Monique T Jones

Rational
Ketamine has been investigated as a treatment alternative for PTSD for the last 20 years, yet there have been limited reports of biological changes or biomarker characterisation related to treatment.

Objectives
To address this significant gap, this study analysed blood samples from 25 participants with PTSD who took part in an open-label 6-week trial of low dose oral ketamine treatment.

Methods
Serum and plasma samples were quantified before and after ketamine treatment for brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor A (VEGF-A), serotonin, FK506 binding protein 51 (FKBP51) and a panel of cytokines (interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-12p70, IL-17 A and tumour necrosis factor alpha (TNFα)).

Results
Analysis of BDNF and VEGF-A levels from serum detected a significant positive correlation between the two biomarkers and a small but statistically significant decrease in both measures after ketamine treatment. This novel finding reinforces theories that ketamine’s effects may rely on a reciprocal interaction between BDNF and VEGF-A, offering potential insights into a biological mechanism underpinning PTSD symptom reduction. Additionally, the analysis of FKBP51 and serotonin revealed novel relationships between these biomarkers and clinical scales, before and after ketamine treatment. Finally, significant changes or relationships involving the immune cytokines were not detected, possibly because half the participants presented with low-grade inflammation while the other half did not.

Conclusions
This study represents a much-needed broad analysis of blood biomarkers before and after ketamine treatment for PTSD and reveals important biological changes and relationships related to this treatment.

Background: The rising prevalence of mental disorders, including anxiety and depression, are significantly contributing to the global burden of disease. Early-stage symptoms, if unaddressed, may persist or worsen over time, and lead to chronic mental health conditions. The COVID-19 pandemic introduced extraordinary levels of stress, isolation, and uncertainty, creating an environment where many individuals experienced heightened symptoms of anxiety, depression, and other psychological issues, including new mental health conditions in individuals who had previously been well. Promoting engagement in early intervention support for mental health was crucial to lessen individual and societal impacts of the pandemic. In March 2020, due to the COVID-19 pandemic, Australia experienced its first major lockdown. This created an opportunity to develop and deliver a clinical service, an 8-week online wellbeing program using lifestyle medicine and health coaching. It supported the general population who had not sought mental health support before to manage early signs of mental health distress (anxiety, stress, depression), and isolation (social connectedness) due to uncertainty, physical distancing, and lockdowns. This was named the EMERging Anxiety, Loneliness, and Depression (EMERALD) program. This thesis discusses how lifestyle medicine, and the modifiable lifestyle factors such as physical activity, nutrition, sleep, substance use, stress management, and social connection are recognised as fundamental to both physical and mental health. A multimodal approach recognises that clusters of health behaviours, rather than single factors, are more strongly associated with improved mental health outcomes. However, key to engaging in improving lifestyle factors, is the individual’s confidence and motivation to engage behaviour change. Health coaching, grounded in behaviour change and psychological theories, offers a collaborative relationship, placing the individual as the expert and driver of change, and employs evidence-based behaviour change techniques to enhance healthy lifestyle behaviours. Aim: The first aim of this thesis was to detail the components of the EMERALD program using a standardised intervention reporting tool. Historically, behaviour change interventions have not been described in sufficient detail to allow for replication. The Template for Intervention Description and Replication (TIDieR) checklist is used to provide detailed description of the intervention, enhancing transparency and replicability of the intervention components used in the program. The second aim was to evaluate changes in self-reported mental health outcomes following participation in the EMERALD wellbeing program, to assess its effectiveness in improving psychological wellbeing. The research hypotheses were: (i) program completion would lead to reduced depression and anxiety, decreased loneliness, improved wellbeing, and enhanced functioning; (ii) greater improvements in overall wellbeing, were predicted for those with mild baseline depression and anxiety symptoms compared to those with moderate symptoms. Methods: This was an observational and retrospective study of the EMERALD program. The TIDieR checklist was utilised to comprehensively describe the program protocol. Clinical outcomes were analysed for program completers using linear mixed-effects models to examine pre- to post intervention change. Eligibility was determined using the Generalised Anxiety Disorder Scale (GAD- 7), and the Patient Health Questionnaire (PHQ-9). Primary Outcome measures included the GAD-7 and PHQ-9, alongside the World Health Organisation (Five) Wellbeing Index (WHO-5), Work and Social Adjustment Scale (WSAS), and the De Jong Gierveld Loneliness Scale (DJGLS) enabling assessment of mental health symptoms, wellbeing, functional impairment, and loneliness. Results: The program was developed to align with the latest evidence-based literature in lifestyle medicine and solution-focused coaching. The online program also offered allied health expertise, online educational modules, and was tailored to participants. Clinical outcomes from 85 participants who completed the 8-week program between August 2020, and June 2021 are reported. Findings revealed significant improvements across all measures. These results support the benefits of online mental health coaching and lifestyle medicine interventions for improving psychological wellbeing during periods of elevated need. Discussion: The program protocol employing the TIDieR tool has been published. In doing so, this extends the current evidence base and offers sufficient detail to support replication. Findings showed the EMERALD program demonstrated the potential of telehealth-delivered lifestyle medicine, and health coaching to support mental health in the general population. These findings contribute to the growing evidence base for early intervention approaches, and highlight the importance of scalable, accessible mental health services. Given the rising global mental health burden, early intervention lifestyle medicine programs may play a vital role in mitigating progression to chronic mental health conditions. Delivering the program as a clinical service, rather than under controlled trial conditions, had notable strengths and limitations. The flexibility built into the program, including participant selection of lifestyle medicine topics and goals, and the use of health coaching and behaviour change techniques, enabled a high level of personalisation and autonomy, which likely enhanced engagement and contributed to the positive outcomes observed. However, the absence of controlled conditions, together with gaps in data collection, limits causal inference and constrained the analyses that was undertaken. This thesis contributes to the evidence of the success of early intervention lifestyle medicine and coaching programs to improve emerging mental health symptoms in the general population. Further research is recommended for the progression of EMERALD to a RCT to strengthen causal inference. The use of a standardised intervention framework to detail the intervention for transparency, and replication would benefit the evidence based.

The COVID-19 pandemic highlighted growing demand on mental health services and the need for scalable early interventions. Lifestyle medicine is a first-line treatment for common mental health disorders. Combining health coaching with lifestyle medicine and online delivery may improve accessibility and effectiveness. This study evaluated the EMERALD program, an 8-week online lifestyle medicine and health coaching intervention delivered as a clinical service during the pandemic. A single arm, pre–post observational design was used, with assessments completed at baseline (week 1) and post-intervention (week 8). Eighty-five adults (M_age = 46.47, SD = 15.47) completed all outcome measures; most participants identified as female (83.5%). Eligible community participants reported mild to moderate anxiety or mood symptoms (PHQ-9 < 14; GAD-7 < 14). Individuals with severe symptoms, suicide risk, or current engagement in psychological or psychiatric treatment were excluded. Depression, anxiety, wellbeing, loneliness, and functioning across life domains (e.g., occupational, social, daily responsibilities) were assessed using validated self-report measures. Significant improvements were observed across all measures, with greater wellbeing gains among those with higher baseline depression severity. These findings support the benefits of online mental health coaching and lifestyle medicine interventions for improving psychological wellbeing during periods of elevated need.

Objective
The rising prevalence of mental health symptoms brought on by the COVID19 pandemic led to the inception and development of EMERging Anxiety, Loneliness, Depression (EMERALD) well-being programme. EMERALD was designed to improve psychological well-being of the general population who had not previously sought mental health support. The programme incorporated a focus on lifestyle medicine and was underpinned by solution focused health coaching. The aim of the paper is to describe the programme according to the Template for Intervention Description and Replication (TIDieR) checklist to provide detailed reporting of the intervention's elements.
Methods
The TIDieR checklist was utilised to comprehensively describe the programme, including theoretical underpinnings, materials, procedures, providers, mode of delivery and tailoring of the programme. The Behaviour Change Technique Taxonomy v2 was used to identify the specific behaviour change techniques used within the solution focused health coaching framework.
Results
The programme was developed to align with the latest evidence-based literature in lifestyle medicine and solution focused coaching. The programme also offered allied health expertise, online educational modules and was tailored to the participants. The programme was delivered online through a telehealth platform.
Conclusion
The TIDieR checklist has enabled the provision of a detailed structure of the EMERALD program intervention. The behaviour change taxonomy has facilitated the outlining of specific techniques used in health coaching sessions. Both structures have operationalised the detail of the intervention for the purposes of replication and informing the literature.

Analysis of cognitive behavioural therapy apps for generalised anxiety disorder: Evidence-based content and user experience. Abstract Mental illness substantially contributes to the global burden of disease, with anxiety high in prevalence. The increase of mobile technology, mental health apps have potential to lessen this burden. However, within apps, the use of evidence-based interventions, such as cognitive behavioural therapy (CBT) are limited. Regardless, many commercially available mental health apps are highly rated by users, highlighting the need to understand what makes mental health apps valuable to the user. The contribution of this study was to uncover apps that support generalised anxiety disorder (GAD) and worry with a CBT basis, explore app functionality, and user experience. Firstly, by identifying apps that support GAD and worry and included CBT. Secondly, by identifying and analysing therapeutic and engagement functions within the apps, and finally, by thematically analysing user reviews. Six apps were identified to support GAD and worry that purported to be CBT-based. However, CBT therapeutic features and engagement features were minimally present in the apps. User reviews yielded 112 comments about the apps and key themes were identified about the app users' global experiences with the app, and about the combination of technological (e.g., useability, reliability) and therapeutic experiences (e.g., learning and using skills). Future development of quality apps to support GAD and worry must consider the empirical standing of both therapeutic and technology aspects, to provide efficacious and engaging interventions.

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.

Research of clinical patients with a pre-existing psychological disorder involved in a disaster is limited. This study investigated relationships between pre-and post-earthquake psychopathology (i.e., anxiety, depression, and posttraumatic stress), peritraumatic distress, work and social impairment, perceived support post-earthquake, and personality dimensions in an outpatient, anxiety disorder population. Thirty-seven patients with pre-existing anxiety disorders completed standard clinical assessments pre-earthquake. They then completed a second set of questionnaires 3 months after exposure to the 2010 Christchurch, Aotearoa New Zealand, earthquake. Bivariate correlations on the variables determined what relationships were present, and paired samples t-tests assessed differences in pre-and post-earthquake anxiety, depression, and alcohol and drug consumption as well as relationships with peritraumatic distress, posttraumatic stress, and personality variables. Significant relationships were found between pre-earthquake psychopathology, peritraumatic distress, post-earthquake psychopathology, and impairment. Paired samples t-tests demonstrated anxiety and depression scores were significantly lower post-earthquake. However, prior anxiety and depression, as well as peritraumatic distress, were significantly associated with post-earthquake psychopathology, including posttraumatic stress and impaired work and social functioning. There were no differences between pre-and post-event alcohol and drug consumption. The personality dimensions of harm avoidance, self-directedness, and persistence significantly associated with post-disaster anxiety and depression. Promisingly, post-earthquake perceived support was significantly negatively correlated with depression and posttraumatic stress.

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.

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 resto-ration of function and wellbeing in antisuicidal and antidepressant therapy, including clinical trials.