Mapping clinical interactions in an Australian tertiary hospital emergency department for patients presenting with risk of suicide or self-harm: Network modeling from observational data.

BACKGROUND: Reliable assessment of suicide and self-harm risk in emergency medicine is critical for effective intervention and treatment of patients affected by mental health disorders. Teams of clinicians face the challenge of rapidly integrating medical history, wide-ranging psychosocial factors, and real-time patient observations to inform diagnosis, treatment, and referral decisions. Patient outcomes therefore depend on the reliable flow of information through networks of clinical staff and information systems. This study aimed to develop a quantitative data-driven research framework for the analysis of information flow in emergency healthcare settings to evaluate clinical practice and operational models for emergency psychiatric care. METHODS AND FINDINGS: We deployed 2 observers in a tertiary hospital emergency department during 2018 for a total of 118.5 h to record clinical interactions along patient trajectories for presentations with risk of self-harm or suicide (n = 272 interactions for n = 43 patient trajectories). The study population was reflective of a naturalistic sample of patients presenting to a tertiary emergency department in a metropolitan Australian city. Using the observational data, we constructed a clinical interaction network to model the flow of clinical information at a systems level. Community detection via modularity maximization revealed communities in the network closely aligned with the underlying clinical team structure. The Psychiatric Liaison Nurse (PLN) was identified as the most important agent in the network as quantified by node degree, closeness centrality, and betweenness centrality. Betweenness centrality of the PLN was significantly higher than expected by chance (>95th percentile compared with randomly shuffled networks) and removing the PLN from the network reduced both the global efficiency of the model and the closeness centrality of all doctors. This indicated a potential vulnerability in the system that could negatively impact patient care if the function of the PLN was compromised. We developed an algorithmic strategy to mitigate this risk by targeted strengthening of links between clinical teams using greedy cumulative addition of network edges in the model. Finally, we identified specific interactions along patient trajectories which were most likely to precipitate a psychiatric referral using a machine learning model trained on features from dynamically constructed clinical interaction networks. The main limitation of this study is the use of nonclinical information only (i.e., modeling is based on timing of interactions and agents involved, but not the content or quantity of information transferred during interactions). CONCLUSIONS: This study demonstrates a data-driven research framework, new to the best of our knowledge, to assess and reinforce important information pathways that guide clinical decision processes and provide complementary insights for improving clinical practice and operational models in emergency medicine for patients at risk of suicide or self-harm. Our findings suggest that PLNs can play a crucial role in clinical communication, but overreliance on PLNs may pose risks to reliable information flow. Operational models that utilize PLNs may be made more robust to these risks by improving interdisciplinary communication between doctors. Our research framework could also be applied more broadly to investigate service delivery in different healthcare settings or for other medical specialties, patient groups, or demographics.

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial.

BACKGROUND: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed. AIMS: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au. METHOD: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5-0.9 mg/kg or midazolam 0.025-0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4. RESULTS: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1-69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2-8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h. CONCLUSIONS: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.

Effects of dietary omega-3 intake on vigilant attention and resting-state functional connectivity in neurotypical children and adolescents.

BACKGROUND: Vigilant Attention (VA) is a critical cognitive function allowing to maintain our attention, particularly in redundant or intellectually unchallenging situations. Evidence has shown that, as the brain develops, VA abilities rapidly improve throughout childhood and adolescence. Dietary omega-3 polyunsaturated fats (PUFA), playing a critical role for proper brain development and maturation of cortical regions, may contribute to variations in VA abilities. OBJECTIVE: The present study investigated the effect of dietary omega-3 PUFA intake (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) on resting-state functional connectivity (rsFC) of a meta-analytically defined VA network in 24 neurotypical children and adolescents (7.3-17.2 years) from the Healthy Brain Network databank. METHODS: Functional MRI and phenotypical information were collected from the Healthy Brain Network databank. Intake of omega-3 DHA and EPA was assessed using a food frequency questionnaire and was adjusted for total calorie intake. Out of scanner VA-related performance was assessed using the VA condition of the Adaptive Cognitive Evaluation tool. RESULTS: Overall, reported intake of omega-3 PUFA was not significantly associated with VA-related performance. Furthermore, energy-adjusted omega-3 intake was not significantly correlated with rsFC within the VA network. A complementary whole-brain analysis revealed that energy-adjusted omega-3 intake was correlated with decreased rsFC between parieto-occipital brain regions. CONCLUSION: The present study was not able to detect a relationship between dietary omega-3 and rsFC or VA performance.

Visual hallucinations in psychiatry - what aren't we seeing?

OBJECTIVE: To increase awareness of practising clinicians and researchers to the phenomenological distinctions between visual hallucinations and trauma-based, dissociative, visual re-experiencing phenomena seen in psychiatric disease. CONCLUSIONS: The experience of visual hallucinations is not exclusive to psychotic disorders in psychiatry. Different forms of experiences that resemble visual hallucinations may occur in patients with a trauma background and may potentially affect diagnosis. Given the paucity of literature around the subject, it is imperative that further research aims to characterise the distinction between visual hallucinations in psychosis and visual phenomena associated with trauma.

Towards high spatial resolution tissue-equivalent dosimetry for microbeam radiation therapy using organic semiconductors.

Spatially fractionated ultra-high-dose-rate beams used during microbeam radiation therapy (MRT) have been shown to increase the differential response between normal and tumour tissue. Quality assurance of MRT requires a dosimeter that possesses tissue equivalence, high radiation tolerance and spatial resolution. This is currently an unsolved challenge. This work explored the use of a 500 nm thick organic semiconductor for MRT dosimetry on the Imaging and Medical Beamline at the Australian Synchrotron. Three beam filters were used to irradiate the device with peak energies of 48, 76 and 88 keV with respective dose rates of 3668, 500 and 209 Gy s-1. The response of the device stabilized to 30% efficiency after an irradiation dose of 30 kGy, with a 0.5% variation at doses of 35 kGy and higher. The calibration factor after pre-irradiation was determined to be 1.02 ±â€…0.005 µGy per count across all three X-ray energy spectra, demonstrating the unique advantage of using tissue-equivalent materials for dosimetry. The percentage depth dose curve was within ±5% of the PTW microDiamond detector. The broad beam was fractionated into 50 microbeams (50 µm FHWM and 400 µm centre-to-centre distance). For each beam filter, the FWHMs of all 50 microbeams were measured to be 51 ±â€…1.4, 53 ±â€…1.4 and 69 ±â€…1.9 µm, for the highest to lowest dose rate, respectively. The variation in response suggested the photodetector possessed dose-rate dependence. However, its ability to reconstruct the microbeam profile was affected by the presence of additional dose peaks adjacent to the one generated by the X-ray microbeam. Geant4 simulations proved that the additional peaks were due to optical photons generated in the barrier film coupled to the sensitive volume. The simulations also confirmed that the amplitude of the additional peak in comparison with the microbeam decreased for spectra with lower peak energies, as observed in the experimental data. The material packaging can be optimized during fabrication by solution processing onto a flexible substrate with a non-fluorescent barrier film. With these improvements, organic photodetectors show promising prospects as a cost-effective high spatial resolution tissue-equivalent flexible dosimeter for synchrotron radiation fields.

Age-related resting-state functional connectivity of the Vigilant Attention network in children and adolescents.

The development of Vigilant Attention (VA), the ability to focus and maintain our attention to repetitive and cognitively unchallenging tasks over time, has been investigated for more than a decade. The development of this critical executive function across the lifespan has been characterised by a rapid improvement in VA performance throughout childhood and adolescence, a steady improvement in adulthood and a slow decline in older adulthood. However, the development of the neural correlates of VA in children and adolescents remains poorly understood. Using a cross-sectional design, the present study used a meta-analytically defined VA network in children and adolescents to explore the developmental trend of the resting-state functional connectivity (rsFC) within the VA network across two independent cohorts. The results showed a linear and non-linear decrease of rsFC between the left and right VA brain regions across age. However, the results could not be reproduced in the replication cohort, potentially due to a smaller sample size. Based on previous findings from behavioural studies, the present findings suggest that changes in rsFC may underlie a developmental shift in cognitive strategies in neurotypical children and adolescents.

Medicinal psychedelics for mental health and addiction: Advancing research of an emerging paradigm.

The medical use of psychedelic substances (e.g. psilocybin, ayahuasca, lysergic acid diethylamide and 3,4-methylenedioxymethamphetamine) is attracting renewed interest, driven by a pressing need for research and development of novel therapies for psychiatric disorders, as well as promising results of contemporary studies. In this Viewpoint, we reflect upon the 'Clinical Memorandum on Psychedelics' recently released by the Royal Australian and New Zealand College of Psychiatrists and note subsequent developments including the application for down-scheduling of psilocybin and 3,4-methylenedioxymethamphetamine presently being considered by the Therapeutic Goods Administration and approvals for access via the Special Access Scheme. We suggest that this field is worthy of rigorous research to assess potential benefits, address safety parameters and clarify therapeutic mechanisms. To this end, we outline recent research findings, provide an overview of current knowledge relating to mechanisms of action and discuss salient aspects of the psychedelic-assisted psychotherapy treatment model. The sum of this research points towards medicinal psychedelics as a potential new class of psychiatric treatments when used within a medically supervised framework with integrated psychotherapeutic support. However, before widespread translation into clinical use can occur, appropriately designed and sufficiently powered trials are required to detect both potential positive and negative outcomes. Unique safety and regulatory challenges also need to be addressed. As for any new medical therapy, psychedelic research needs to be conducted in a rigorous manner, through the dispassionate lens of scientific enquiry. Carte blanche availability to practitioners, without specific protocols and appropriate training, would be potentially harmful to individuals and detrimental to the field.

Use of mental-health services by Australian medical students: a cross-sectional survey.

OBJECTIVE: Medical students have higher rates of mental illness compared to the general population. Little is known about services accessed by medical students for mental-health problems. This study aimed to assess the use of mental-health services by Australian medical students and to identify barriers that may prevent students from using mental-health services. METHOD: A cross-sectional online survey was designed and administered to medical students at the University of Western Australia. Questions focused on self-reported psychological well-being, use of mental-health services, the perceived usefulness of services and barriers to the use of services. RESULTS: The response rate was 41% ( n=286). Sixty-two per cent self-reported experiencing mental-health problems, and of these, 75% had used at least one service. General practitioners and psychiatrists were rated as the most effective service type. The main barriers to seeking help were not enough time, affordability and concerns regarding stigma, including disclosure and peer judgement. CONCLUSION: A high proportion of students with self-reported mental-health problems had accessed services. However, barriers were also identified. Access to mental-health services needs to be improved, and strategies aimed at reducing stigma and raising awareness of mental-health issues should be encouraged by medical faculties.

Reduced heart rate variability in remitted bipolar disorder and recurrent depression.

OBJECTIVE: There is evidence that mood disorders are associated with impaired parasympathetic nervous system function and consequently increased morbidity and mortality. Our study addresses whether this impairment persists into remission in unipolar and bipolar disorders. METHODS: Heart Rate Variability was measured in groups of subjects during remission, with Bipolar Affective Disorder I (n = 29), recurrent Major Depressive Disorder (n = 41) and a healthy control group (n = 38), during the bedtime period. RESULTS: Heart Rate Variability was found to be lower in the bipolar and depression groups, compared with control subjects, using the Root Mean Square of Successive Distances variable, and lower in the depression group using the Standard Deviation of Normal to Normal variable and the Standard Deviation, Poincare Plot variable. CONCLUSION: Autonomic function during bedtime was impaired in subjects with Bipolar I and recurrent Major Depressive Disorder, despite clinical remission. This has significant implications for the morbidity and mortality of patients with major mood disorders.

Latest guidelines for the management of the anxiety disorders - a report from The International Anxiety Disorders Society Conference, Melbourne 2014.

OBJECTIVE: The International Anxiety Disorders Society Conference, held in Melbourne in November 2014, enabled key researchers from Australia and internationally to interact with mental health practitioners with an interest in clinical anxiety disorders. The proceedings of previous conferences in 2006 and 2011 formed the basis of two well-received textbooks on anxiety disorders; this time we have taken up the invitation to publish the proceedings as articles in this issue of Australasian Psychiatry. At the end of the first day of the conference a lecture and linked international expert panel explored the topic of guidelines for the management of the anxiety disorders in conjunction with an engaged audience for 90 minutes - key elements of this discussion are presented here. CONCLUSIONS: Guidelines for anxiety disorder management should be applied with caution in clinical practice settings.

Benzodiazepine dependence and its treatment with low dose flumazenil.

Globally benzodiazepines remain one of the most prescribed medication groups, especially in the primary care setting. With such high levels of prescribing it is not surprising that benzodiazepine dependence is common, cutting across all socioeconomic levels. Despite recognition of the potential for the development of iatrogenic dependence and the lack of any effective treatment, benzodiazepines continue to be widely prescribed in general practice. Conventional dependence management, benzodiazepine tapering, is commonly a protracted process over several weeks or months. It is often associated with significant withdrawal symptoms and craving leading to patient drop out and return to use. Accordingly, there is a worldwide need to find effective pharmacotherapeutic interventions for benzodiazepine dependence. One drug of increasing interest is the GABAA benzodiazepine receptor antagonist/partial agonist, flumazenil. Multiple bolus intravenous infusions of low dose flumazenil used either with or without benzodiazepine tapering can reduce withdrawal sequelae, and/or longer term symptoms in the months following withdrawal. Preliminary data suggest that continuous intravenous or subcutaneous flumazenil infusion for 4 days significantly reduces acute benzodiazepine withdrawal sequelae. The subcutaneous infusion was shown to be tissue compatible so the development of a longer acting (i.e. several weeks) depot flumazenil formulation has been explored. This could be capable of managing both acute and longer term benzodiazepine withdrawal sequelae. Preliminary in vitro water bath and in vivo biocompatibility data in sheep show that such an implant is feasible and so is likely to be used in clinical trials in the near future.

Systematic review and network meta-analysis of agomelatine for the treatment of generalized anxiety disorder in adult patients.

This systematic literature review aimed to assess the efficacy and tolerability of agomelatine versus approved medications for the treatment of generalized anxiety disorder (GAD) in adult patients. We selected randomized controlled trials on various medications used to treat GAD in adult patients. An existing systematic literature review (Kong et al., 2020) was used to identify relevant studies published before 2020. Outcomes of remission and discontinuation due to adverse events (AEs) were analyzed, following a random-effects network meta-analysis approach. Of 25 identified studies, 20 and 22 studies were included in the network meta-analysis for studying the remission and discontinuation (due to AEs) outcomes, respectively. A statistically significant difference in the remission rate was observed between agomelatine and pregabalin [odds ratio (OR), 2.22; 95% confidence interval (CI), 1.19-4.21]. For the other comparators, the results were nonsignificant; however, all the point estimates were in favor of agomelatine. Similarly, for discontinuation because of AEs, the point estimates leaned consistently toward agomelatine suggesting its higher tolerability. The probabilities of agomelatine having the highest remission rate and lowest discontinuation (due to AEs) rate were 67% and 68%, respectively. Based on its demonstrated effectiveness and tolerability, agomelatine can be considered as a drug of choice for the treatment of GAD.

Cognitive outcomes from the randomised, active-controlled Ketamine for Adult Depression Study (KADS).

BACKGROUND: Due to its rapid antidepressant effect, ketamine has recently been clinically translated for people with treatment-resistant depression. However, its cognitive profile remains unclear, particularly with repeated and higher doses. In the present study, we report the cognitive results from a recent large multicentre randomised controlled trial, the Ketamine for Adult Depression Study (KADS). METHODS: In this randomised, double-blind, active-controlled, parallel group, multicentre phase 3 trial study we investigated potential cognitive changes following repeated treatment of subcutaneous racemic ketamine compared to an active comparator, midazolam, over 4 weeks, which involved two cohorts; Cohort 1 involved a fixed dose treatment protocol (0.5 mg/kg ketamine), Cohort 2 involved a dose escalation protocol (0.5-0.9 mg/kg) based on mood outcomes. Participants with treatment-resistant Major Depressive Disorder (MDD) were recruited from 7 mood disorder centres and were randomly assigned to receive ketamine (Cohort 1 n = 33; Cohort 2 n = 53) or midazolam (Cohort 1 n = 35; Cohort 2 n = 53) in a 1:1 ratio. Cognitive measurements were assessed at baseline and at the end of randomised treatment. RESULTS: Results showed that in Cohort 1, there were no differences between ketamine and midazolam in cognitive outcomes. For Cohort 2, there was similarly no difference between conditions for cognitive outcomes. LIMITATIONS: The study included two Cohorts with different dosing regimes. CONCLUSIONS: The findings support the cognitive safety of repeated fixed and escalating doses at least in the short-term in people with treatment resistant MDD.

The definition of treatment resistance in anxiety disorders: a Delphi method-based consensus guideline.

Anxiety disorders are very prevalent and often persistent mental disorders, with a considerable rate of treatment resistance which requires regulatory clinical trials of innovative therapeutic interventions. However, an explicit definition of treatment-resistant anxiety disorders (TR-AD) informing such trials is currently lacking. We used a Delphi method-based consensus approach to provide internationally agreed, consistent and clinically useful operational criteria for TR-AD in adults. Following a summary of the current state of knowledge based on international guidelines and an available systematic review, a survey of free-text responses to a 29-item questionnaire on relevant aspects of TR-AD, and an online consensus meeting, a panel of 36 multidisciplinary international experts and stakeholders voted anonymously on written statements in three survey rounds. Consensus was defined as ≥75% of the panel agreeing with a statement. The panel agreed on a set of 14 recommendations for the definition of TR-AD, providing detailed operational criteria for resistance to pharmacological and/or psychotherapeutic treatment, as well as a potential staging model. The panel also evaluated further aspects regarding epidemiological subgroups, comorbidities and biographical factors, the terminology of TR-AD vs. "difficult-to-treat" anxiety disorders, preferences and attitudes of persons with these disorders, and future research directions. This Delphi method-based consensus on operational criteria for TR-AD is expected to serve as a systematic, consistent and practical clinical guideline to aid in designing future mechanistic studies and facilitate clinical trials for regulatory purposes. This effort could ultimately lead to the development of more effective evidence-based stepped-care treatment algorithms for patients with anxiety disorders.

The role of flumazenil in generalised anxiety disorder: a pilot naturalistic open-label study with a focus on treatment resistance.

Background: Anxiety disorders are highly prevalent and chronic disorders with treatment resistance to current pharmacotherapies occurring in approximately one in three patients. It has been postulated that flumazenil (FMZ) is efficacious in the management of anxiety disorders via the removal of α4ß2δ gamma-aminobutyric acid A receptors. Objective: To assess the safety and feasibility of continuous low-dose FMZ infusions for the management of generalised anxiety disorder (GAD) and collect preliminary efficacy data. Design: Uncontrolled, open-label pilot study. Method: Participants had a primary diagnosis of generalised anxiety disorder (GAD) and received two consecutive subcutaneous continuous low-dose FMZ infusions. Each infusion contained 16 mg of FMZ and was delivered over 96 ± 19.2 h. The total dose of FMZ delivered was 32 mg over approximately 8 days. Sodium valproate was given to participants at risk of seizure. The primary outcome was the change in stress and anxiety subscale scores on the Depression Anxiety Stress Scale-21 between baseline, day 8, and day 28. Results: Nine participants with a primary diagnosis of GAD were treated with subcutaneous continuous low-dose FMZ infusions; seven participants met the criteria for treatment resistance. There was a significant decrease in anxiety and stress between baseline and day 8 and baseline and day 28. There was also a significant improvement in subjective sleep quality from baseline to day 28 measured by the Jenkins Sleep Scale. No serious adverse events occurred. Conclusion: This study presents preliminary results for subcutaneous continuous low-dose FMZ's effectiveness and safety in GAD. The findings suggest that it is a safe, well-tolerated, and feasible treatment option in this group of patients. Future randomised control trials are needed in this field to determine the efficacy of this treatment.

Mental Health Status, Risk and Protective Factors for Healthcare Staff Prior to the First Major COVID-19 Outbreak in Western Australia.

Objectives: Western Australia's unique public health response delayed the first wave of community COVID-19 transmission for 2 years. We aimed to determine the status of post-traumatic stress (PTSS), depressive, and anxiety symptoms among healthcare staff in major tertiary hospitals, together with associated risk and protective factors prior to the first substantial outbreak of COVID-19. Methods: A cross-sectional study was conducted with 431 healthcare staff immediately prior to the Western Australian border re-opening in 2022. Staff were recruited via notices in email newsletters, at four tertiary hospitals and a public mental health clinic in metropolitan Perth. Validated and original questionnaires were administered via Qualtrics. Results: Moderate levels of PTSS (22.3%), depression (21.9%), and anxiety (25.9%) were reported. Pathway analyses indicated that sleep difficulties, workplace stressors, and infectious disease training were associated with higher PTSS, depression and anxiety symptoms, and younger age was associated with higher levels of depression and anxiety. Nursing roles were associated with higher PTSS. Social support and workplace support were associated with lower levels of depression and anxiety but were not associated with PTSS. Conclusion: The findings illustrate high levels of resilience, but indicate a need for structural supports within the health system to foster staff mental health prior to the onset of emergencies.

Utility of pharmacogenetic testing to optimise antidepressant pharmacotherapy in youth: a narrative literature review.

Pharmacogenetics (PGx) is the study and application of how interindividual differences in our genomes can influence drug responses. By evaluating individuals' genetic variability in genes related to drug metabolism, PGx testing has the capabilities to individualise primary care and build a safer drug prescription model than the current "one-size-fits-all" approach. In particular, the use of PGx testing in psychiatry has shown promising evidence in improving drug efficacy as well as reducing toxicity and adverse drug reactions. Despite randomised controlled trials demonstrating an evidence base for its use, there are still numerous barriers impeding its implementation. This review paper will discuss the management of mental health conditions with PGx-guided treatment with a strong focus on youth mental illness. PGx testing in clinical practice, the concerns for its implementation in youth psychiatry, and some of the barriers inhibiting its integration in clinical healthcare will also be discussed. Overall, this paper provides a comprehensive review of the current state of knowledge and application for PGx in psychiatry and summarises the capabilities of genetic information to personalising medicine for the treatment of mental ill-health in youth.

N-Acetylcysteine as a novel rapidly acting anti-suicidal agent: A pilot naturalistic study in the emergency setting.

OBJECTIVE: N-acetylcysteine has a demonstrated role as an adjunctive therapy in psychotic and affective disorders as a treatment to reduce symptoms of Bipolar Affective Disorder, Major Depressive Disorder and Schizophrenia. However, its potential as a rapidly acting anti-suicidal agent has not yet been assessed. This naturalistic study evaluates its effect in thirty patients presenting following intentional medication overdose. METHODS: Eighteen patients who ingested toxic doses of paracetamol received NAC whilst twelve other patients with other overdoses received standard supportive treatment in the emergency department setting. Symptoms were measured using the Montgomery-Asberg Depression Rating Scale and Clinical Global Impression scale at time of presentation, 24 hours, and seven days. RESULTS: Baseline characteristics between groups were similar. Both groups showed a significant reduction in suicidality, as measured by the suicide item of the MADRS, over time (p < 0.001). However, there was a greater reduction in suicidality in the 'NAC group' compared to the 'no-NAC group' one-week post presentation (p = 0.014). A greater proportion of the 'no-NAC group' still exhibited severe depressive symptoms (MADRS >32) compared to the 'NAC group' (p = 0.044). CONCLUSION: This naturalistic study suggests NAC may have potential use as a rapidly acting treatment adjunct in major depressive disorder, warranting further investigation of its effects.

Long-Term Management of Generalised Anxiety Disorder with Low-Dose Continuous Infusions of Flumazenil: A Case Series.

BACKGROUND: Generalised anxiety disorder (GAD) is a common anxiety disorder associated with social and occupational impairment. Recently, a theory was postulated that dysfunctional gamma aminobutyric acid type A receptors (GABAA) are implicated in anxiety symptomology, which could be corrected by flumazenil, an antagonist at the benzodiazepine binding site on the GABAA receptor. METHOD: Participants had a primary diagnosis of GAD and were treated initially with an eight-day continuous low-dose flumazenil infusion (total 32 mg at a rate of 4 mg/24 h). Some participants were re-treated with a further four- or eight-day infusion. Treatment response was measured as a 50% reduction in anxiety or stress scores on the Depression Anxiety Stress Scale-21 (DASS-21). Remission was measured as scores ≤3 or ≤7 on the anxiety and stress subscales of the DASS-21, respectively. RESULTS: Eight cases are reported. All cases met the criteria for treatment response on the anxiety and stress subscale of the DASS-21. Remission was achieved in seven participants on the anxiety subscale and in five on the stress subscale. No changes in hepatic, renal, or haematological function were likely attributed to flumazenil. CONCLUSION: Data suggest that low-dose continuous flumazenil infusion manages GAD symptoms and is safe. Although these results are promising, future randomised control trials are required to confirm these results.