorders, 5th edition [PCL-5]) and anger (Dimensions of Anger Reactions Scale-5 [DAR-5]) at treatment intake, discharge, and three-month follow-up. Bidirectional influences were assessed using cross-lagged panel analyses. RESULTS: The majority of participants (78%) exhibited significant anger problems at intake. Cross-lagged analyses showed anger was associated with relative increases in PTSD symptoms of intrusive reexperiencing and avoidance at posttreatment, whereas no reverse effects of any PTSD symptoms on anger were observed. Anger continued to influence changes in heightened sense of threat and avoidance symptoms at three-months posttreatment. CONCLUSIONS: Anger influences change in specific PTSD symptoms over time among military veterans in treatment and may interfere with treatments for PTSD. Veterans who present to clinical services with anger problems may benefit from anger interventions prior to commencing trauma-focused treatment. The findings have additional implications for conceptual models of the relationship between anger and PTSD. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Initiatives to shorten duration of untreated psychosis: systematic review.

BACKGROUND: Long duration of untreated psychosis (DUP) is common and associated with poor outcomes. Strategies to enhance early detection of first-episode psychosis have been advocated. AIMS: To evaluate initiatives for early detection of psychosis. METHOD: Systematic review of available evidence on the effectiveness of early detection initiatives to reduce the DUP. RESULTS: The review included 11 studies which evaluated 8 early detection initiatives. Evidence suggests that general practitioner education campaigns and dedicated early intervention services do not by themselves reduce DUP or generate more treated cases. Evidence for multifocus initiatives is mixed: intensive campaigns targeting the general public as well as relevant professionals may be needed. No studies evaluated initiatives targeting young people or professionals from non-health organisations. CONCLUSIONS: How early detection can be achieved is not clear. Evidence is most promising for intensive public awareness campaigns: these require organisation and resourcing at a regional or national level. More good-quality studies are needed to address gaps in knowledge.

Service user and carer experiences of seeking help for a first episode of psychosis: a UK qualitative study.

BACKGROUND: Long duration of untreated psychosis (DUP) is associated with poor outcomes and low quality of life at first contact with mental health services. However, long DUP is common. In order to inform initiatives to reduce DUP, we investigated service users' and carers' experiences of the onset of psychosis and help-seeking in two multicultural, inner London boroughs and the roles of participants' social networks in their pathways to care. METHOD: In-depth interviews were conducted with service users and carers from an early intervention service in North London, purposively sampled to achieve diversity in sociodemographic characteristics and DUP and to include service users in contact with community organisations during illness onset. Interviews covered respondents' understanding of and reaction to the onset of psychosis, their help-seeking attempts and the reactions of social networks and health services. Thematic analysis of interview transcripts was conducted. RESULTS: Multiple barriers to prompt treatment included not attributing problems to psychosis, worries about the stigma of mental illness and service contact, not knowing where to get help and unhelpful service responses. Help was often not sought until crisis point, despite considerable prior distress. The person experiencing symptoms was often the last to recognise them as mental illness. In an urban UK setting, where involved, workers in non-health community organisations were frequently willing to assist help-seeking but often lacked skills, time or knowledge to do so. CONCLUSION: Even modest periods of untreated psychosis cause distress and disruption to individuals and their families. Early intervention services should prioritise early detection. Initiatives aimed at reducing DUP may succeed not by promoting swift service response alone, but also by targeting delays in initial help-seeking. Our study suggests that strategies for doing this may include addressing the stigma associated with psychosis and community education regarding symptoms and services, targeting not only young people developing illness but also a range of people in their networks, including staff in educational and community organisations. Initiatives to enhance the effective involvement of staff in community organisations working with young people in promoting help-seeking merit research.

Neural activity during response inhibition associated with improvement of dysphoric symptoms of PTSD after trauma-focused psychotherapy-an EEG-fMRI study.

Although trauma-focused cognitive behavioural therapy (TF-CBT) is the frontline treatment for posttraumatic stress disorder (PTSD), up to one half of patients do not respond optimally to this treatment. Inhibitory functions are important for successful management of PTSD, yet there is a dearth of knowledge regarding the extent to which neural mechanisms unpinning response inhibition are associated with TF-CBT response. Treatment-seeking PTSD patients (n = 40) were assessed during a response inhibition task (the Go/No-Go task) while undergoing functional magnetic imaging (fMRI) and event-related potentials (ERP) in separate sessions. PTSD symptom severity was assessed with the Clinician-Administered PTSD Scale, before undergoing nine sessions of TF-CBT. They were then reassessed post-treatment to estimate reduction in fear and dysphoric symptoms of PTSD. Although neural responses during the inhibitory task did not predict overall symptom change, reduced activation in the left precuneus and the right superior parietal cortex predicted greater improvement in dysphoric symptoms. ERP responses during response inhibition indicated that lower P3 peak latency predicted greater reduction of dysphoric symptoms. There were no significant predictors of changes of fear symptoms. These findings indicate that neural activity associated with response inhibition can act as a predictive biomarker of TF-CBT response for PTSD symptoms. This pattern of findings underscores the importance of delineating the role of biomarkers to predict remission of subtypes of PTSD.

Clinical experience with the AKT1 inhibitor miransertib in two children with PIK3CA-related overgrowth syndrome.

BACKGROUND: PIK3CA-related overgrowth spectrum (PROS) refers to a group of rare disorders, caused by somatic activating mutations in PIK3CA, resulting in abnormal PI3K-AKT-mTOR pathway signalling. Significant associated morbidity is frequently observed, and approved treatments are lacking. Miransertib (ARQ 092) is a novel, orally available, selective pan-AKT inhibitor with proven in vitro efficacy. Following recent results of the use of AKT inhibitors in Proteus syndrome (PS) and AKT-mutant cancers, we investigated its therapeutic use in two patients with severe PROS who had exhausted conventional treatment methods. RESULTS: Two patients, one with CLOVES variant (P1) and one with facial infiltrating lipomatosis and hemimegalencephaly (P2), were commenced on miransertib treatment on a compassionate use basis. In patient one, intra-abdominal and paraspinal overgrowth had resulted in respiratory compromise, obstructive uropathy, dysfunctional seating and lying postures, and chronic pain. In patient two, hemifacial overgrowth and hemimegalencephaly had caused difficulties with articulation and oral function, and refractory epilepsy. Miransertib treatment was continued for a median duration of 22 months (range 22-28). In patient one, alleviation of respiratory compromise was observed and functionally, seating and lying postures improved. Serial volumetric MRI analysis revealed 15% reduction in calculated volumes of fatty overgrowth between treatment commencement and end. In patient two, reduction in seizure burden and improved parent-reported quality of life measures were reported. Treatment was discontinued in both patients due to lack of sustained response, and poor compliance in year two of treatment (P2). No significant toxicities were reported. CONCLUSION: We report the first paediatric case series of the use of miransertib in two children with PROS. Objective clinical response was observed in patient one, and improvement in key qualitative outcomes was reported in patient two. Treatment was well tolerated with no significant toxicities reported. This case series highlights the potential therapeutic utility of miransertib in selected paediatric patients with severe PROS, and further demonstrates the potential for re-purposing targeted therapies for the treatment of rare diseases. An open label, Phase 1/2 study of miransertib in children with PROS and PS is underway to more accurately assess the efficacy of miransertib in the treatment of PROS disorder (NCT03094832).

Defining post-traumatic stress disorder recovery in veterans: Benchmarking symptom change against functioning indicators.

Improved metrics of Post-traumatic stress disorder (PTSD) treatment response that extend beyond a focus on symptom reduction to incorporate meaningful, patient-centred indicators of functioning are needed in veteran populations. The aim of this study was to extend previous research by investigating whether indicators of functioning can successfully distinguish against symptom response categories derived from the Post-Traumatic Stress Disorder Checklist (PCL-5) pre- and post- PTSD treatment. Participants were 472 veterans receiving hospital-based treatment for PTSD. In addition to the PCL-5, measures included quality of life, social relationships, physical health and psychological distress. Four mutually exclusive, progressive response categories were used to define treatment response including: No Response, Response, Response and Below Threshold, and Remission. PTSD symptom reductions were associated with corresponding improvements in broader indicators of functioning. However, it was only when the magnitude of symptom reduction placed the individual in the 'Response and Below Threshold' category that improvement on functioning measures achieved levels indicative of a good end state. Traditional metrics of treatment 'response' in PTSD treatment do not necessarily indicate recovery on important functioning indicators. Only when an individual both responds to treatment and drops below threshold for probable disorder are they likely to report having meaningful levels of functioning.

Modelling the relationship between poor sleep and problem anger in veterans: A dynamic structural equation modelling approach.

OBJECTIVE: Problem anger and poor sleep are common, particularly in military and veteran populations, but the nature of the relationship is poorly understood, and treatment approaches would benefit from improved understanding of how these constructs interact. Ecological momentary assessment (EMA) is suitable for monitoring day-to-day fluctuations in symptoms, and modelling dynamic relationships between variables. METHODS: This study aimed to examine these fluctuations and relationships involving sleep quality and anger experiences among veterans. A sample of n = 60 veterans with problem anger as assessed by the recommended cut off on the Dimensions of Anger Reactions 5 scale (DAR-5) completed daily assessments of sleep quality and four times daily assessments of anger frequency, over a 10-day period. RESULTS: A Dynamic Structural Equation Model (DESM) estimated and revealed a unidirectional relationship across daily measurements, in that previous night poor sleep quality was associated with more frequent anger on the next day (φASi Estimate -0.791, one-tailed p = .075), but not the reverse. CONCLUSIONS: These are the first longitudinal, naturalistic findings in relation to anger and sleep in a sample self-identifying with significant anger problems. The observed patterns point to the need for further research on mechanisms underpinning this relationship, and raises potential for early intervention for problem anger to include a focus on improving sleep quality.

Cross-Lagged Relationships Between Insomnia and Posttraumatic Stress Disorder in Treatment-Receiving Veterans.

Insomnia is a risk factor for the development of posttraumatic stress disorder (PTSD) while it is also plausible that PTSD symptoms can maintain insomnia symptoms. The present study examined longitudinal bidirectional relationships between insomnia and PTSD symptoms in treatment-seeking veterans. Participants were 693 ex-serving members of the Australian Defence Force who participated in an accredited, hospital-based outpatient PTSD program. Participants completed self-reported assessments of PTSD and insomnia symptoms at four time points: intake, discharge, 3-month, and 9-months posttreatment follow-up. Cross-lagged pathway analyses indicated significant bi-directional pathways between insomnia symptoms and PTSD symptoms at most time points. A final cross-lagged model between insomnia symptoms and the PTSD symptom clusters indicated that the PTSD symptom paths on insomnia symptoms, between intake and discharge, were attributable to reexperiencing PTSD symptoms. In contrast, across posttreatment follow-up time points there were significant paths of insomnia symptoms on all PTSD symptom clusters except from insomnia at 3-months to avoidance symptom at 9-months. PTSD symptoms and insomnia symptoms have bidirectional associations over time that may lead to the mutual maintenance or exacerbation of each condition following PTSD treatment. Where residual insomnia symptoms are present post-treatment, a sleep-focussed intervention is indicated and a sequenced approach to treatment recommended.

Evidence of the effectiveness of a specialist vocational intervention following first episode psychosis: a naturalistic prospective cohort study.

BACKGROUND: Employment rates among people with severe mental illness are low and work has beneficial effects on mental health. There is now good evidence of the effectiveness of a specialist vocational intervention (supported employment) in people with schizophrenia. However, the potential benefits of modifying this model for use in first episode psychosis cohorts remain relatively untested. METHODS: The aim of our study was to evaluate the effectiveness of a specialist vocational intervention in aiding vocational recovery following the onset of first episode psychosis. In a naturalistic prospective cohort study, 114 first episode psychosis service users were followed up during 12 months of engagement with an early intervention service; 44 resident in an area where a vocational intervention was available and 70 in an area where it was not. RESULTS: The main finding in our study was that having access to the specialist vocational intervention was a statistically significant independent predictor of vocational recovery during 12 months of follow-up (after adjusting for confounders). Service users who had access to the intervention had odds of achieving vocational recovery 3.53 times greater than those who did not (OR = 3.53, 95% CI = 1.25-10.00). CONCLUSION: This study provides further preliminary evidence of the effectiveness of a specialist vocational intervention following first episode psychosis. This is an important outcome from the perspective of service users and clinicians alike (as well as having wider societal value). Other important predictors of vocational recovery cannot be modified by the time a first episode psychosis emerges.

The role of advanced MRI in the development of treat-to-target therapeutic strategies, patient stratification and phenotyping in rheumatoid arthritis.

In this commentary, we discuss the potential of advanced imaging, particularly Dynamic Contrast Enhanced (DCE) magnetic resonance imaging (MRI) for the objective assessment of the inflammatory process in rheumatoid arthritis (RA). We emphasise the potential of DCE-MRI in advancing the field and exploring new areas of research and development in RA. We hypothesize that different grades of bone marrow edema (BME) and synovitis in RA can be examined and monitored in a more sensitive manner with DCE-MRI. Future treatments for RA may benefit from the application of enhanced imaging of BMEs and synovitis. DCE-MRI may also facilitate enhanced stratification and phenotyping of patients enrolled in clinical trials.

Exploring Theta Burst Stimulation for Post-traumatic Stress Disorder in Australian Veterans-A Pilot Study.

INTRODUCTION: Post-traumatic stress disorder (PTSD) is a severe and debilitating condition affecting a significant proportion of the veteran community. A substantial number of veterans with PTSD fail to benefit from trauma-focused psychological therapies or pharmacotherapy or are left with residual symptoms, and therefore, investigation of new and innovative treatment is required. Theta Burst Stimulation (TBS) is a novel form of Repetitive Transcranial Magnetic Stimulation, which has been shown to improve depression symptoms and associated cognitive deficits. The current pilot study aimed to explore the acceptability, safety, and tolerability of intermittent TBS (iTBS) as a treatment for PTSD in Australian veterans. MATERIALS AND METHODS: This study employed a case series, repeated-measures design. Eight Australian Defence Force veterans with PTSD received 20 bilateral iTBS treatments (1 session per day, 5 days per week over a 4-week period) and were assessed on a range of mental health and neuropsychological measures, including the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and Hamilton Depression Rating Scale (HAM-D), at pretreatment, post-treatment, and a 3-month follow-up. RESULTS: Treatment was generally welltolerated, with reported side-effects including mild to moderate site-specific cranial pain and headaches during stimulation, which were relieved with the use of low dose analgesics. No serious side effects or adverse events were reported. Participants exhibited reductions in both PTSD and depression symptom severity (the repeated-measures effect size [dRM] for the CAPS-5 was -1.78, and the HAM-D was -1.16 post-treatment), as well as improvements in working memory and processing speed. Although significance cannot be inferred, these preliminary estimates of effect size indicate change over time. CONCLUSIONS: Bilateral iTBS appears to be welltolerated by Australian veterans. Within this repeated-measures case series, iTBS treatment shows promise in reducing both PTSD and mood symptoms, as well as improving cognitive difficulties associated with these disorders. Large-scale randomized controlled trials of this promising treatment are warranted.

Beta-adrenergic enhancement of sarcoplasmic reticulum calcium leak in cardiac myocytes is mediated by calcium/calmodulin-dependent protein kinase.

Enhanced cardiac diastolic Ca leak from the sarcoplasmic reticulum (SR) ryanodine receptor may reduce SR Ca content and contribute to arrhythmogenesis. We tested whether beta-adrenergic receptor (beta-AR) agonists increased SR Ca leak in intact rabbit ventricular myocytes and whether this depends on protein kinase A or Ca/calmodulin-dependent protein kinase II (CaMKII) activity. SR Ca leak was assessed by acute block of the ryanodine receptor by tetracaine and assessment of the consequent shift of Ca from cytosol to SR (measured at various SR Ca loads induced by varying frequency). Cytosolic [Ca] ([Ca](i)) and SR Ca load ([Ca](SRT)) were assessed using fluo-4. beta-AR activation by isoproterenol dramatically increased SR Ca leak. However, this effect was not inhibited by blocking protein kinase A by H-89, despite the expected reversal of the isoproterenol-induced enhancement of Ca transient amplitude and [Ca](i) decline rate. In contrast, inhibitors of CaMKII, KN-93, or autocamtide-2-related inhibitory peptide II or beta-AR blockade reversed the isoproterenol-induced enhancement of SR Ca leak, and CaMKII inhibition could even reduce leak below control levels. Forskolin, which bypasses the beta-AR in activating adenylate cyclase and protein kinase A, did not increase SR Ca leak, despite robust enhancement of Ca transient amplitude and [Ca](i) decline rate. The results suggest that beta-AR stimulation enhances diastolic SR Ca leak in a manner that is (1) CaMKII dependent, (2) not protein kinase A dependent, and 3) not dependent on bulk [Ca](i).

A Novel Amino Acid Composition Ameliorates Short-Term Muscle Disuse Atrophy in Healthy Young Men.

Skeletal muscle disuse leads to atrophy, declines in muscle function, and metabolic dysfunction that are often slow to recover. Strategies to mitigate these effects would be clinically relevant. In a double-blind randomized-controlled pilot trial, we examined the safety and tolerability as well as the atrophy mitigating effect of a novel amino acid composition (AXA2678), during single limb immobilization. Twenty healthy young men were randomly assigned (10 per group) to receive AXA2678 or an excipient- and energy-matched non-amino acid containing placebo (PL) for 28d: days 1-7, pre-immobilization; days 8-15, immobilization; and days 16-28 post-immobilization recovery. Muscle biopsies were taken on d1, d8 (immobilization start), d15 (immobilization end), and d28 (post-immobilization recovery). Magnetic resonance imaging (MRI) was utilized to assess quadriceps muscle volume (Mvol), muscle cross-sectional area (CSA), and muscle fat-fraction (FF: the fraction of muscle occupied by fat). Maximal voluntary leg isometric torque was assessed by dynamometry. Administration of AXA2678 attenuated muscle disuse atrophy compared to PL (p < 0.05) with changes from d8 to d15 in PL: ΔMvol = -2.4 ± 2.3% and ΔCSA = -3.1% ± 2.1%, both p < 0.001 vs. zero; against AXA2678: ΔMvol: -0.7 ± 1.8% and ΔCSA: -0.7 ± 2.1%, both p > 0.3 vs. zero; and p < 0.05 between treatment conditions for CSA. During immobilization, muscle FF increased in PL but not in AXA2678 (PL: 12.8 ± 6.1%, AXA2678: 0.4 ± 3.1%; p < 0.05). Immobilization resulted in similar reductions in peak leg isometric torque and change in time-to-peak (TTP) torque in both groups. Recovery (d15-d28) of peak torque and TTP torque was also not different between groups, but showed a trend for better recovery in the AXA2678 group. Thrice daily consumption of AXA2678 for 28d was found to be safe and well-tolerated. Additionally, AXA2678 attenuated atrophy, and attenuated accumulation of fat during short-term disuse. Further investigations on the administration of AXA2678 in conditions of muscle disuse are warranted. Clinical Trial Registration: https://clinicaltrials.gov, identifier: NCT03267745.