A Novel Blended Transdiagnostic Intervention (eOrygen) for Youth Psychosis and Borderline Personality Disorder: Uncontrolled Single-Group Pilot Study.

BACKGROUND: Integrating innovative digital mental health interventions within specialist services is a promising strategy to address the shortcomings of both face-to-face and web-based mental health services. However, despite young people's preferences and calls for integration of these services, current mental health services rarely offer blended models of care. OBJECTIVE: This pilot study tested an integrated digital and face-to-face transdiagnostic intervention (eOrygen) as a blended model of care for youth psychosis and borderline personality disorder. The primary aim was to evaluate the feasibility, acceptability, and safety of eOrygen. The secondary aim was to assess pre-post changes in key clinical and psychosocial outcomes. An exploratory aim was to explore the barriers and facilitators identified by young people and clinicians in implementing a blended model of care into practice. METHODS: A total of 33 young people (aged 15-25 years) and 18 clinicians were recruited over 4 months from two youth mental health services in Melbourne, Victoria, Australia: (1) the Early Psychosis Prevention and Intervention Centre, an early intervention service for first-episode psychosis; and (2) the Helping Young People Early Clinic, an early intervention service for borderline personality disorder. The feasibility, acceptability, and safety of eOrygen were evaluated via an uncontrolled single-group study. Repeated measures 2-tailed t tests assessed changes in clinical and psychosocial outcomes between before and after the intervention (3 months). Eight semistructured qualitative interviews were conducted with the young people, and 3 focus groups, attended by 15 (83%) of the 18 clinicians, were conducted after the intervention. RESULTS: eOrygen was found to be feasible, acceptable, and safe. Feasibility was established owing to a low refusal rate of 25% (15/59) and by exceeding our goal of young people recruited to the study per clinician. Acceptability was established because 93% (22/24) of the young people reported that they would recommend eOrygen to others, and safety was established because no adverse events or unlawful entries were recorded and there were no worsening of clinical and social outcome measures. Interviews with the young people identified facilitators to engagement such as peer support and personalized therapy content, as well as barriers such as low motivation, social anxiety, and privacy concerns. The clinician focus groups identified evidence-based content as an implementation facilitator, whereas a lack of familiarity with the platform was identified as a barrier owing to clinicians' competing priorities, such as concerns related to risk and handling acute presentations, as well as the challenge of being understaffed. CONCLUSIONS: eOrygen as a blended transdiagnostic intervention has the potential to increase therapeutic continuity, engagement, alliance, and intensity. Future research will need to establish the effectiveness of blended models of care for young people with complex mental health conditions and determine how to optimize the implementation of such models into specialized services.

A Personalized, Transdiagnostic Smartphone Intervention (Mello) Targeting Repetitive Negative Thinking in Young People With Depression and Anxiety: Pilot Randomized Controlled Trial.

BACKGROUND: Repetitive negative thinking (RNT) is a key transdiagnostic mechanism underpinning depression and anxiety. Using "just-in-time adaptive interventions" via smartphones may disrupt RNT in real time, providing targeted and personalized intervention. OBJECTIVE: This pilot randomized controlled trial evaluates the feasibility, acceptability, and preliminary clinical outcomes and mechanisms of Mello-a fully automated, personalized, transdiagnostic, and mechanistic smartphone intervention targeting RNT in young people with depression and anxiety. METHODS: Participants with heightened depression, anxiety, and RNT were recruited via social media and randomized to receive Mello or a nonactive control over a 6-week intervention period. Assessments were completed via Zoom sessions at baseline and at 3 and 6 weeks after baseline. RESULTS: The findings supported feasibility and acceptability, with high rates of recruitment (N=55), uptake (55/64, 86% of eligible participants), and retention (52/55, 95% at 6 weeks). Engagement was high, with 90% (26/29) and 59% (17/29) of the participants in the Mello condition still using the app during the third and sixth weeks, respectively. Greater reductions in depression (Cohen d=0.50), anxiety (Cohen d=0.61), and RNT (Cohen d=0.87) were observed for Mello users versus controls. Mediation analyses suggested that changes in depression and anxiety were accounted for by changes in RNT. CONCLUSIONS: The results indicate that mechanistic, targeted, and real-time technology-based solutions may provide scalable and effective interventions that advance the treatment of youth mental ill health. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12621001701819; http://tinyurl.com/4d3jfj9f.

Suicide among health professionals in Australia: A retrospective mortality study of trends over the last two decades.

OBJECTIVE: To examine the relative risk of suicide among healthcare professionals compared to other occupations and examine changes in suicide rates over time. METHODS: Suicide cases were identified using the National Coronial Information System and were included if they were recorded as a death by intentional self-harm between 2001 and 2017 and were by an employed adult aged 20-69 with a known occupation at the time of death. Suicide methods were reported descriptively. Workforce data at the population level was extracted from the Australian Bureau of Statistics 2011 Census. Age-standardised suicide rates per 100,000 person-years for each of the four occupational groups were calculated using direct standardisation and using the Australian Bureau of Statistics population-level data from the 2011 Census. Negative binomial regression was used to estimate suicide risk by healthcare employment status and profession, to investigate differences by sex and to examine trends in suicide rates over time, using rate ratios and 95% confidence intervals. RESULTS: Healthcare professionals were at increased risk of suicide compared to other occupations (rate ratio = 1.30, 95% confidence interval = [1.19, 1.42], p < 0.001), controlling for age, sex and year of death. Nurses and midwives were identified as being at significantly increased risk of suicide (rate ratio = 1.95, 95% confidence interval = [1.73, 2.19], p < 0.001). Suicide rates among female medical practitioners increased substantially over time (p = 0.01). CONCLUSION: Health professionals are at significantly increased risk of suicide, though the relative risk of different groups is changing over time. There has been a substantial increase in the risk of suicide among female medical practitioners with rates of suicide in this group more than doubling over the last two decades. Findings highlight the need for targeted suicide prevention initiatives for healthcare professionals.

Hotel Suicides in Australia 2006-2017.

Background: This study investigated the frequency, characteristics, and geospatial clustering of hotel suicides in Australia to inform suicide prevention efforts. Aims: (1) To determine the proportion of suicide deaths that occurred in hotels, (2) to determine differences in demographic characteristics of hotel deaths compared to other locations, (3) to assess level of planning, and (4) to determine whether these deaths form geographic clusters amenable to targeted suicide prevention activities. Methods: Archival data on suicide mortality were used to examine associations between incident location (hotels, home, away from home), demographic characteristics, and suicide means. Kernel density visualization was used to assess geospatial clustering of hotel suicides, and the degree of planning involved was assessed using the modified Suicide Intent Scale. Results: Hotels accounted for 2% of all suicide deaths and 6.2% of suicides occurring away from home. Females were over-represented (p < .0001), as were deaths by drug overdoses (p < .0001) and falls (p < .0001). Approximately 40% of incidents occurred within seven geospatial clusters. 85% of those who died were state residents, with a median distance from home of 13.0 km. Most individuals checked in to the hotel alone, for short stays, and displayed a high degree of suicidal planning. Limitations: Coronial records had limited information on narrative circumstances of deaths; other indicators of risk may not have been identified. A comparison against a general population of hotel guests, rather than all other suicide deaths would be more useful in terms of preventative activities, however these data were not readily available. Conclusion: This study identified characteristics, behaviors, and geographic locations associated with hotel suicides to inform training of hotel staff to recognize and respond to signs of risk. Males of working age who live locally and arrive alone for short stays could be considered at a higher risk of suicide, and prevention efforts should be prioritized in the identified high-risk areas.

Machine learning algorithms to classify self-harm behaviours in New South Wales Ambulance electronic medical records: A retrospective study.

BACKGROUND: There is increasing interest in suicide surveillance solutions to identify non-fatal suicidal and self-harming behaviours in the Australian community not currently captured through national administrative datasets. OBJECTIVE: The aim of the present study was to develop machine learning models to classify self-harm related behaviours using unstructured clinical note text from New South Wales (NSW) Ambulance data and compare their performance via traditional methods. METHODS: Primary data were derived from NSW Ambulance electronic medical records (eMRs) for potential self-harm related NSW Ambulance attendances for the period 2013-2019. Data included paramedic clinical notes detailing the nature of the attendance, clinical outcome, and narrative information. We assessed sensitivity, specificity, positive predictive value, negative predictive value, F-score, and the Matthews correlation coefficient (MCC) for four algorithms (Support Vector Machine, random forest, decision tree, and logistic regression). RESULTS: The performance of these algorithms was compared using the MCC measure. In a test sample of 3157 ambulance attendances (1349 self-harm related behaviours and 1808 unrelated), the MCC for classification of self-harm related behaviour ranged from +0.681 to +0.730. The Support Vector Machine (sensitivity = 82.7%, specificity = 89.6%, MCC = 0.730) and the logistic regression (sensitivity = 83.1%, specificity = 89.3%, MCC = 0.727) models performed best. CONCLUSIONS: This study demonstrates that machine learning models can be applied to paramedic notes within unstructured medical records to classify self-harm related behaviours. The resulting model could be used to compliment current manual abstraction of self-harm behaviours and provide more timely approximations to be used for self-harm surveillance.

M1 muscarinic receptor activation decreases alcohol consumption via a reduction in consummatory behavior.

Muscarinic acetylcholine receptors (mAChRs) have been shown to mediate alcohol consumption and seeking. Both M4 and M5 mAChRs have been highlighted as potential novel treatment targets for alcohol use disorders (AUD). Similarly, M1 mAChRs are expressed throughout reward circuitry, and their signaling has been implicated in cocaine consumption. However, whether the same effects are seen for alcohol consumption, or whether natural reward intake is inadvertently impacted is still unknown. To determine the role of M1 mAChRs in alcohol consumption, we tested operant self-administration of alcohol under both fixed ratio (FR3) and progressive ratio (PR3-4) schedules. Enhancing M1 mAChR signaling (via the M1 PAM-Agonist PF-06767832, 1 mg/kg, i.p.) reduced operant alcohol consumption on a fixed schedule but had no effect on motivation to acquire alcohol. To determine whether these actions were specific to alcohol, we examined the effects of M1 enhancement on natural reward (sucrose) self-administration. Systemic administration of PF-06767832 (1 mg/kg, i.p.) also reduced operant sucrose self-administration, suggesting the actions of the M1 receptor may be non-selective across drug and natural rewards. Finally, to understand whether this reduction extended to natural consummatory behaviors, we assessed home cage standard chow and water consumption. M1 enhancement via systemic PF-06767832 administration reduced food and water consumption. Together our results suggest the M1 PAM-agonist, PF-06767832, non-specifically reduces consummatory behaviors that are not associated with motivational strength for the reward. These data highlight the need to further characterize M1 agonists, PAMs, and PAM-agonists, which may have varying degrees of utility in the treatment of neuropsychiatric disorders including AUD.

Characteristics of Online Comments Following High-Profile Celebrity Suicide.

Background: On the Internet, individuals can freely read about or talk to others about suicide. However, little is known about the nature of these online interactions and the potential impact on users. Aims: This study aimed to examine the characteristics of online comments following high-profile celebrity suicide, comparing top-rated comments with controversial comments. Method: Comments from a popular thread on Reddit made following the deaths of Kate Spade and Anthony Bourdain were examined using Linguistic Inquiry and Word Count and qualitative content analysis. Results: Top-scoring comments were associated with a higher level of authenticity, a higher word count, and a greater focus on the past. These comments were characterized by personal stories of experiences with suicidality or knowing someone who had attempted/died by suicide. Limitations: Our small sample size was underpowered for the linguistic characteristic analyses, and differences in some characteristics may not have been identified. Conclusions: Despite concerns over the potential dangers of the Internet on suicide, it can serve as a place for individuals to share personal stories and obtain support from others.

Nonwillingness to Return to the Emergency Department and Nonattendance of Follow-Up Care Arrangements Following an Initial Suicide-Related Presentation.

Background: For people experiencing a suicidal crisis the emergency department (ED) is often the only option to find help. Aims: The aims of this study were (a) to identify predictors of patients' nonwillingness to return to the ED for help with a future suicidal crisis, and (b) whether nonwillingness to return was associated with follow-up appointment nonattendance. Method: This study utilized baseline data from the RESTORE online survey, and included 911 participants who had presented to an ED for suicidal crisis in the past 18 months, across participating local health districts in the Australian Capital Territory and New South Wales. Results: Patients who reported a more negative ED experience and longer triage wait times were less willing to return. Those who were less willing to return were also less likely to attend their follow-up appointment. Limitations: Due to the cross-sectional study design, causal inferences are not possible. Additionally, the self-report measures used are susceptible to recall bias. Conclusion: Patients' experience of service at EDs is a key indicator to drive improvement of patient outcomes for individuals experiencing a suicidal crisis.

Profiles of Passive and Active Suicidal Ideation and Attempts Among Secondary School Students in Australia: A Cross-Sectional Analysis.

INTRODUCTION: Suicide is a leading cause of death among young people (aged 15-24 years), and as such, identifying targets for early intervention is essential to reducing this risk. Using baseline data from a school-based universal suicide prevention trial, we investigate factors associated with different types of suicidal ideation in secondary school students with implications for youth suicide preventive efforts. METHODS: A self-report questionnaire was administered to students aged 13-16 years (Year 9) before program delivery in four regions across New South Wales, Australia (N = 556). Multinomial logistic regression was used to identify correlates of suicidal ideation type (passive vs. active). RESULTS: Approximately half the total sample reported recent suicidal ideation (51.6% in the previous two weeks), which included almost one-third reporting active suicidal ideation (32.2% seriously considered suicide or made plans). Participants that were significantly more likely to report active suicidal ideation compared to passive suicidal ideation identified as female (OR = 1.91, 95% CI = 1.02-3.59), Indigenous (OR = 0.21, 95% CI = 0.05-0.80), as sexual minorities (OR = 0.36, 95% CI = 0.13-0.97), and had greater depression severity (OR = 1.11, 95% CI = 1.04-1.19). CONCLUSIONS: Suicidal thoughts are prevalent among young people. Universal and indicated preventive interventions that address depression, as well as bullying and discrimination of minority groups would benefit all young people, particularly those more vulnerable to severe suicidal ideation and suicide attempts.HighlightsActive suicidal ideation (SI) was reported by 32.2% of our student sample aged 13-16 years.Active SI is linked to sex (female), Indigeneity status, sexual minority status, and greater depression severity.Improved bullying and discrimination policy within schools, and well-being programs targeting depression and promoting help-seeking, would benefit youth.

The Youth Aware of Mental Health program in Australian Secondary Schools: 3- and 6-month outcomes.

OBJECTIVE: The evidence base for suicide prevention programs in Australian schools is limited. The aim of this study was to examine the impact of a universal, mental health promotion and suicide prevention program-Youth Aware of Mental Health (YAM)-on suicidal ideation, mental health, and help-seeking in Australian secondary school students from baseline to post-intervention and 6-month follow up. METHODS: Using a single-arm design, the YAM program was delivered to Year 9 students (13-16 years) in secondary schools located within four regions across New South Wales, Australia. A structured self-report questionnaire using validated scales was administered at each time point. Linear mixed-effects modelling was used to examine differences in suicidal ideation scores across time, while accounting for random effects of individual schools. RESULTS: Suicidal ideation reduced significantly from baseline to post, and from baseline to follow-up (p < 0.001). Depression severity declined (p < 0.001) and help-seeking intentions increased (p < 0.001) at post-intervention and 6- months following the intervention period. No suicide deaths were reported for any study participants. CONCLUSION: The current findings provide preliminary evidence that the YAM program is a promising preventive intervention for Australian schools, particularly for reducing suicidal ideation, depression and increasing help-seeking intentions in young people. The implementation of YAM in a large number of schools across New South Wales demonstrates the feasibility, and acceptability by schools, of implementing this program at scale. TRIAL REGISTRATION: ANZCTR, ACTRN12619000338167. Registered 5 March 2019-Retrospectively registered, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376989&isReview=true .

Muscarinic M4 and M5 receptors in the ventral subiculum differentially modulate alcohol seeking versus consumption in male alcohol-preferring rats.

BACKGROUND AND PURPOSE: Muscarinic acetylcholine receptors mediate alcohol consumption and seeking in rats. While M4 and M5 receptors have recently been implicated to mediate these behaviours in the striatum, their role in other brain regions remain unknown. The ventral tegmental area (VTA) and ventral subiculum (vSub) both densely express M4 and M5 receptors and modulate alcohol-seeking, via their projections to the nucleus accumbens shell (AcbSh). EXPERIMENTAL APPROACH: In Indiana alcohol-preferring (iP) male rats, we examined Chrm4 (M4 ) and Chrm5 (M5 ) expression in the VTA and vSub following long-term alcohol consumption and abstinence using RT-qPCR. Using a combination of retrograde tracing and RNAscope, we examined the localisation of Chrm4 and Chrm5 on vSub cells that project to the AcbSh. Using selective allosteric modulators, we examined the functional role of M4 and M5 receptors within the vSub in alcohol consumption, context-induced alcohol-seeking, locomotor activity, and food/water consumption. KEY RESULTS: Long-term alcohol and abstinence dysregulated the expression of genes for muscarinic receptors in the vSub, not in the VTA. Chrm4 was down-regulated following long-term alcohol and abstinence, while Chrm5 was up-regulated following long-term alcohol consumption. Consistent with these data, a positive allosteric modulator (VU0467154) of intra-vSub M4 receptors reduced context-induced alcohol-seeking, but not motivation for alcohol self-administration, while M5 receptor negative allosteric modulator (ML375) reduced initial motivation for alcohol self-administration, but not context-induced alcohol-seeking. CONCLUSION AND IMPLICATIONS: Collectively, our data highlight alcohol-induced cholinergic dysregulation in the vSub and distinct roles for M4 and M5 receptor allosteric modulators to reduce alcohol consumption or seeking.

A Qualitative Analysis of Motivators to Participation in Suicide-Focused Research from a Community-Based Australian Sample.

Suicide prevention strategies internationally appear to be falling short of making a meaningful impact on global suicide deaths. Increasing the rates of general community participation in suicide research may improve knowledge generalisability as it relates to suicidal behaviour and leads to new suicide prevention approaches. This study aims to explore the motivations of a community-based sample to participate in suicide research. A subsample of the Australian general population took part in an online survey which is part of a multilevel suicide prevention trial. The survey concluded with an optional open-text question asking about peoples' motivations for participating in the study; 532 participants left a response to this question. These responses were qualitatively analysed using Thematic Network Analysis. Motivations to participate in suicide research were represented by four global themes: altruism, solve systemic problems, lived experience, and personal benefit. Of these themes, three were focused on the benefit of others, while only the final theme articulated motivation to participate that was self-focused. The impact of suicide is felt throughout the wider community. This new understanding of the motivations of community-based samples to participate in suicide research should be used to increase participation rates and reach people who would not normally contribute their voice to suicide research.

Surveillance of suicide deaths involving gases in Australia using the National Coronial Information System, 2006 to 2017.

BACKGROUND: There have been concerns about the increased use of helium and nitrogen gas as a suicide mechanism in Australia. METHODS: National Coronial Information System data were used to investigate gas-specific suicides in Australia over the period 2006-2017. Characteristics were compared between helium or nitrogen, carbon monoxide and seven other gases. RESULTS: Gas inhalation accounted for 10% (3,103/31,002) of all suicide deaths in Australia between 2006 and 2017. The mean age of individuals who died by suicide was 47.6 years (SD 16.9, R 14-97) and 83.3% were male. The number of gas suicides declined over the study period (IRR=0.96). The fall was associated with a 47% decline in carbon monoxide suicides (IRR=0.93). There was an increase in deaths due to argon (IRR=1.60) and nitrogen (IRR=1.27). Compared to individuals using other non-carbon monoxide gases, individuals who died by suicide from helium or nitrogen were significantly more likely to be older, have a physical illness and/or disability, have contacted a euthanasia group and have accessed instructional material and purchased gas online. CONCLUSIONS: Suicides by carbon monoxide decreased between 2006 and 2017 alongside an increase in argon and nitrogen gas use - particularly among older adults. The ease of access to these gases points to new targets for means restriction. Implications for public health: Identifying the types of gases used in suicide deaths and emerging trends may enable targeted interventions that could potentially reduce access.

Performance, Cost-Effectiveness, and Representativeness of Facebook Recruitment to Suicide Prevention Research: Online Survey Study.

BACKGROUND: Researchers are increasingly using social media advertisements to recruit participants because of their many advantages over traditional methods. Although there is growing evidence for the effectiveness and cost-effectiveness of social media recruitment in the health sciences, no studies have yet examined this in the context of suicide prevention, which remains to be a highly stigmatized and sensitive topic. OBJECTIVE: This study aims to recruit a general community sample to complete a survey on suicide literacy, stigma, and risk via Facebook advertisements. Specifically, we aim to establish the performance of the advertisements, cost-effectiveness, sample representativeness, and the impact of gender-specific advertising on recruiting men into the study. METHODS: From June 2017 to March 2019, we released Facebook advertisements targeted at adults 18 years or older, residing in the New South Wales (NSW) trial or control regions, and involved in the LifeSpan suicide prevention trial. Cost-effectiveness was examined descriptively using metrics provided by Facebook. Chi-square analyses were conducted to determine demographic differences between our sample and the general NSW population as well as the impact of gender-specific advertisements on gender engagement. RESULTS: The 14 Facebook advertisement campaigns reached a total of 675,199 people, yielding 25,993 link clicks and resulting in 9603 individuals initiating the survey (7487 completions) at an overall cost of Aus $2.81 (US $2.01) per participant. There was an overrepresentation of younger (P=.003), female (P=.003), highly educated (P<.001) participants and mental health conditions (P<.001) compared with the total NSW population. The use of male-specific advertisements resulted in a significantly higher proportion of men completing the survey relative to gender-neutral advertisements (38.2% vs 24.6%; P<.001). CONCLUSIONS: This study demonstrates the potential of Facebook to be an effective, low-cost strategy for recruiting a large sample of general community participants for suicide prevention research. Strategies to improve sample representativeness warrant further investigation in future research.

Study protocol for a mixed methods prospective cohort study to explore experiences of care following a suicidal crisis in the Australian healthcare system.

INTRODUCTION: For individuals presenting to the emergency department (ED) for a suicide attempt, the period after discharge from hospital is marked by heightened vulnerability for further suicide attempts. Effective care following a suicidal crisis has the potential to significantly decrease this risk. The current study aims to examine the impact of the LifeSpan multilevel suicide prevention model on experiences of care following a suicidal crisis. Perspectives from healthcare consumers (individuals who have presented to the ED following a suicidal crisis), carers, and health professionals will be explored. The LifeSpan model is currently being evaluated as a high-fidelity trial in four geographically defined regions in New South Wales, Australia. METHODS AND ANALYSIS: This study will use a mixed methods prospective cohort design. Quantitative data collection includes a structured survey, administered to healthcare consumers from LifeSpan sites and control sites. Two cohorts of healthcare consumers will be recruited 12 months apart with baseline assessment occurring within 18 months of the ED presentation, and follow-up 12 months after the initial assessment. Survey participants will be recruited online and through participating EDs, mental health organisations and aftercare services. Qualitative interview data from healthcare consumers, carers who have accompanied a loved one to the ED following a suicidal crisis and health professionals who provide care to people at risk of suicide will be collected concurrently with the recruitment of the first cohort of survey participants. Purposive and convenience sampling techniques will be used for recruitment of interview participants. The primary outcome for this study will be healthcare consumers' experiences of service provided at the ED. Analysis will be undertaken of the change over time within LifeSpan sites, as well as between LifeSpan sites and control sites, using mixed effects repeated measures models as principal means of data analysis. ETHICS AND DISSEMINATION: This research has been approved by the Hunter New England Human Research Ethics Committee (HREC/17/HNE/144). Results will be disseminated via conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12617000457347.

Short report: Understanding the process of multilevel suicide prevention research trials.

This paper reviews process evaluations associated with multilevel suicide prevention research trials. Process evaluations can provide important information about how multilevel suicide prevention models are implemented, their mechanisms of impact, and the context and elements of implementation that mediate effectiveness. Out of 42 papers identified, only four met selection criteria for including a process evaluation. Of these four, there was large variation in the level of detail provided, and only two studies specifically focused on the process of implementing a multilevelsuicide prevention model. Future trials should include targeted process evaluation, which can benefit a range of knowledge users.

Acetylcholine Muscarinic M4 Receptors as a Therapeutic Target for Alcohol Use Disorder: Converging Evidence From Humans and Rodents.

BACKGROUND: Alcohol use disorder (AUD) is a major socioeconomic burden on society, and current pharmacotherapeutic treatment options are inadequate. Aberrant alcohol use and seeking alters frontostriatal function. METHODS: We performed genome-wide RNA sequencing and subsequent quantitative polymerase chain reaction and receptor binding validation in the caudate-putamen of human AUD samples to identify potential therapeutic targets. We then back-translated our top candidate targets into a rodent model of long-term alcohol consumption to assess concordance of molecular adaptations in the rat striatum. Finally, we adopted rat behavioral models of alcohol intake and seeking to validate a potential therapeutic target. RESULTS: We found that G protein-coupled receptors were the top canonical pathway differentially regulated in individuals with AUD. The M4 muscarinic acetylcholine receptor (mAChR) was downregulated at the gene and protein levels in the putamen, but not in the caudate, of AUD samples. We found concordant downregulation of the M4 mAChR, specifically on dopamine D1 receptor-expressing medium spiny neurons in the rat dorsolateral striatum. Systemic administration of the selective M4 mAChR positive allosteric modulator, VU0467154, reduced home cage and operant alcohol self-administration, motivation to obtain alcohol, and cue-induced reinstatement of alcohol seeking in rats. Local microinjections of VU0467154 in the rat dorsolateral striatum reduced alcohol self-administration and cue-induced reinstatement of alcohol seeking. CONCLUSIONS: Collectively, these results identify the M4 mAChR as a potential therapeutic target for the treatment of AUD and the D1 receptor-positive medium spiny neurons in the dorsolateral striatum as a key site mediating the actions of M4 mAChR in relation to alcohol consumption and seeking.

Protocol for a stepped-wedge, cluster randomized controlled trial of the LifeSpan suicide prevention trial in four communities in New South Wales, Australia.

BACKGROUND: Despite increasing investment in suicide prevention, Australian suicide rates have increased steadily in the past decade. In response to growing evidence for multicomponent intervention models for reducing suicide, the LifeSpan model has been developed as the first multicomponent, evidence-based, system-wide approach to suicide prevention in Australia. The LifeSpan model consists of nine evidence-based strategies. These include indicated, selective and universal interventions which are delivered simultaneously to community and healthcare systems over a 2-year implementation period. This study will evaluate the effectiveness of the LifeSpan model in reducing suicide attempts and suicide deaths in four geographically defined regions in New South Wales, Australia. METHODS: We outline the protocol for a stepped-wedge, cluster randomized controlled trial. Following a 6-month transition phase, the trial sites will move to the 2-year active implementation phase in 4-monthly intervals with evaluation extending a minimum of 24 months after establishment of the full active period. Analysis will be undertaken of the change attributable to the invention across the four sites. The primary outcome for the study is the rate of attempted suicide in the regions involved. Rate of suicide deaths within each site is a secondary outcome. DISCUSSION: If proven effective, the LifeSpan model for suicide prevention could be more widely delivered in Australian communities, providing a valuable new approach to tackle rising suicide rates. LifeSpan has the potential to significantly contribute to the mental health of Australians by improving help-seeking for suicide, facilitating early detection, and improving aftercare to reduce re-attempts. The findings from this research should also contribute to the evidence base for multilevel suicide prevention programs internationally. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Register, ID: ACTRN12617000457347. Prospectively registered on 28 March 2017. https://www.anzctr.org.au/TrialSearch.aspx#&&conditionCode=&dateOfRegistrationFrom=&interventionDescription=&interventionCodeOperator=OR&primarySponsorType=&gender=&distance=&postcode=&pageSize=20&ageGroup=&recruitmentCountryOperator=OR Protocol Version: 1.0, 31 May 2019.

Muscarinic M5 receptors modulate ethanol seeking in rats.

Despite the cost to both individual and society, alcohol use disorders (AUDs) remain a major health risk within society, and both relapse and heavy drinking are still poorly controlled with current medications. Here we demonstrate for the first time that a centrally active and selective negative allosteric modulator for the rat M5 muscarinic acetylcholine receptor (mAChR), ML375, decreases ethanol self-administration and attenuates cue-induced reinstatement of ethanol seeking in ethanol-preferring (iP) rats. Importantly, ML375 did not affect sucrose self-administration or general locomotor activity indicative of a selective effect on ethanol seeking. Based on the expression profile of M5 mAChRs in the brain and the distinct roles different aspects of the dorsal striatum have on long-term and short-term ethanol use, we studied whether intra-striatal microinjection of ML375 modulated ethanol intake in rats. We show in iP rats with an extensive history of ethanol intake that intra-dorsolateral (DL), but not intra-dorsomedial, striatal injections of ML375 reduced ethanol self-administration to a similar extent as the nicotinic acetylcholine receptor ligand varenicline, which has preclinical and clinical efficacy in reducing the reinforcing effects of ethanol. These data implicate the DL striatum as a locus for the effects of cholinergic-acting drugs on ethanol seeking in rats with a history of long-term ethanol use. Accordingly, we demonstrate in rats that selectively targeting the M5 mAChR can modulate both voluntary ethanol intake and cue-induced ethanol seeking and thereby provide direct evidence that the M5 mAChR is a potential novel target for pharmacotherapies aimed at treating AUDs.

Knockdown of corticotropin-releasing factor 1 receptors in the ventral tegmental area enhances conditioned fear.

The neuropeptide corticotropin-releasing factor (CRF) coordinates the physiological and behavioural responses to stress. CRF receptors are highly expressed in the ventral tegmental area (VTA), an important region for motivated behaviour. Therefore, we examined the role of CRF receptor type 1 (CRFR1) in the VTA in conditioned fear, using a viral-mediated RNA interference approach. Following stereotaxic injection of a lentivirus that contained either shCRF-R1 or a control sequence, mice received tone-footshock pairings. Intra-VTA shCRF-R1 did not affect tone-elicited freezing during conditioning. Once conditioned fear was acquired, however, shCRF-R1 mice consistently showed stronger freezing to the tone even after extinction and reinstatement. These results implicate a novel role of VTA CRF-R1 in conditioned fear, and suggest how stress may modulate aversive learning and memory.