Electrophysiological phenotypes of suicidality predict prolonged response to oral ketamine treatment.

Oral ketamine has shown to be a rapid-acting antidepressant and a potential treatment option for suicidality, however, repeated doses are often required. Objective markers of prolonged treatment response are needed to help individuals and clinicians make informed treatment decisions. This secondary analysis sought to identify objective electrophysiological predictors of both prolonged response and dose sensitivity to low-dose oral ketamine in people with chronic suicidality. Individuals with a Beck Scale for Suicide Ideation total score (BSS) ≥ 6 (N = 29) completed a six-week ketamine treatment, pre-treatment electroencephalography and follow-up assessment of suicidality (four weeks from the final ketamine dose). Prolonged response was observed in 52% of participants (follow-up BSS reduced by 50% or ≤6); nearly half were prolonged non-responders. There was decisive evidence for a predictive Bayesian linear regression model with follow-up BSS score as the response variable and pre-treatment auditory evoked power bands as predictors (theta, alpha and beta frequencies, BF10 = 17,948, R2 = 0.70). A Bayesian one-way ANOVA indicated strong evidence for a model of positive association between auditory evoked power and ketamine dose sensitivity (theta-alpha BF+0 = 108, effect size δ = 1.3, 95% CI 0.5-2.1; high-beta BF+0 = 7.4, δ = 0.8, 95% CI 0.1-1.6). Given auditory evoked power may index serotonin neurotransmission, these results suggest that a prolonged response to ketamine may, in part, be mediated by pre-treatment serotonergic functioning. In addition, the observed beta power differences may arise from GABAergic functioning. These suicidality phenotypes, identifiable by pre-treatment electrophysiology, may aid diagnosis, treatment selection and prediction of prolonged treatment outcome.

The effect of mindfulness training on resting-state networks in pre-adolescent children with sub-clinical anxiety related attention impairments.

Mindfulness training has been associated with improved attention and affect regulation in preadolescent children with anxiety related attention impairments, however little is known about the underlying neurobiology. This study sought to investigate the impact of mindfulness training on functional connectivity of attention and limbic brain networks in pre-adolescents. A total of 47 children with anxiety and/or attention issues (aged 9-11 years) participated in a 10-week mindfulness intervention. Anxiety and attention measures and resting-state fMRI were completed at pre- and post-intervention. Sustained attention was measured using the Conners Continuous Performance Test, while the anxiety levels were measured using the Spence Children's Anxiety Scale. Functional networks were estimated using independent-component analysis, and voxel-based analysis was used to determine the difference between the time-points to identify the effect of the intervention on the functional connectivity. There was a significant decrease in anxiety symptoms and improvement in attention scores following the intervention. From a network perspective, the results showed increased functional connectivity post intervention in the salience and fronto-parietal networks as well as the medial-inferior temporal component of the default mode network. Positive correlations were identified in the fronto-parietal network with Hit Response Time and the Spence Children's Anxiety Scale total and between the default mode network and Hit Response Time. A 10-week mindfulness intervention in children was associated with a reduction in anxiety related attention impairments, which corresponded with concomitant changes in functional connectivity.

Social Connectedness, Cyberbullying, and Well-Being: Preliminary Findings from the Longitudinal Adolescent Brain Study.

Social connectedness is well established as an important aspect of adolescence, with higher levels typically resulting in positive mental health and well-being. Cyberbullying is a prevalent concern during adolescence and is a significant contributor to poor mental health outcomes during this important phase of life. Research shows that social connectedness may act as a protective factor for mental health and well-being when young people experience cyberbullying. However, further research is required to elucidate associations between social connectedness, well-being, and cyberbullying over time. This article outlines preliminary findings from the Longitudinal Adolescent Brain Study (LABS). Data are reported from N = 64 LABS participants recruited at age 12 and assessed at four timepoints over a 12-month period, with a total of 204 completed assessments. Structural equation modeling revealed a mediating effect of social connectedness on the relationship between cyberbullying and well-being. In other words, the negative influences of cyberbullying and cybervictimization on well-being scores over time are influenced by levels of social connectedness. The present findings highlight that increased social connectedness in young people is vital to promoting positive well-being over time and can protect well-being in those experiencing cyberbullying and/or cybervictimization. Findings can inform cyberbullying education programs, health care practitioners, parents, and educators on the importance of young people remaining socially connected when experiencing cyberbullying and/or cybervictimization.

Oral ketamine reduces the experience of stress in people with chronic suicidality.

BACKGROUND: Stress is prevalent in people experiencing suicidality and is a major contributor to the development of mental disorders. Evidence suggests ketamine shows capacity to reverse stress-induced brain changes. Though stress and ketamine have been explored individually for suicidality, this study is the first to examine ketamine treatment for self-reported stress in adults with chronic suicidality, building on pre-clinical evidence of ketamine's capacity to normalize stress-induced responses and contributing to our understanding of oral ketamine in clinical populations. METHODS: Thirty two adult participants (22-72 years; 17 female) with chronic suicidality completed 6 weeks of active treatment, receiving low (0.5 mg/kg - 3.0 mg/kg) doses of oral ketamine once per week, with a 4-week follow-up phase, to assess the effect of ketamine on their perceived stress. Stress was measured via self-report utilizing the Depression Anxiety Stress Scale-21(DASS-21), and analysed at pre-treatment (week 0), post-treatment (week 6) and at follow-up (week 10). RESULTS: Repeated measures ANOVA showed a significant reduction in stress (p<.001) post-treatment and Reliable Change Index calculations confirmed this to be clinically significant. Furthermore, those classified as 'prolonged responders' demonstrated a sustained reduction in stress at follow-up (i.e. after 4 weeks of nil ketamine). LIMITATIONS: Small sample size, open label design, expectancy, secondary analysis CONCLUSIONS: Ketamine showed the capacity to produce a robust and sustained improvement in stress symptoms, in people with chronic suicidality. Future larger, controlled studies examining treatment suitability in a range of stress related disorders are warranted.

Relationships between reduction in symptoms and restoration of function and wellbeing: Outcomes of the Oral Ketamine Trial on Suicidality (OKTOS).

Recovery of functioning is integral to successful treatment outcomes in depressive illness. Optimal antidepressant treatment results in both symptomatic remission and functional recovery. Oral ketamine rapidly reduces suicidality and depression; however, reports of functional and wellbeing outcomes are lacking. This study examines participants' social and occupational functioning and wellbeing outcomes in the Oral Ketamine Trial on Suicidality (OKTOS). Thirty adults with chronic suicidality participated in the trial over 10 weeks. Functional recovery and wellbeing were assessed using the Social and Occupational Functioning Scale (SOFAS) and World Health Organization Well-Being Index (WHO-5). Suicidality and depressive symptoms were assessed using the Beck Scale for Suicidal ideation (BSS) and Montgomery-Asberg Depression Rating Scale (MADRS). Relationships between the four treatment outcomes were analysed. Forty-three percent of participants achieved healthy function (SOFAS ≥ 80) and 27% reported healthy wellbeing (WHO-5 > 60%) at the four-week post-treatment follow-up. Wellbeing was revealed as the data-derived treatment endpoint for the sample. Effect sizes for functioning and wellbeing outcomes were smaller than for suicidality and depression outcomes. Results suggest that reduction in depressive symptoms and suicidal ideation may be necessary but not sufficient for full restoration of function and wellbeing in antisuicidal and antidepressant therapy, including clinical trials.

Can measures of sleep quality or white matter structural integrity predict level of worry or rumination in adolescents facing stressful situations? Lessons from the COVID-19 pandemic.

INTRODUCTION: COVID-19 has resulted in major life changes to the majority of the world population, particularly adolescents, with social-distancing measures such as home-based schooling likely to impact sleep quality. Increased worry is also likely considering the substantial financial, educational and health concerns accompanying COVID-19. White matter (WM) integrity has been shown to be associated with anxiety and depression symptoms, including worry, as well being closely associated with sleep quality. This study aimed to investigate the associations between pre-COVID sleep quality, WM structural integrity and levels of worry and rumination about COVID. METHODS: N = 30 adolescent participants from Queensland, Australia, completed diffusion tensor imaging (DTI) scanning pre-COVID, the Pittsburgh Sleep Quality Index (PSQI) pre and during COVID, and 9 items designed to measure 3 constructs, perceived impact of COVID, general worry, and COVID-specific worry and rumination. RESULTS: Sleep quality (PSQI total) was significantly poorer during COVID compared with pre-COVID. Sleep onset latency measured pre-COVID was significantly associated with COVID-specific worry and rumination. While the structural integrity of a number of WM tracts (measured pre-COVID) were found to be significantly associated with COVID-specific worry and rumination. Follow-up regression analysis using a model including pre-COVID sleep onset latency, structural integrity of the posterior limb of the internal capsule (PLIC), gender and change in PSQI explained a significant 47% of the variance in COVID-specific worry and rumination. CONCLUSIONS: These findings suggest that adolescents with poor sleep quality and perturbed WM integrity may be at risk of heightened reactivity to future stressful events and interventions should focus on improving sleep onset latency.

A novel, complex systems approach to modelling risk of psychological distress in young adolescents.

Adolescence is a period of significant anatomical and functional brain changes, and complex interactions occur between mental health risk factors. The Longitudinal Adolescent Brain Study commenced in 2018, to monitor environmental and psychosocial factors influencing mental health in 500 adolescents, for 5 years. Participants are recruited at age 12 from the community in Australia's Sunshine Coast region. In this baseline, cross-sectional study of N = 64 participants, we draw on the network perspective, conceptualising mental disorders as causal systems of interacting entities, to propose a Bayesian network (BN) model of lifestyle and psychosocial variables influencing chances of individuals being psychologically well or experiencing psychological distress. Sensitivity analysis of network priors revealed that psychological distress (Kessler-10) was most affected by eating behaviour. Unhealthy eating increased the chance of moderate psychological distress by 600%. Low social connectedness increased the chance of severe psychological disorder by 200%. Certainty for psychological wellness required 33% decrease in unhealthy eating behaviours, 11% decrease in low social connectedness, and 9% reduction in less physical activity. BN can augment clinician judgement in mental disorders as probabilistic decision support systems. The full potential of BN methodology in a complex systems approach to psychopathology has yet to be realised.

Low dose oral ketamine treatment in chronic suicidality: An open-label pilot study.

Recently, low-dose ketamine has been proposed as a rapid-acting treatment option for suicidality. The majority of studies to date have utilised intravenous (IV) ketamine, however, this route of administration has limitations. On the other hand, oral ketamine can be administered in a range of settings, which is important in treating suicidality, although studies as to safety and feasibility are lacking. n = 32 adults (aged 22-72 years; 53% female) with chronic suicidal thoughts participated in the Oral Ketamine Trial on Suicidality (OKTOS), an open-label trial of sub-anaesthetic doses of oral ketamine over 6 weeks. Participants commenced with 0.5 mg/kg of ketamine, which was titrated to a maximum 3.0 mg/kg. Follow-up assessments occurred at 4 weeks after the final dose. The primary outcome measure was the Beck Scale for Suicide Ideation (BSS) and secondary measures included scales for suicidality and depressive symptoms, and measures of functioning and well-being. Mean BSS scores significantly reduced from a high level of suicidal ideation at the pre-ketamine (week 0) timepoint to below the clinical threshold at the post-ketamine (week 6) timepoint. The proportion of participants that achieved clinical improvement within the first 6 weeks was 69%, whereas 50% achieved a significant improvement by the follow-up (week 10) timepoint. Six weeks of oral ketamine treatment in participants with chronic suicidality led to significant reduction in suicidal ideation. The response observed in this study is consistent with IV ketamine trials, suggesting that oral administration is a feasible and tolerable alternative treatment for chronic suicidality.

Suicidality in 12-Year-Olds: The Interaction Between Social Connectedness and Mental Health.

Suicidal thoughts and behaviors (STB) are a leading cause of death in adolescence. To date, most research with youth has focused on risk factors for suicide; and less attention has been paid to resilience factors. This study examined whether positive beliefs and social connectedness moderate associations between mental health symptoms and STB. A community sample of 12-year-olds (N = 60) completed self-report questionnaires on their STB, mental health symptoms, positive beliefs and social connectedness. Nearly 20% of the adolescents reported STB. STB was associated with increased mental health symptoms and lower scores on the resilience measures. A significant moderating effect of social connectedness showed that youth with a combination of poor mental health and high levels of social support exhibited lower levels of STB. There was no significant moderating effect of positive beliefs. These results indicate that social support should be screened for in primary care and incorporated into youth suicide prevention programs.

Short strides to important findings: A short interval longitudinal study of sleep quality, psychological distress and microstructure changes to the uncinate fasciculus in early adolescents.

BACKGROUND: Developmental studies have shown adolescence is a period of ongoing white matter (WM) development, reduced sleep quality and the onset of many mental disorders. Findings indicate the WM development of the uncinate fasciculus (UF), a WM tract suggested to play a key role in mental disorders, continues throughout adolescence. While these studies provide valuable information, they are limited by long intervals between scans (1 to 4 years) leaving researchers and clinicians to infer what may be occurring between time-points. To allow inferences to be made regarding the impact that sleep quality may be having on WM development, longitudinal studies with much shorter between-scan intervals are required. METHODS: The current study reports longitudinal data of self-reported sleep quality (PSQI), diffusion tensor imaging (DTI) measures of WM development and psychological distress (K10) for n = 64 early adolescents spanning the first twelve months (four time-points; Baseline, 4, 8, & 12 months) of the Longitudinal Adolescent Brain Study (LABS) study currently underway at the Thompson Institute. RESULTS: Generalised Estimating Equation analysis showed a significant relationship between sleep quality and psychological distress over the four time-points. Reduced radial diffusivity and increased fractional anisotropy of the UF is also reported with increasing age suggesting that ongoing myelination is occurring. Adding sleep quality to the model, however, negatively impacted this myelination process. CONCLUSION: These findings represent an important step towards elucidating how sleep, psychological distress and maturation of the UF may co-develop during early adolescence.

Associations between sleep quality and psychological distress in early adolescence.

Background: Although numerous studies have reported an association between sleep quality and mental health, few have focused on this association exclusively in early adolescence. Targeting this age group is vital as many mental illnesses first emerge during adolescence and remain a significant burden throughout life. Method: In the current study n = 60 participants aged 12 years completed the Pittsburgh Sleep Quality Index (PSQI) and Kessler Psychological Distress Scale (K10). Results: Consistent with previous findings, bivariate correlations revealed significant positive linear relationships between K10 total score and (i) PSQI total score; (ii) sleep quality; (iii) daytime dysfunction; and (iv) sleep disturbance. However, contrary to previous findings, there was no significant correlation between K10 scores and sleep duration. Conclusion: The association between sleep quality and psychological distress in early adolescents provides some important clues about the role that sleep may play in predicting the onset of anxiety and depressive disorders. Longitudinal studies should be undertaken to investigate age-related changes in sleep and psychological distress.

Predicting therapeutic response to oral ketamine for chronic suicidal ideation: a Bayesian network for clinical decision support.

BACKGROUND: The glutamatergic modulator ketamine has been shown to result in rapid reductions in both suicidal ideation (SI) and depressive symptoms in clinical trials. There is a practical need for identification of pre-treatment predictors of ketamine response. Previous studies indicate links between treatment response and body mass index (BMI), depression symptoms and previous suicide attempts. Our aim was to explore the use of clinical and demographic factors to predict response to serial doses of oral ketamine for chronic suicidal ideation. METHODS: Thirty-two participants completed the Oral Ketamine Trial on Suicidality (OKTOS). Data for the current study were drawn from pre-treatment and follow-up time-points of OKTOS. Only clinical and sociodemographic variables were included in this analysis. Data were used to create a proof of concept Bayesian network (BN) model of variables predicting prolonged response to oral ketamine, as defined by the Beck Scale for Suicide Ideation (BSS). RESULTS: The network of potential predictors of response was evaluated using receiver operating characteristic (ROC) curve analyses. A combination of nine demographic and clinical variables predicted prolonged ketamine response, with strong contributions from BMI, Social and Occupational Functioning Assessment Scale (SOFAS), Montgomery-Asberg Depression Rating Scale (MADRS), number of suicide attempts, employment status and age. We evaluated and optimised the proposed network to increase the area under the ROC curve (AUC). The performance evaluation demonstrated that the BN predicted prolonged ketamine response with 97% accuracy, and AUC = 0.87. CONCLUSIONS: At present, validated tools to facilitate risk assessment are infrequently used in psychiatric practice. Pre-treatment assessment of individuals' likelihood of response to oral ketamine for chronic suicidal ideation could be beneficial in making more informed decisions about likelihood of success for this treatment course. Clinical trials registration number ACTRN12618001412224, retrospectively registered 23/8/2018.

Using measures of intrinsic homeostasis and extrinsic modulation to evaluate mental health in adolescents: Preliminary results from the longitudinal adolescent brain study (LABS).

Adolescence is a period when complex interactions occur between mental health risk factors. The Longitudinal Adolescent Brain Study (LABS) commenced in 2018, to monitor environmental and psychosocial factors thought to influence mental health in 500 young people. Participants commence at 12 years of age, via a community-based recruitment model, and data is collected at 15 time-points over five years. This study examines demographic and psychosocial self-report data from time-point 1, for the first 50 participants. Here we investigate associations between environmental and psychosocial factors, considered as measures of intrinsic homeostasis and extrinsic modulation. Numerous strong correlations were found. Findings indicate that sleep dysfunction and social connectedness were strongly associated external modulators of intrinsic homeostasis in this sample of 12-year old participants. To successfully address the increase in mental health problems in young people, comprehensive evaluation of lifestyle and environmental risk factors is recommended in addition to medicalised approaches. Interventions to promote mental health wellbeing in young adolescents should include a focus on sleep quality and patterns and the positive and negative aspects of social connectedness.

Associations between Facial Emotion Recognition and Mental Health in Early Adolescence.

Research shows that adolescents with mental illnesses have a bias for processing negative facial emotions, and this may play a role in impaired social functioning that often co-exists with a mental health diagnosis. This study examined associations between psychological and somatic problems and facial emotion recognition in early adolescence; as any processing biases in this age-group may be an early indicator of later mental illnesses. A community sample of 40 12-year-olds self-rated their symptoms of anxiety, depression, and somatization via two mental health screeners. They also completed a computerized emotion recognition task in which they identified photographs of 40 faces showing expressions of anger, fear, sadness, happiness, or neutral expression. Results showed that increased symptoms of anxiety, depression, and somatization were significantly associated with fewer correct responses to angry expressions. These symptoms were also associated with faster and more accurate recognition of fearful expressions. However, there was no association between mental health and recognition of sad affect. Finally, increased psychological and/or somatic symptomology was also associated with better identification of neutral expressions. In conclusion, youth with increased psychological and/or somatic problems exhibited a processing bias for negative anger and fear expressions, but not sadness. They showed better processing of neutral faces than youth with fewer psychological and/or somatic problems. Findings are discussed in relation to indicators of mental illnesses in early adolescence and the potential underpinning neural mechanisms associated with mental health and emotional facial recognition.

Subcortical Volume Correlates of Psychological Distress in Early Adolescence.

The hippocampus and amygdala have justifiably been the focus of much mental health research due to their putative roles in top-down processing control of emotion, fear, and anxiety. However, understanding the causal relationship between these regions and mental illness has been limited as current literature is lacking in the observation of neuro-structural changes preceding first episodes. Here, we report whole and sub-structural hippocampal and amygdala volume correlates of psychological distress in early adolescence. Automated hippocampal subfield and amygdala nuclei segmentation was carried out in 32 participants (12-13 years old) recruited for the Longitudinal Adolescent Brain Study (LABS) who had psychological distress scores measured by the Kessler-10. Partial correlation analyses revealed significant negative association between left whole amygdala volume and psychological distress. Sub-structure analysis revealed that smaller left hippocampal CA1 volume and left basal and accessory basal amygdala nuclei volumes were all significantly associated with higher levels of psychological distress. Four-month follow-up analysis also revealed an association between change in K10 and CA1 volume suggesting a continued relationship between this hippocampal substructure and psychological distress. Grey matter volume of subcortical sub-structures involved within the hippocampal-basolateral amygdala-prefrontal cortex loop are highly correlated and are significantly reduced in adolescents with higher levels of psychological distress, indicating these nuclei and subfields play an important role in the emergence of mental illness.

Utility of Bayesian networks in QMRA-based evaluation of risk reduction options for recycled water.

BACKGROUND: Quantitative microbial risk assessment (QMRA), the current method of choice for evaluating human health risks associated with disease-causing microorganisms, is often constrained by issues such as availability of required data, and inability to incorporate the multitude of factors influencing risk. Bayesian networks (BNs), with their ability to handle data paucity, combine quantitative and qualitative information including expert opinions, and ability to offer a systems approach to characterisation of complexity, are increasingly recognised as a powerful, flexible tool that overcomes these limitations. OBJECTIVES: We present a QMRA expressed as a Bayesian network (BN) in a wastewater reuse context, with the objective of demonstrating the utility of the BN method in health risk assessments, particularly for evaluating a range of exposure and risk mitigation scenarios. As a case study, we examine the risk of norovirus infection associated with wastewater-irrigated lettuce. METHODS: A Bayesian network was developed following a QMRA approach, using published data, and reviewed by domain experts using a participatory process. DISCUSSION: Employment of a BN facilitated rapid scenario evaluations, risk minimisation, and predictive comparisons. The BN supported exploration of conditions required for optimal outcomes, as well as investigation of the effect on the reporting nodes of changes in 'upstream' conditions. A significant finding was the indication that if maximum post-treatment risk mitigation measures were implemented, there was a high probability (0.84) of a low risk of infection regardless of fluctuations in other variables, including norovirus concentration in treated wastewater. CONCLUSION: BNs are useful in situations where insufficient empirical data exist to satisfy QMRA requirements and they are exceptionally suited to the integration of risk assessment and risk management in the QMRA context. They allow a comprehensive visual appraisal of major influences in exposure pathways, and rapid interactive risk assessment in multifaceted water reuse scenarios.

Modelling microbial health risk of wastewater reuse: A systems perspective.

There is a widespread need for the use of quantitative microbial risk assessment (QMRA) to determine reclaimed water quality for specific uses, however neither faecal indicator levels nor pathogen concentrations alone are adequate for assessing exposure health risk. The aim of this study was to build a conceptual model representing factors contributing to the microbiological health risks of reusing water treated in maturation ponds. This paper describes the development of an unparameterised model that provides a visual representation of theoretical constructs and variables of interest. Information was collected from the peer-reviewed literature and through consultation with experts from regulatory authorities and academic disciplines. In this paper we explore how, considering microbial risk as a modular system, following the QMRA framework enables incorporation of the many factors influencing human exposure and dose response, to better characterise likely human health impacts. By using and expanding upon the QMRA framework we deliver new insights into this important field of environmental exposures. We present a conceptual model of health risk of microbial exposure which can be used for maturation ponds and, more importantly, as a generic tool to assess health risk in diverse wastewater reuse scenarios.

Beyond QMRA: Modelling microbial health risk as a complex system using Bayesian networks.

BACKGROUND: Quantitative microbial risk assessment (QMRA) is the current method of choice for determining the risk to human health from exposure to microorganisms of concern. However, current approaches are often constrained by the availability of required data, and may not be able to incorporate the many varied factors that influence this risk. Systems models, based on Bayesian networks (BNs), are emerging as an effective complementary approach that overcomes these limitations. OBJECTIVES: This article aims to provide a comparative evaluation of the capabilities and challenges of current QMRA methods and BN models, and a scoping review of recent published articles that adopt the latter for microbial risk assessment. Pros and cons of systems approaches in this context are distilled and discussed. METHODS: A search of the peer-reviewed literature revealed 15 articles describing BNs used in the context of QMRAs for foodborne and waterborne pathogens. These studies were analysed in terms of their application, uses and benefits in QMRA. DISCUSSION: The applications were notable in their diversity. BNs were used to make predictions, for scenario assessment, risk minimisation, to reduce uncertainty and to separate uncertainty and variability. Most studies focused on a segment of the exposure pathway, indicating the broad potential for the method in other QMRA steps. BNs offer a number of useful features to enhance QMRA, including transparency, and the ability to deal with poor quality data and support causal reasoning. CONCLUSION: The method has significant untapped potential to describe the complex relationships between microbial environmental exposures and health.