Arts and Social Sciences, Irving K. Barber Faculty of (Okanagan)
Psychology, Department of (Okanagan)
DSpace
UBCO
Gregoire, Nina Honor Dyson
Doctor of Philosophy - PhD
University of British Columbia
Mental illness remains a leading cause of disability, with treatment-resistant conditions presenting significant challenges to clinicians and patients alike. This research explores the baseline characteristics, early treatment outcomes, and patient experiences of individuals undergoing ketamine-assisted therapy for treatment-resistant psychological conditions. Study 1 utilized latent profile analysis (LPA) on patients seeking ketamine treatment to identify three personality profiles and four symptom clusters. Personality and symptom profiles were associated with many meaningful baseline differences between participants but were not associated with treatment outcomes; that is, ketamine-assisted therapy led to reductions in both depression and anxiety across the personality and symptom profiles. Trauma history, however, predicted greater improvements in both depression and anxiety following ketamine treatment. Study 2 examined patient-reported experiences, revealing high levels of satisfaction with the treatment but significant barriers related to financial cost, accessibility, and post-treatment support. Together, these findings highlight the importance of tailoring ketamine-assisted therapy protocols to individual characteristics, emphasizing trauma-informed care, and addressing systemic inequities to enhance the accessibility and efficacy of this emerging therapy. Future research should prioritize longitudinal studies and randomized controlled trials to further refine personalized approaches to ketamine-assisted therapy.
PERSONALIZED APPROACHES TO MENTAL HEALTH INTERVENTIONS: EFFECTIVENESS OF KETAMINE-ASSISTED THERAPY FOR TREATMENT-RESISTANT PSYCHOLOGICAL CONDITIONS by Nina Honor Dyson Gregoire B.Sc. (Hons), University of British Columbia, 2017 M.A., University of British Columbia, 2021 A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE COLLEGE OF GRADUATE STUDIES (Psychology) THE UNIVERSITY OF BRITISH COLUMBIA (Okanagan) April 2025 © Nina Honor Dyson Gregoire, 2025 ii The following individuals certify that they have read, and recommend to the College of Graduate Studies for acceptance, a dissertation entitled: PERSONALIZED APPROACHES TO MENTAL HEALTH INTERVENTIONS: EFFECTIVENESS OF KETAMINE-ASSISTED THERAPY FOR TREATMENT-RESISTANT PSYCHOLOGICAL CONDITIONS submitted by Nina Honor Dyson Gregoire in partial fulfillment of the requirements of the degree of Doctor of Philosophy Dr. Paul G. Davies, Irving K. Barber Faculty of Arts and Social Sciences Supervisor Dr. Harry Miller, Irving K. Barber Faculty of Arts and Social Sciences Supervisory Committee Member Dr. Susan Holtzman, Irving K. Barber Faculty of Arts and Social Sciences Supervisory Committee Member Dr. Sally Stewart, Faculty of Health and Social Development University Examiner Dr. David Creswell, Carnegie Mellon University External Examiner iii Abstract Mental illness remains a leading cause of disability, with treatment-resistant conditions presenting significant challenges to clinicians and patients alike. This research explores the baseline characteristics, early treatment outcomes, and patient experiences of individuals undergoing ketamine-assisted therapy for treatment-resistant psychological conditions. Study 1 utilized latent profile analysis (LPA) on patients seeking ketamine treatment to identify three personality profiles and four symptom clusters. Personality and symptom profiles were associated with many meaningful baseline differences between participants but were not associated with treatment outcomes; that is, ketamine-assisted therapy led to reductions in both depression and anxiety across the personality and symptom profiles. Trauma history, however, predicted greater improvements in both depression and anxiety following ketamine treatment. Study 2 examined patient-reported experiences, revealing high levels of satisfaction with the treatment but significant barriers related to financial cost, accessibility, and post-treatment support. Together, these findings highlight the importance of tailoring ketamine-assisted therapy protocols to individual characteristics, emphasizing trauma-informed care, and addressing systemic inequities to enhance the accessibility and efficacy of this emerging therapy. Future research should prioritize longitudinal studies and randomized controlled trials to further refine personalized approaches to ketamine-assisted therapy. iv Lay Summary Many people struggle with mental illnesses that do not respond to standard treatments, leaving them searching for new options. This research investigates the potential of ketamine-assisted therapy as a treatment for people with complex and co-occurring mental health challenges, such as severe depression, anxiety, and trauma-related disorders. In the first study, personality traits and symptoms were analyzed to understand how patients differ before starting treatment, which revealed three personality subgroupings and four symptom subgroupings. In other words, not all patients seeking ketamine had the same personality or symptoms; rather, they clustered into groups based on personality and symptom measures. It was found that individuals with a history of trauma often experience better outcomes from ketamine-assisted therapy, showing particular improvements in depression and anxiety. However, some patients without trauma histories experienced worsening anxiety, suggesting the need for tailored support. The second study focused on patients' experiences, showing that while many felt significant emotional relief from ketamine, barriers like high costs, travel requirements, and limited follow-up care made the process challenging. These findings emphasize the importance of designing personalized treatment plans and making ketamine therapy more accessible to those who need it. Future research should explore making this promising treatment more effective and accessible. v Preface This dissertation is the original and unpublished of the author, N. Gregoire. The method and results reported in Chapters 2 & 3 were covered by UBC Behavioural Research Ethics # H23-02976. The method and results reported in Chapters 4 & 5 were covered by UBC Behavioural Research Ethics # H24-02658. Generative AI was not used for this research. vi Table of Contents Table of Contents Abstract .......................................................................................................................................... iii Lay Summary ................................................................................................................................ iv Preface ............................................................................................................................................. v Table of Contents .......................................................................................................................... vi List of Tables .................................................................................................................................. x List of Figures ............................................................................................................................... xi Acknowledgements ....................................................................................................................... xii Dedication.................................................................................................................................... xiv Chapter 1 - Introduction ................................................................................................................ 1 The Realities of Comorbidities ............................................................................................................... 2 Anxiety ................................................................................................................................................................. 2 Posttraumatic Stress Disorder ............................................................................................................................... 3 Chronic Pain ......................................................................................................................................................... 5 Quality of Life ...................................................................................................................................................... 6 Potential Treatment – Ketamine ............................................................................................................ 6 Personality and Mental Illness ............................................................................................................. 10 The relationship between personality and mental illness ................................................................................... 11 The role of personality in treatment ................................................................................................................... 12 Severity of Symptoms ............................................................................................................................ 14 The Current Realities of Mental Health Care in Canada ................................................................. 16 Barriers to Accessing Care ................................................................................................................... 17 Present Research ................................................................................................................................... 18 Study 1 ................................................................................................................................................................ 18 Study 2 ................................................................................................................................................................ 20 Chapter 2 Method – Study 1 ........................................................................................................ 23 Participants ............................................................................................................................................ 23 Treatment Eligibility Criteria .............................................................................................................. 23 Treatment Exclusions/Contraindications............................................................................................ 24 Treatment Protocol ............................................................................................................................... 24 Procedure ............................................................................................................................................... 25 Measures................................................................................................................................................. 26 Personality Measure ........................................................................................................................................... 26 Symptomology Measures ................................................................................................................................... 27 Depression. ......................................................................................................................................................... 27 Anxiety. .............................................................................................................................................................. 27 PTSD. ................................................................................................................................................................. 28 Adverse Childhood Events. ................................................................................................................................ 28 vii Treatment Expectations. ..................................................................................................................................... 28 Quality of Life. ................................................................................................................................................... 29 Analytic Approach ................................................................................................................................ 30 Descriptive Statistics .......................................................................................................................................... 30 Latent Profiles .................................................................................................................................................... 30 Mean Differences ............................................................................................................................................... 32 Categorical Differences ...................................................................................................................................... 33 Chapter 3 Results – Study 1 ......................................................................................................... 34 Descriptive Baseline Statistics .............................................................................................................. 34 Relationship between demographic information and Personality Profiles ...................................... 40 Sex at birth .......................................................................................................................................................... 40 Age ..................................................................................................................................................................... 41 Education ............................................................................................................................................................ 41 Descriptions of Traumatic Events in the Sample ............................................................................... 42 Trauma and Personality ....................................................................................................................... 43 PTSD .................................................................................................................................................................. 43 ACEs................................................................................................................................................................... 44 Depression/Anxiety and Personality .................................................................................................... 44 Treatment Expectations and Personality ............................................................................................ 46 Symptom LPA........................................................................................................................................ 47 Relationship between demographic information and Symptom Clusters ....................................... 49 Sex at birth .......................................................................................................................................................... 49 Age ..................................................................................................................................................................... 50 Education ............................................................................................................................................................ 50 Trauma and Symptomology ................................................................................................................. 51 PTSD .................................................................................................................................................................. 51 Adverse Childhood Events ................................................................................................................................. 52 Depression/Anxiety Change Scores and Symptomology ................................................................... 52 Depression .......................................................................................................................................................... 52 Anxiety ............................................................................................................................................................... 52 Clinical Change Among the 65 Patients Who Received Ketamine Infusions and Completed Clinical Follow-up. ................................................................................................................................ 53 Category Change ................................................................................................................................................ 53 Caseness Threshold Among the 65 Patients Who Received Ketamine Infusions.............................................. 54 Reliable Change Index for PHQ-9 Among the 65 Patients Who Received Ketamine Infusions ....................... 55 Relationships Between Demographics and Reliable Change Outcomes in Depression Among the 65 Patients Who Received Ketamine Infusions .................................................................................. 55 Personality and Reliable Change Index Scores in Depression ........................................................................... 55 Symptom Clusters and Reliable Change Index Scores in Depression ............................................................... 56 History of Trauma and Reliable Change Index Scores in Depression ............................................................... 57 Reliable Change Index for GAD-7 Among the 65 Patients Who Received Ketamine Infusions ...................... 57 Relationships Between Demographics and Reliable Change Outcomes in Anxiety Among the 65 Patients Who Received Ketamine Infusions ....................................................................................... 57 Personality Profiles and Reliable Change Index Scores in Anxiety ................................................................... 57 Symptomology and Reliable Change Index Scores in Anxiety ......................................................................... 58 History of Trauma and Reliable Change Index Scores in Anxiety .................................................................... 58 viii Reliable Recovery Among the 65 Patients Who Received Ketamine Infusions ................................................ 59 Descriptive Analyses of 65 Patients Who Received Ketamine Infusions ......................................... 59 Exploratory Paired t-tests for Change in Depression Scores among the 65 Patients who received Ketamine Treatment ............................................................................................................................. 60 History Of Trauma ............................................................................................................................................. 60 Presence of Significant Pain ............................................................................................................................... 60 Sex at Birth ......................................................................................................................................................... 60 Exploratory Paired t-tests for Change in Anxiety Scores among the 65 Patients who received Ketamine Treatment ............................................................................................................................. 61 History Of Trauma ............................................................................................................................................. 61 Presence of Significant Pain ............................................................................................................................... 61 Sex at Birth ......................................................................................................................................................... 61 Exploratory Paired t-tests for Change in Quality of Life Scores among the 65 Patients who received Ketamine Treatment .............................................................................................................. 61 History Of Trauma and Physical Quality of Life ............................................................................................... 61 History Of Trauma and Psychological Quality of Life ...................................................................................... 62 Presence of Significant Pain and Physical Quality of Life ................................................................................. 62 Presence of Significant Pain and Psychological Quality of Life ........................................................................ 62 Sex at Birth and Physical Quality of Life ........................................................................................................... 62 Sex at Birth and Psychological Quality of Life .................................................................................................. 63 Chapter 4 Method – Study 2 ........................................................................................................ 65 Data Collection ...................................................................................................................................... 65 Analytic Procedure ................................................................................................................................ 65 Chapter 5 Results – Study 2 ......................................................................................................... 67 Pre-Treatment Considerations ............................................................................................................. 67 Quantitative ........................................................................................................................................................ 67 Open Ended Responses ...................................................................................................................................... 68 Treatment Considerations .................................................................................................................... 70 Quantitative ........................................................................................................................................................ 70 Open Ended - Relief ........................................................................................................................................... 71 Open Ended - Benefits ........................................................................................................................................ 73 Open Ended – No Improvement or Worsening .................................................................................................. 74 Post-Treatment Considerations ........................................................................................................... 76 Quantitative ........................................................................................................................................................ 76 Open Ended—Life Impacted .............................................................................................................................. 77 Chapter 6 – General Discussion .................................................................................................. 80 Study 1 – Clinical Data ......................................................................................................................... 80 Personality Profiles ............................................................................................................................................. 80 Demographics and Personality ........................................................................................................................... 81 Depression, Anxiety, and Personality ................................................................................................................ 82 Changes in Depression and Anxiety Following Treatment ................................................................................ 84 Trauma and Personality ...................................................................................................................................... 85 Symptom Clusters .............................................................................................................................................. 86 Symptoms and Demographic Factors ................................................................................................................. 86 Trauma and Symptomology ............................................................................................................................... 87 Changes in Depression and Anxiety Post-Treatment ......................................................................................... 88 Clinical Change and Reliable Change Index ...................................................................................................... 88 ix Improvements in Depression and Anxiety ......................................................................................................... 89 Quality of Life Changes ..................................................................................................................................... 89 History of Trauma .............................................................................................................................................. 90 Presence of Significant Pain ............................................................................................................................... 90 Sex at Birth ......................................................................................................................................................... 91 Study 2: Patient Experiences and Perceptions ................................................................................... 91 Strengths and Limitations .................................................................................................................... 92 Strengths ............................................................................................................................................................. 92 Limitations .......................................................................................................................................................... 93 Implications ............................................................................................................................................ 94 Clinical Implications .......................................................................................................................................... 94 Policy Implications ............................................................................................................................................. 96 Future Directions ................................................................................................................................................ 98 Conclusion .............................................................................................................................................. 98 References .................................................................................................................................. 100 Appendices .................................................................................................................................. 137 Appendix 1 ............................................................................................................................................................ 137 Appendix 2 ............................................................................................................................................................ 138 x List of Tables Table 1. Demographics………………………………………………………...………………..35 Table 2. Personality Descriptives…………………………………………………...…………..37 Table 3. Symptom Descriptives……………………………………………….………………..38 Table 4. Personality Fit Indices…………………………………………………..……………..39 Table 5. Personality Profile Descriptives………...……………………………………………..40 Table 6. Personality Frequency Chart…………………………………………………………..40 Table 7. Symptom Fit Indices…………………………………………………………………..47 Table 8. Symptom Profile Descriptives………………………………….……………………..49 Table 9. Symptom Frequency Chart…………………………………………..………………..49 Table 10. Depression Category Change…………………………………………...……………53 Table 11. Anxiety Category Change……………………………………………………………54 Table 12. Mean Change (Hx Trauma)……………………………………………….…………63 Table 13. Mean Change (Presence of Pain)………………………………….…………………63 Table 14. Mean Change (Sex at Birth)…………………………………………………………64 Table 15. Pretreatment Descriptives……………………………………………………………68 Table 16. Treatment Descriptives………………………………………………………………71 Table 17. Post Treatment Descriptives…………………………………………………………76 xi List of Figures Figure 1. Personality Profiles…………………………………………………………………39 Figure 2. Symptom Profiles …….……………………………………………………………48 xii Acknowledgements My parents always wanted something better for me and my siblings, better than what they had. I didn’t know what that something was until I found psychology. Throughout my academic journey, I discovered it wasn’t just my family who wanted more for me; there were many on this path. It is my honour to thank them here now. I will begin with my kind, generous, and brilliant supervisor, Dr. Paul Davies. Having someone like you believe in me gave me enough to start to believe in myself. I have been made better in a million different ways for having you as my mentor. I can never pay you back, but I can pay it forward, and when I do, I hope to be to someone what you have been to me. Next, I would like to thank my committee members, Drs. Harry Miller and Susan Holtzman, for your years of thoughtful leadership and support. Your generous contributions to my work and success have been invaluable. I further thank the many professors who have taken the time to share their experiences and insights, particularly Drs. Leanne ten Brinke and Trudy Kavanagh. You have been such sources of wisdom, comfort, and perseverance. I am so lucky to have you. I want to thank my incredible collaborators, Dr. Kimberley Kaseweter, Ethan Klukas, Dr. Kathleen Scullion, Dr. Mark Nazemi, and Zak Draper. Each of you has offered mentorship and expertise that has shaped my PhD research; I am deeply thankful. A special Thanks to Dr. Francois Louw, I am grateful for your vast contributions to my academic and professional endeavours. In this same regard, I thank EntheoMed and those who participated for trusting me with your data and undertaking this work; it has been a sincere privilege. On a personal note, I would like to thank my mum and dad for teaching me the value of a growth mindset, discipline, and hard work, even when it’s uncomfortable; it has paid many dividends in this process. My sister, Tasha, without you, none of this would be, and my brother, Aidan, you have given me a lifetime of practising for a defence. You two have always been my best friends, and as we get older, the link to our shared past. I love you both so much. I am thankful to my siblings, their spouses, and my in-laws for sharing your beautiful children with me - my nibblings have been my greatest joy in moments of overwhelm and deadlines. Thanks to Auntie Helen for your thoughtfulness and my MIL, Patricia, for your kind words and belief. My life has been blessed with friends who feel like family. Kimmy, thank you for always being there and often dragging me to the finish line, I am certain I wouldn’t have made it without you. Thank you for your loyalty and trust. Aves, you have a magical ability to make everything fun, and I love you for it! Alanna, thank you for calming even the most emotionally turbulent of times, and Ashley, for always finding the sunshine in the rain. Marta, Amanda, Mik, Diana, and Chris, thank you all for the brunches, phone chats, trips, encouragement, love and support you’ve given me through the years. I am so touched to have this much love in my life. In the tradition of saving the best for last, I’d like to thank my hubby, Dusty; you have given me everything so I could chase my PhD dreams. I love you. There is no one I know who is more generous than you. You are the most supportive, encouraging, and patient partner I could ever have asked for – your heart is true, you’re a pal and a confidant. xiii Finally, this dissertation aims to make mental healthcare more accessible. It represents the culmination of thousands of hours of commitment and sacrifice from those I’ve thanked, those who participated, and those who might read it. Thank you for believing in something better. xiv Dedication In loving memory of the hilarious Kathleen McGee. 1 Chapter 1 - Introduction Mental illness is a long-standing leading cause of disability in Canada (Institute for Health Metrics and Evaluation, 2015; Lim et al., 2008; Mental Health Commission of Canada, 2014). For example, approximately half a million Canadians miss work each week due to mental illness (Canadian Psychological Association, 2024), and Canadians who experience mental health-related disabilities earn, on average, 31% less than their non-disabled peers (Statistics Canada, 2023). In any given year, 20% of Canadians experience a mental illness, and by age 40, 50% have lived with some form of mental illness (Dobson et al., 2020). Yet, despite this high prevalence, mental health care in Canada remains underfunded and difficult to access (Dyck, 2022; Moroz et al., 2020). Without improvements or changes in how Canada approaches mental health, it is estimated that the total cost to the economy will add up to more than $2.5 trillion by 2040 (Mental Health Commission of Canada, 2016). Accounting for a large proportion of mental illnesses are mood disorders, with major depressive disorder being the most prevalent (Dobson et al., 2020). Depression can cause severe challenges such as sleep, thinking, and memory issues and is characterized by persistent sadness, hopelessness, loss of interest in pleasurable activities, and sleep disturbance (DSM-5). Unfortunately, amid the COVID-19 pandemic, there was a rise in major depressive disorder among adults (Liu et al., 2021). Specifically, in the Fall of 2020, 15% of Canadian adults screened positive for major depressive disorder, rising to 19% in the Spring of 2021 (Liu et al., 2021). This increase in major depressive disorder has persisted beyond the end of the pandemic (Statistics Canada, 2024). It is further estimated that only half of Canadians who experience a major depressive episode receive “potentially adequate care” (Patten et al., 2016). This 2 undertreatment is particularly concerning, given that with adequate treatment and support, most people recover (CAMH, 2021). The Realities of Comorbidities Anxiety. Anxiety and depression rarely occur in isolation, with comorbidity between generalized anxiety disorder and major depressive disorder presenting a complex and pervasive public health challenge. The co-occurrence of these disorders exacerbates symptom severity, impairs daily functioning, and complicates treatment approaches (Pelletier et al., 2017). In 2012, approximately 700,000 Canadians aged 15 and older (2.5% of the population) reported symptoms of generalized anxiety disorder, with half also experiencing symptoms consistent with a major depressive episode. Individuals with both generalized anxiety disorder and major depressive disorder reported significantly worse health outcomes than those experiencing either disorder alone. Furthermore, around 50% of individuals with comorbid generalized anxiety disorder and major depressive disorder indicated unmet or only partially met mental health care needs, compared to 30% among those with either generalized anxiety disorder or major depressive disorder alone (Pelletier et al., 2017). More recent data underscore the growing magnitude of the issue. In 2023, 7.6% of Canadians aged 15 or older met the criteria for a major depressive episode (i.e., five or more depressive symptoms for two weeks), while 5.2% were diagnosed with generalized anxiety disorder (Stephenson, 2023). Among individuals with mood, anxiety, or substance use disorders, one in three reported unmet or only partially met mental health care needs (Stephenson, 2023). These challenges were further amplified by the COVID-19 pandemic, during which rates of both depression and anxiety surged and have since remained elevated (Statistics Canada, 2023b; Statistics Canada, 2024). 3 The high prevalence of anxiety-depression comorbidity is well-documented in the literature. For instance, Lamers et al. (2011) found that 63–67% of individuals with major depressive disorder also experienced concurrent anxiety, with 75–81% demonstrating more severe clinical presentations. Similarly, Kessler et al. (2015) estimated that over half of individuals diagnosed with a major depressive episode will experience an anxiety disorder at some point in their lifetime. These findings are consistent with recent data indicating that comorbid generalized anxiety disorder and major depressive disorder often lead to more complicated and chronic illness trajectories (Davies et al., 2023). Compared to individuals with a single diagnosis of either anxiety or depression, those with comorbid anxiety and depression report worse health outcomes across several dimensions. Specifically, these individuals frequently experience heightened exposure to trauma, greater functional impairment, more severe psychiatric symptoms, and the onset of symptoms tends to be earlier, more chronic, or recurrent, contributing to a higher overall burden of illness (Cyranowski et al., 2012; Kessler et al., 2015; Lamers et al., 2011; Moffitt et al., 2007; Ruscio et al., 2017). Individuals with comorbid anxiety and depression are also at greater risk of suicide ideation or attempts, with research indicating significantly higher rates of suicidal behaviour in this population (Cyranowski et al., 2012). The complex interplay between these disorders not only complicates treatment but also necessitates more comprehensive, integrated approaches to care, particularly given the elevated severity and chronicity of symptoms. Posttraumatic Stress Disorder. Posttraumatic stress disorder (PTSD) and depression frequently co-occur, with comorbidity rates ranging between 30% and 50% (Creamer et al., 2001; Gros et al., 2012; Kessler et al., 2005; Shalev et al., 2017) suggesting that up to half of individuals diagnosed with PTSD may also experience major depressive disorder at some point 4 in their lives. PTSD alone is debilitating, with a lifetime prevalence of approximately 8-9% in the general population (Kessler, 2000; Van Ameringen et al., 2008). The high rates of comorbidity complicate the clinical picture, as the overlapping symptoms of both disorders, such as sleep disturbances, emotional outbursts, and loss of interest in activities, can intensify the overall psychological burden (Gros et al., 2012). In recent years, mental health disorders, including PTSD and major depressive disorder, have been on the rise, possibly due to heightened awareness, diagnostic capabilities, and global stressors such as the COVID-19 pandemic. During the autumn of 2020, one in five Canadian adults reported moderate to severe symptoms of depression, anxiety, or PTSD, with this figure increasing to one in four by early 2021. This elevated rate persisted through 2023 (Statistics Canada, 2023b; Statistics Canada, 2024). Like the comorbid relationship between major depressive disorder and generalized anxiety disorder, treatment for PTSD and major depressive disorder can pose serious challenges. For example, it has been observed that trauma-focused psychological therapies, despite their efficacy, are associated with higher dropout rates, with those rates ranging from 16% to 18% for patients undergoing various forms of therapy (Cooper & Conklin, 2015; Imel et al., 2013; Lewis et al., 2020). One explanation for this is that trauma-focused treatments often require patients to relive their traumatic experiences, which can trigger an increase in intrusive thoughts, nightmares, or even new symptoms such as shame and anger, all of which may be distressing enough to lead to premature termination of treatment (Berk & Parker, 2009). The treatment of PTSD and major depressive disorder comorbidity also presents unique clinical challenges. Comorbid patients may not respond as well to standard treatment protocols for either disorder in isolation, and the combination of symptoms can complicate therapeutic 5 progress. For example, patients with both PTSD and major depressive disorder are more likely to experience heightened levels of emotional dysregulation, which could exacerbate the emotional exhaustion associated with trauma-focused therapies (Shapiro et al., 2021). Additionally, the overlapping cognitive distortions and avoidance behaviours seen in both disorders can make adherence to treatment particularly difficult (Karatzias et al., 2019). Chronic Pain. It is not only mental health conditions that co-occur; mental and physical health are closely interconnected, with each significantly influencing the other. Chronic pain alone can be a debilitating condition, both physically and psychologically, and it is highly prevalent, affecting about one in five Canadians, resulting in substantial personal and societal costs (Campbell et al., 2021). The International Association for the Study of Pain (IASP) defines chronic pain as any persistent or intermittent pain that lasts longer than three months beyond the anticipated time of healing. Individuals living with chronic pain often experience exhaustion, cognitive difficulties, and physical limitations, which, when combined with a mood disorder such as major depressive disorder, can further reduce their quality of life (Dionisie, 2023; Raffaeli, 2021). Individuals with chronic medical conditions, such as chronic pain, are also at significantly higher risk of developing mood disorders, particularly major depressive disorder (Cosio & Meshreki, 2017; Mayo Clinic Proceedings, 2016; Public Health Agency of Canada, 2008). This relationship has been found to be bi-directional, meaning that people diagnosed with mood disorders are also more susceptible to developing chronic medical conditions (Smetanin et al., 2015). This reciprocal relationship exacerbates the difficulties faced by individuals suffering from both conditions (Smetanin et al., 2015). The comorbidity of chronic pain and major depressive disorder is very common. Studies have shown that up to 85% of individuals with chronic pain also suffer from major depressive 6 disorder (Bair et al., 2003; Williams et al., 2003), and this co-occurrence tends to create a destructive cycle where both conditions exacerbate one another. For instance, depression can heighten an individual’s sensitivity to pain, which in turn worsens the depressive symptoms (Sheng et al., 2017). Further, those who experience depression induced by chronic pain typically have a poorer prognosis and are more likely to experience greater functional impairment compared to individuals suffering from chronic pain alone (Fishbain et al., 1997). This reality highlights the importance of integrated care approaches that address both chronic pain and associated mental health conditions. Quality of Life. Mental health significantly influences an individual’s quality of life, encompassing physical health, psychological state, social relationships, and environmental context. Research indicates that mental health disorders, such as depression and anxiety, are associated with diminished quality of life across various domains (Saarni et al., 2007). For instance, individuals with mental health conditions often report reduced well-being, autonomy, self-perception, and social belonging, all of which contribute to a lower quality of life (Saarni et al., 2007). Interventions targeting mental health concerns have demonstrated efficacy in enhancing quality of life. Pharmacological treatments can alleviate depressive symptoms and improve overall well-being, though their impact on quality of life may vary among individuals depending on treatment response and side effects (Fournier et al., 2010). Potential Treatment – Ketamine Given the considerable complexities and overlap in conditions and their concomitant impacts, it is essential to investigate how treatments can help those experiencing co-occurring mental health disorders. One treatment emerging as potentially beneficial across many disorders 7 is ketamine (e.g., Feder et al., 2014; Peyrovian et al., 2020; Wan et al., 2014). Ketamine is an exemplar fast-acting glutamatergic antidepressant, which has been shown through clinical trials and meta-analyses to be effective for treatment-resistant depression (Marcantoni et al., 2020; Phillips et al., 2019; Wilkinson et al., 2018). Research on treatment-resistant depression reveals significant positive effects on depressive symptoms following ketamine administration, particularly when traditional antidepressants have failed to yield adequate results (Shiroma et al., 2014). A smaller but growing body of research indicates ketamine’s efficacy for treating anxiety disorders (e.g., Grabski et al., 2017), PTSD (e.g., Feder et al., 2021), chronic pain (e.g., Orhurhu et al., 2019), and comorbidities between these conditions (e.g., treatment-resistant depression and PTSD, Albott et al., 2018; pain and depression, Humo et al., 2020). Ketamine may be particularly useful in these populations in part due to its speed of treatment. Aan Het Rot et al. (2012) and Rosenblat et al. (2019) describe the rapid antidepressant effects of ketamine, suggesting that its efficacy often becomes apparent within hours or days, contrasting the delayed onset of traditional treatments. Shiroma et al. (2014) further support this by examining the effects of six ketamine infusions on treatment-resistant depression patients, reporting that 91.6% of participants showed a significant improvement in their depression, with 66.6% achieving remission after four weeks. This rapid response to ketamine provides a critical therapeutic option for individuals who have not responded to standard treatments, highlighting its potential to mitigate the severe and often life-threatening aspects of treatment-resistant depression. Similarly, ketamine shows promise for anxiety disorders. Preliminary evidence from Grabski et al. (2017) indicates that subanesthetic doses of ketamine lead to a rapid reduction in anxiety symptoms in patients with generalized anxiety disorder. This finding is particularly 8 promising, as generalized anxiety disorder and other anxiety disorders are often resistant to first-line treatments such as selective serotonin reuptake inhibitors (Grabski et al., 2017). Additionally, Feder et al. (2021) found that patients with PTSD, who frequently experience co-occurring mental disorders, responded positively to ketamine infusions. Their randomized control trial compared six intravenous infusions of ketamine with midazolam (a benzodiazepine) and found that those in the ketamine condition exhibited significant symptom improvement over two weeks (Feder et al. 2021). Specifically, 65% of patients in the ketamine group experienced a 30% reduction in symptoms, compared to only 20% of those in the midazolam condition. This finding aligns with earlier work, which found that a single intravenous infusion of ketamine led to a rapid reduction in both PTSD and depressive symptoms in patients with comorbid conditions (Feder et al., 2014). Moreover, Fremont et al. (2023) argue that ketamine holds promise for addressing PTSD in civilian populations. These findings indicate that ketamine may address the critical therapeutic gap in both PTSD and anxiety treatments, particularly for patients who are unresponsive to traditional interventions. In the context of chronic pain, ketamine’s efficacy extends beyond psychological relief to analgesia. Ketamine infusions have been shown to produce short-term pain relief during administration, with longer infusion periods (e.g., ranging from 4 to 14 days) leading to analgesic effects lasting up to three months (Noppers et al., 2010; Schwartzman et al., 2011; Sigtermans et al., 2009), suggesting that ketamine’s benefits for chronic pain are dose- and duration-dependent, making it a potential option for sustained pain relief. Ketamine’s role in treating chronic pain-induced depression has also been documented. Humo et al. (2020) found that ketamine significantly improved depressive symptoms in patients suffering from chronic pain, suggesting an overlap in its analgesic and antidepressant effects. Additionally, Culp et al. (2021) highlight 9 ketamine’s potential utility in reducing opioid dependence in chronic pain treatment, offering a safer alternative to long-term opioid use. Given the current opioid crisis, ketamine may offer a dual benefit of pain relief and depression treatment while reducing reliance on addictive pain medications (McIntyre et al., 2021). Most of the existing research on ketamine therapy has been conducted in academic medical centers as clinical trials (i.e., with strict enrollment criteria such as having no comorbidities), with fewer emerging studies exploring comorbidities (McIntyre et al., 2020; Kryst et al., 2020). Randomized studies have reported that 50–70% of patients experience a therapeutic response within the first three days following a single infusion (Zarate et al., 2006; Murrough et al., 2013a, 2013b; Fava et al., 2018). It has also been found that these effects are often short-lived, with approximately 90% of patients reverting to their baseline range within two weeks (Kryst et al., 2020; Newport et al., 2015). As ketamine clinics become more common, so have studies exploring more commonplace therapeutic use. For instance, Sakurai et al. (2020) analyzed data from 85 outpatients treated with repeated ketamine intravenous therapy at Massachusetts General Hospital over 13 months, finding clinically significant improvements in roughly 20% of patients. Further extending the evidence base, McInnes et al. (2022) conducted a large retrospective study evaluating ketamine intravenous therapy in real-world clinical settings, analyzing data from 9,016 patients treated at 178 community practices across the United States between 2016 and 2020. Among 537 patients with sufficient data, 53.6% demonstrated a treatment response for depression within 14–31 days post-induction, and 28.9% achieved remission. Moreover, improvements in suicidal ideation were observed in 73.0% of patients with baseline suicidal ideation, though 6.0% experienced increased suicidal ideation, and 8.4% reported worsening depressive symptoms. Response rates were consistent across varying levels 10 of baseline depression severity, with more severe cases showing larger symptom reductions but lower remission likelihood. Recent research (Vestring et al., 2024) emphasizes that early response to treatment predicts success, with a low likelihood of benefit from extended therapy if no improvement occurs after five sessions. For multiple treatment-resistant depression, ketamine has demonstrated significant symptom reductions, aligning with findings from other naturalistic studies (McInnes et al., 2022; McIntyre et al., 2020). Currently, in Canada, ketamine is approved solely for anesthetic purposes, and its use in mental health treatments is considered “off-label” (Health Canada, 2022). Although formal regulatory approval is absent, a wide body of research has demonstrated ketamine’s efficacy in treating mental health disorders and managing chronic pain (e.g., Albott et al., 2018; Feder et al., 2021; Humo et al., 2020). There are many valid medical reasons for off-label use, including a lack of success with other forms of treatment (Wittich et al., 2012). The lack of regulatory approval is primarily attributed to expired patents and the high cost of trials, which reduce the commercial motivation for pharmaceutical companies to pursue the required regulatory submissions (Wittich et al., 2012). It is, therefore, important to contribute to the research on the use of ketamine in more complex cases. Personality and Mental Illness Research on personality utilizing factor analysis has converged on five principal traits (Davis & Panksepp, 2018; Goldberg et al., 1990), with the predominant framework of personality being the Big Five model (Allen & DeYoung, 2017; Ashton & Lee, 2007; DeYoung et al., 2007; Saulsman & Page, 2004). This framework posits that personality can be characterized through five comprehensive traits: neuroticism (encompassing stress-reactivity and avoidance), extraversion (reflecting sociability and positive emotion), conscientiousness 11 (characterized by delayed gratification and organization), agreeableness (denoting politeness and compassion), and openness (representing creativity and aesthetic appreciation; Costa & McCrea, 1992; Goldberg et al., 1990). The relationship between personality and mental illness. Research indicates that individuals exhibiting symptoms of mental illness tend to score significantly higher in neuroticism and lower in extraversion and conscientiousness compared to non-symptomatic individuals (Santesteban‐Echarri et al., 2021). For instance, in terms of broader assessments, a study which employed the Mental Wellness Inventory Scale, assessing mental health using the dual continuum model (i.e., Mental Health and Mental Illness; Abdel-Khalek, 2022), found that Mental Health was correlated positively with extraversion, agreeableness, openness, and conscientiousness; whereas, it was negatively correlated with neuroticism. Conversely, the Mental Illness Subscale scores correlated positively with neuroticism and negatively with extraversion (Abdel-Khalek, 2022). Most sub-facets of neuroticism are positively correlated with affective disorders, whereas positive emotions (associated with extraversion), competence, and self-discipline (facets of conscientiousness) demonstrate negative correlations with such disorders (Lyon et al., 2021). Certain traits within agreeableness and openness also play distinct roles in mental health. For example, trust (a facet of agreeableness) and actions (a facet of openness) are negatively linked to anxiety disorders; whereas, fantasy (another facet of openness) shows a positive association with these disorders (Lyon et al., 2021). With respect to depression, withdrawal (within neuroticism) is positively associated with major depressive disorder, while industriousness (within conscientiousness) is negatively associated with major depressive disorder (Lyon et al., 2021). It has also been reported that individuals experiencing a major depressive episode 12 demonstrate increased neuroticism along with decreased extraversion and conscientiousness (Harkness, Bagby, Joffe, & Levitt, 2002; Karsten et al., 2012). Research into personality and PTSD has identified specific personality typologies that emerge following trauma exposure. A review conducted by Jakšić et al. (2012) found that personality traits are correlated with PTSD symptoms both before and after trauma. Specifically, neuroticism was related to the development of PTSD, while conscientiousness and extraversion were not. Other research has similarly found lower conscientiousness and extraversion and higher levels of neuroticism are linked to PTSD severity, and lower degrees of neuroticism, extraversion, and agreeableness are linked to maladaptive coping strategies (McDevitt-Murphy et al., 2012). The role of personality in treatment. In addition to being related to mental health scores at baseline, studies have indicated that certain personality traits may predict varying treatment outcomes (Canuto et al., 2009; Koorevaar et al., 2013). For example, low neuroticism correlates with better treatment outcomes (Canuto et al., 2009), while low openness and agreeableness are linked to poorer treatment outcomes (Canuto et al., 2008). In the context of depression, a profile characterized by high neuroticism and low agreeableness forecasts a poorer response to cognitive behavioural therapy (Bagby et al., 2008). Kalbitzer et al. (2009) identified that individuals with genotypes associated with higher openness to experience were more vulnerable to depression onset but also demonstrated superior outcomes following treatment. Interestingly, Stoltenberg et al. (2002) found that this genetic association was significant only in men, highlighting the potential gender differences in how personality and genetics interact with mental health. These findings suggest that openness to experience may be a double-edged sword, 13 increasing the risk of depression but also enhancing the potential for recovery (Chiappelli et al., 2021). Dale et al. (2020) explored the role of the Big Five personality traits in predicting initial and sustained responses to ketamine in 125 participants with treatment-resistant depression. The study found that elevated levels of neuroticism, combined with lower levels of conscientiousness and extraversion, were characteristic of individuals with baseline treatment-resistant depression. They found that this pattern of personality traits may create barriers to sustained treatment success, as neuroticism is often associated with increased emotional reactivity and stress sensitivity, which could negatively impact the response to ketamine. This same study found that openness was the only facet associated with treatment success (Dale et al., 2020). Openness may play an important role in ketamine-assisted therapy due to its significant role in shaping individuals’ experiences with altered states of consciousness. Research has shown that individuals high in openness are more likely to report profound, meaningful experiences during psychedelic treatments (MacLean et al., 2011). These experiences, characterized by heightened introspection and emotional insight, may facilitate the therapeutic effects of ketamine. For instance, a study by Romero-García et al. (2022) found that ketamine-induced altered states of consciousness led to significant reductions in depressive symptoms among individuals with higher levels of openness, suggesting that personality may be a critical factor in determining treatment outcomes. Despite these personality differences, many studies on ketamine therapy fail to consider the role of individual personality differences in treatment outcomes. Therefore, identifying specific personality profiles could be beneficial for predicting treatment outcomes and for selecting appropriate treatments (Santesteban‐Echarri et al., 2021). 14 Severity of Symptoms The severity of symptoms in conditions such as depression, anxiety, PTSD, and chronic pain is a critical determinant of health outcomes and treatment efficacy. For depression, higher symptom severity has been associated with numerous adverse factors, including diminished health-related quality of life (Fattori et al., 2017), functional impairment (Goethe et al., 1993; Luty et al., 2002), and increased risk of suicidality (Bradvik et al., 2008; Kessing, 2004; Wang et al., 2015). Additionally, severe depression often predicts poorer longitudinal outcomes (Katon et al., 2010; Keller et al., 1992) and correlates with specific biological anomalies, such as thyroid hormone dysregulation and white matter abnormalities (Berent et al., 2014; de Diego-Adelino et al., 2014). These associations underscore the necessity of tailoring interventions to address symptom severity, as it significantly influences treatment responsiveness, risk of treatment resistance, and long-term outcomes (Zimmerman et al., 2018). Patients with severe depression often demonstrate greater absolute reductions in symptoms post-treatment than those with milder cases, though relative improvements may remain comparable (Fournier et al., 2010). However, severe cases typically require intensive, multimodal approaches, combining pharmacotherapy and psychotherapy to achieve meaningful outcomes (Cuijpers et al., 2014). Evidence suggests that cognitive-behavioural therapy and antidepressant medications are effective treatments, with the combination proving most beneficial for severe symptoms (Hollon et al., 2014). Even when treated rigorously, severe depression remains a strong predictor of treatment resistance and dropout (Wilkinson et al., 2018). Symptom severity in anxiety disorders also influences treatment outcomes. Severe anxiety often necessitates more intensive and prolonged interventions to achieve symptom relief 15 (Cuijpers et al., 2014b). Baseline severity serves as a robust predictor of treatment success, with combined pharmacological and psychotherapeutic approaches showing greater efficacy for individuals with severe anxiety compared to monotherapies (Bandelow et al., 2015). Moreover, severe anxiety symptoms are frequently complicated by comorbid conditions such as depression, requiring integrated treatment strategies to optimize outcomes (Fava et al., 2008). Treatments like cognitive-behavioural therapy with exposure therapy, augmented with mindfulness techniques, have demonstrated significant benefits for severe anxiety cases (Hofmann et al., 2012). For individuals with PTSD, baseline symptom severity is a critical determinant of treatment trajectory and response rates. Severe PTSD often requires multimodal interventions that integrate evidence-based therapies such as prolonged exposure and cognitive processing therapy with pharmacological agents like selective serotonin reuptake inhibitors or prazosin (Watts et al., 2013; Bernardy et al., 2012). Patients with severe PTSD may experience slower rates of improvement and are at a higher risk of treatment dropout, particularly in therapies involving trauma confrontation (Imel et al., 2013). Finally, chronic pain severity has profound implications for treatment outcomes, with higher baseline pain intensity often requiring comprehensive, multimodal strategies. Severe chronic pain is frequently accompanied by comorbidities such as depression and sleep disturbances, necessitating interventions that address both physical and psychological dimensions (Gatchel et al., 2007). Psychological therapies like cognitive-behavioural therapy and acceptance and commitment therapy are effective but may need to be extended or intensified for individuals with severe pain (Williams et al., 2020). Emerging interventions, including ketamine 16 infusions and neuromodulation techniques, have demonstrated potential for alleviating refractory pain in severe cases (McIntyre et al., 2021). Across conditions, symptom severity plays a pivotal role in shaping treatment approaches, determining the intensity and duration of therapy, and influencing long-term outcomes. Addressing the unique challenges posed by severe symptoms through tailored, evidence-based interventions is essential to improving the health and well-being of affected individuals. The Current Realities of Mental Health Care in Canada Mental health care in Canada faces significant challenges, largely due to chronic underfunding. This underfunding affects both individuals and the healthcare system at large. On an individual level, people often experience undertreatment or lack of treatment altogether, leading to secondary issues such as substance misuse, strained relationships, and difficulties with sleep and work. Systemically, this burden contributes to an over-reliance on primary care providers and increased visits to emergency departments, straining already limited resources (Faber et al., 2023). Additionally, with the lack of universal coverage for mental health services, access becomes unaffordable for many, particularly those who do not have private insurance or whose benefits do not fully cover necessary treatments. The long waitlists for psychologists and the shortage of psychiatrists exacerbate the accessibility issue. Even when individuals can afford services, determining the most effective treatment option can be daunting. As such, there is a need for studies that investigate which treatment plans best serve patients based on their symptoms and personalities. Understanding how patients present at baseline is equally crucial, as this insight can improve the precision of 17 treatments like ketamine-assisted therapy and help tailor interventions to individual needs (Faber et al., 2023). Treatment accessibility issues intersect with ongoing legislative and ethical discussions in Canada, particularly regarding Medical Assistance in Dying (MAiD). Although the 2019 Superior Court of Québec decision expanded MAiD eligibility to individuals whose death is not reasonably foreseeable, the inclusion of mental illness under this provision is not slated to take effect until March 2027 (Government of Canada, 2021; Bastidas-Bilbao et al., 2023). This extension of eligibility raises concerns about the accessibility of mental health care, as financial barriers may prevent individuals from receiving the treatment they need before considering MAiD as an option (Bastidas-Bilbao et al., 2023). The legislation specifies that for an individual to qualify for MAiD without a reasonably foreseeable death, they must suffer from a grievous and irremediable condition, defined as both “serious and incurable,” with an irreversible decline causing enduring physical or psychological suffering (Government of Canada, 2021). Additionally, patients must be informed of all available and appropriate treatment options, including mental health support services, and must seriously consider these options before proceeding with MAiD (Government of Canada, 2021). However, individuals retain the right to refuse treatments they do not find acceptable, further complicating the ethical landscape surrounding this decision (Superior Court of Québec, 2019). Barriers to Accessing Care The barriers to mental health care in Canada are substantial and disproportionately affect marginalized groups. Recent surveys indicate that over half of Canadians who sought mental health services encountered barriers to care. These barriers are especially pronounced for people of colour, Indigenous communities, younger adults, and those with lower incomes (Faber et al., 18 2023). The most commonly reported challenges were long waitlists, financial barriers, and a shortage of resources, including a lack of mental health professionals in many regions. These structural barriers have been exacerbated by difficulties accessing in-person care, particularly during the COVID-19 pandemic (Faber et al., 2023). Moreover, negative experiences with mental health professionals were reported by over a third of respondents, further deterring individuals from seeking necessary care (Faber et al., 2023). Addressing these systemic issues is critical for improving access to mental health care, particularly for individuals from marginalized communities who may face compounding barriers due to socioeconomic and geographic disparities. Present Research Study 1 As research on ketamine for various illnesses and disorders, both mental and physical, is continuing to develop, the goal of the present research was to contribute to the literature by addressing aspects of ketamine administration that have not yet been studied. Importantly, this research examined multiple variables simultaneously to explore how patients initially present in a naturalistic setting and then how their heterogeneity in symptoms may influence their early response to ketamine treatment. In doing so, this research aimed to meaningfully expand on the current body of research, which has largely examined physical and mental health conditions in isolation (e.g., via single morbidity clinical trials). Data for this research came from patients either seeking or undergoing ketamine treatment at a specialty clinic in British Columbia, Canada. The goal of Study 1 was to explore the impact of individual differences on response trajectories to ketamine treatment. Findings from this research may offer deeper insight into the effectiveness of ketamine and help advance 19 new clinical guidelines that will increase the likelihood of patient success. Specifically, this study explored if clusters of patients emerged based on self-reported personality and symptomology indicators at baseline and how these clusters responded to ketamine therapy both during treatment and in the week that followed their treatment. Analyses were conducted on data collected from a ketamine clinic following patients during intake (i.e., before administration of ketamine) and one week after infusions to determine: Q1: Are there subgroups of patients based on personality and symptomology measures? Analytic Overview: The potential heterogeneity in patient personality characteristics and symptomology features was explored using latent profile analysis (LPA) to detect underlying patient subgroups. H1: It was anticipated that personality and symptomology profiles would emerge. Due to the exploratory nature of this analytic approach, there were no specific hypotheses as to the number or arrangements of the profiles. Q2: How did the personality and symptomology profile subgroups respond to treatment? Analytic Overview: Mean differences in baseline and change scores were analyzed using Analyses of Variance (ANOVAs). H2: It was anticipated the different personality and symptomology profiles would have statistically different scores at baseline and follow-up one week after infusion. Due to the exploratory nature of this analytic approach, there were no specific hypotheses as to the pattern of change. Q3: How did patients respond to treatment in general, and did any individual or demographic differences affect patient outcomes? 20 Analytic Overview: Clinical change indices were used to understand the clinical response to treatment. Categorical measures of observed frequencies were used to test if observed frequencies match the expected frequencies of clinical recovery. ANOVAs were employed to test mean differences when considering demographic factors. H3: It was anticipated that the overall response to treatment would be favourable. H4: It was anticipated that certain demographic factors or individual differences would be related to patient outcomes. Study 2 To date, there is little information about how patients experience (e.g., their feelings) ketamine treatment and if they face any burdens (e.g., cost of treatment) during the process. This study aimed to contribute to developing evidence-based policies and best-practice approaches that support individualized care strategies by surveying therapeutic ketamine patients on their experiences and burdens. Although the Ketamine Experience Survey used in Study 2 is anonymous and cannot be directly linked to corresponding clinical data from Study 1, it provided valuable insights into patient experiences, concerns, and satisfaction with treatment. From a policy perspective, understanding patient perceptions is crucial for developing guidelines that ensure clinical efficacy, addressing patient concerns, and enhancing the overall treatment experience. Such patient-centred policies can improve adherence and access, reduce treatment-related anxiety, and foster a more supportive therapeutic environment. Additionally, because therapeutic ketamine in clinics is not covered by the Medical Services Plan (MSP) for British Columbia residents, the results of this survey can be shared when considering coverage opportunities for this treatment. 21 The survey employed quantitative (i.e., Visual Analogue and Likert-type scales) and qualitative (open-ended questions) approaches to understand patient experiences with ketamine therapy holistically. Broadly, the survey covered the following topics: Pre-treatment Considerations, Treatment Considerations, and Post-treatment Considerations. Analyses of data collected from a Ketamine Experience Survey were used to understand patient perspectives on ketamine-assisted therapy, including: Q1: What are patient perspectives on their pre-treatment considerations? Analytic overview: Descriptive statistics were employed to determine what conditions participants were seeking treatments for, the severity of the conditions they were experiencing, how many medications they tried before ketamine, and if cost was a challenge in initiating treatment. Qualitative analysis was used to extract the main themes from the open-ended data and contextualize the quantitative responses. H1: It was anticipated that participants would report suffering from multiple conditions and would report their symptoms as severe. It was also anticipated that most participants would be hindered by the cost of ketamine-assisted therapy and would have explored multiple pharmacological options. Q2: What are patient perspectives on their treatment considerations? Analytic overview: Descriptive statistics were employed to determine how comfortable participants were during treatment, if they experienced any side effects, the amount of relief they experienced post-treatment, and if the cost was a challenge in the continuation of treatment. Qualitative analysis was employed to extract the main themes from the open-ended data and contextualize the quantitative responses. 22 H2: It was anticipated that participants would have been moderately comfortable during treatment and that most participants would not have experienced serious negative side effects. It was also anticipated that participants would experience considerable relief following treatment and that cost would hinder subsequent treatments. Q3: What are patient perspectives on their post-treatment considerations? Analytic overview: Descriptive statistics were employed to determine the lasting effects of treatment and if patients have returned to baseline. Mean differences between baseline and post-treatment severity were also analyzed. Qualitative analysis was used to extract the main themes from the open-ended data and contextualize the quantitative responses. H3: It was anticipated that patients would report positive but short-term effects of ketamine treatment. It was also anticipated that there would be a significant difference between retrospective baseline and post-treatment survey scores. 23 Chapter 2 Method – Study 1 Participants Participants (N = 184) were individuals who sought treatment at the EntheoMed Ketamine Clinic in Kelowna, British Columbia. Participants completed all screeners and personality measures on an online platform (i.e., Thrive Health) as part of their general intake at the clinic. There were no specific inclusion criteria beyond being a patient who is seeking treatment at the facility, nor were there any exclusion criteria. Treatment Eligibility Criteria Although the present study did not have specific inclusion or exclusion criteria, the clinic itself has eligibility requirements for patients. Patients treated at the clinic must be aged 19 or older and have a referral from a primary care practitioner for emotional health challenges (e.g., burnout, adjustment disorder, mood disorder or seasonal affective disorder) or mental health challenges (e.g., depression, anxiety, PTSD, eating and/or sleeping disorders) and these conditions have failed to improve with other approaches (e.g., medication and therapy). Additionally, patients must also confirm that they have the ability, energy, and time to commit to the treatment process and approach it with an open mind and heart, in addition to enough stability to enable commitment to the process and be fully present during counselling sessions and on treatment day. Patients must have a phone or computer with reliable internet to attend virtual counselling sessions and utilize the online app that features therapeutic/educational content. They must also be able to travel to the clinic and have a designated driver to pick them up after treatment. Finally, if the patient is a parent, they must be able to access childcare for counselling sessions and on treatment day. 24 All patients must complete a medical intake form and pass a physical and psychiatric screening. Staff physicians at the clinic review the completed patient intake form prior to the first treatment and identify and address any medical concerns. During screening, a patient may be declined from proceeding with ketamine treatment. Treatment Exclusions/Contraindications Patients are not eligible for treatment if they exhibit or experience intense emotional instability, active symptoms of psychosis, high blood pressure (defined as 160/90) that is not controlled, acute cardiovascular disease, symptomatic traumatic brain injury, Body Mass Index greater than 35, hepatic/kidney/vascular disorder (reviewed on a case-by-case basis), delirium and/or dementia, ketamine allergy, a history of ketamine use disorder, alcohol or substance use disorder within the past six months, a seizure disorder or epilepsy, a history of increased intracranial pressure, a brain tumour/aneurysm/arterio-venous malformation, untreated sleep apnea (reviewed on a case-by-case basis), or are pregnant. Treatment Protocol After patients have been referred to the program, they undergo a multistep treatment plan, which is described in greater detail below. Briefly, the initial framework involves a comprehensive intake, mental health consult, physical health consult, preparation counselling, ketamine injections, and a follow-up counselling session. Additionally, each patient is provided access to online resources for use at their discretion and the instruction of their care team. For patients undergoing additional injections, their subsequent framework involves preparation counselling and a follow-up counselling session for each follow-up injection. The intake involves a battery of self-report measures (Appendix 1) and a medical and psychological history. The intake is used by practitioners to assist in clinical decision-making 25 and treatment planning. It is also used as a baseline for comparison. The initial mental health consult is a virtual meeting with a registered psychiatric nurse to learn the patient’s psychological history and help determine whether therapeutic ketamine is the appropriate course of treatment. Patients then move on to a more in-depth health history and review process. Physical health is assessed by a physician who carefully reviews the patient’s medical history and any medications to ensure they are physiologically fit for the ketamine experience. Preparation counselling involves a one-hour meeting with a registered psychologist or clinical counsellor, who helps the patient clarify their goals and intentions and take steps needed to ensure they are fully prepared. The intramuscular ketamine injections is administered at an individual dosage for the patient based on weight and other clinical indications. Patients are supported in a safe and comfortable environment while the medication is active. Patients meet again with their therapist to discuss their ketamine experience, including insights gained and integration techniques. The average duration of treatment spans one week. Patients also have lifetime access to online resources, which are filled with guidance on what to expect with therapeutic ketamine – as well as holistic integration practices (e.g., breathwork and meditation) to support their long-term healing. Procedure This study was conducted using deidentified patient data collected as part of routine clinical care at EntheoMed Ketamine Clinic in British Columbia, Canada. Research funds were provided by Interior Health Authority via Mitacs. Ethics approval was obtained from the University of British Columbia Okanagan Campus’s Behavioural Research Ethics Board to perform a secondary data analysis on the de-identified data. All data were collected as part of the clinic’s standard ketamine treatment protocol for mental and/or physical health conditions. 26 Baseline data were gathered from individuals prior to the initiation of ketamine treatment. These data included self-reported measures of personality traits, symptom severity, and various demographic and clinical factors. Data collection was facilitated through the Thrive Health platform, which is integrated into the clinic’s routine care system to monitor patient progress. It should be noted that 184 individuals originally sought treatment at the clinic and completed all their baseline measures; however, only 65 of those individuals received ketamine infusions and adhered to their clinical follow-up one week after treatment. Data from the above 184 individuals will be referred to as Baseline data and data from the subset of 65 individuals who received ketamine infusions and completed their clinical follow-up will be referred to as Follow-up data. The questionnaires used to collect Baseline and Follow-up data are listed in Appendix 1. Measures Personality Measure. Personality was defined using one of the most common conceptualizations of personality, the Five-Factor Model (McCrae and Costa, 2003). Participants’ dimensions of personality were assessed using the five subscales of the Mini International Personality Item Pool (Mini-IPIP; Goldberg, 1999). The Mini-IPIP is a 20-item short form of the 50-item International Personality Item Pool—Five-Factor Model measure. This measure assesses Extraversion (vs. introversion), Agreeableness (vs. antagonism), Conscientiousness (vs. negligence), Openness to Experience (vs. closedness to experience), and Neuroticism (vs. emotional stability). The Mini-IPIP scales, with four items per Big Five trait, have demonstrated consistent and acceptable internal consistencies, similar coverage of facets as other broad Big Five measures, and test-retest correlations that are similar to the parent measure. Moreover, the Mini-IPIP scales have demonstrated a comparable pattern of convergent, discriminant, and criterion-related validity 27 with other Big Five measures. These results indicate that the Mini-IPIP is a psychometrically acceptable and useful short measure of the Big Five personality factors. Symptomology Measures Depression. Participants’ depression was assessed using the Patient Health Questionnaire (PHQ-9; Kroenke & Spitzer, 2002). The PHQ-9 is a self-assessment questionnaire used to measure the severity of depression symptoms in individuals. This measure consists of nine questions that ask about the frequency and intensity of depressive symptoms experienced over the previous two weeks, including low mood, loss of interest or pleasure, feelings of worthlessness, and changes in appetite or sleep patterns. Each question is scored from 0 to 3, with a total possible range of scores from 0 to 27. The higher the score, the greater the severity of depression symptoms. The PHQ-9 uses cut scores of 5 (mild), 10 (moderate), 15 (moderately severe), and 20 (severe) to categorize depression severity. A score of ≥10 has a sensitivity of and specificity of 88% for detecting major depressive disorder. The PHQ-9 is widely used in clinical settings to screen for and monitor depression. (Kroenke et al., 2001). Anxiety. The Generalized Anxiety Disorder (GAD-7; Spitzer et al., 2006) questionnaire was used to assess patients’ anxiety. The GAD-7 is a seven-item, self-report anxiety questionnaire designed to assess the patient’s health status during the previous two weeks. The items ask about the degree to which the patient has been bothered by feeling nervous, anxious or on edge, not being able to stop or control worrying, worrying too much about different things, having trouble relaxing, being so restless that it is hard to sit still, becoming easily annoyed or irritable and feeling afraid as if something might happen (Spitzer et al., 2006). Scores of 0, 1, 2, or 3 are given for experiencing symptoms’ not at all,’ for ‘several days,’ for ‘more than half the days,’ and for ‘nearly every day,’ respectively. The scores are then totalled and presented from 0 28 to 21. The GAD-7 uses cut scores of 5 (mild), 10 (moderate), and 15 (severe) to categorize anxiety severity. A score of ≥ 8 has a sensitivity of 92% and a specificity of 76% for diagnosing generalized anxiety disorder (Kroenke et al., 2007; Plummer et al., 2016). PTSD. The National Stressful Events Survey for PTSD-Short Scale (NSESSS-PTSD-S; American Psychiatric Association, 2013) is a brief, self-report measure designed to assess symptoms of Post-Traumatic Stress Disorder (PTSD) following exposure to a stressful or traumatic event. The NSESSS-PTSD-S includes seven items that reflect core PTSD symptoms such as re-experiencing, avoidance, and hyperarousal. Respondents rate their symptoms over the past 7 days using a 5-point Likert scale ranging from 0 (“Not at all”) to 4 (“Extremely”), yielding a total score between 0 and 28, with higher scores indicating greater symptom severity. Psychometric studies demonstrate high internal consistency and strong construct validity aligned with DSM-5 criteria. The NSESSS-PTSD-S is commonly used in both clinical and research settings for symptom monitoring. Adverse Childhood Events. The Adverse Childhood Events Questionnaire for Adults (ACE; Felitti et al., 1998) assessed participants’ history of adverse events. The ACE is a checklist of adverse events that occurred to an individual before age 18 (Felitti et al., 1998). Participants endorse either 1 = Yes or 0 = No for each of the ten experiences listed in the measure. The scores are then totalled and presented from 0 to 10, with higher scores indicating a greater number and diversity of events. Events include abuse (physical, emotional, and sexual), neglect (physical and emotional), and household dysfunction. Treatment Expectations. Participants’ expectations for relief of symptoms following treatment were assessed using single-item visual analogue scales. The Treatment Expectations scale was modified from The Pain Relief Scale (PRS; Haythornthwaite & Fauerbach, 2001) to 29 assess participant’s anticipated relief from depression and anxiety. The PRS is a single-item scale in which patients rate their expected pain relief on a visual analogue scale (VAS) from 0% (no relief) to 100% (complete relief). The PRS has been used to reliably and validly assess treatment expectations (Choinière et al. 2017). The modified versions substituted pain relief with depression and anxiety symptom relief and used the same VAS. Quality of Life. Patients’ quality of life was assessed using the World Health Organization Brief Quality of Life measure (WHOQOL-BREF; Scoring Manual by Harper & Power, 1999). The WHOQOL-BREF is a 26-item instrument consisting of four domains: physical health (7 items), psychological health (6 items), social relationships (3 items), and environmental health (8 items). Each item of the WHOQOL-BREF is scored from 1 (“disagree” or “not at all”) to 5 (“completely agree” or “extremely”) on a response scale, with higher scores indicating higher quality of the domain being measured. The scale was converted to a 0-20 scale for each domain per the scoring manual. The environmental health domain was not employed in the present study. Insomnia. The Insomnia Severity Index (ISI; Morin et al., 2011) is a brief, self-report questionnaire designed to assess the severity of insomnia symptoms and their impact on daily functioning. It consists of 7 items that evaluate the nature and severity of sleep problems, including difficulty falling asleep, staying asleep, waking too early, satisfaction with sleep patterns, interference with daily functioning, noticeable impairments, and distress caused by sleep difficulties. Each item is rated on a 5-point Likert scale from 0 (“No problem”) to 4 (“Very severe problem”), producing a total score ranging from 0 to 28, with higher scores indicating more severe insomnia. The ISI is widely used in both clinical and research contexts for 30 screening, severity assessment, and treatment monitoring, demonstrating strong psychometric properties, including high internal consistency and validity. Analytic Approach All analyses were conducted using IBM SPSS Statistics (Version 29) and R (Version 2024.09.0+375). The purpose of the analyses was to examine demographic and clinical characteristics, determine if subgroups of participants existed within the cohort, evaluate group differences in mental health scores, and determine changes over time among a cohort of diverse and complex patients administered ketamine for mental illness. Descriptive Statistics Descriptive statistics, including means, standard deviations, frequencies, ranges, and percentages, were calculated to summarize the demographic and baseline characteristics of the sample. These analyses provided a foundational understanding of the cohort and informed subsequent inferential tests. Latent Profiles Latent Profile Analysis (LPA) was employed on the Baseline data to identify distinct subgroups of participants based on intake measures categorized into two domains: (a) Personality (measured by a Big Five model inventory), and (b) Symptomology (measured by insomnia, physical-psychological-social quality of life, depression, and anxiety). LPA is a categorical latent variable modelling approach that identifies latent subpopulations within a population based on observed variables, assuming that individuals can be assigned to latent profiles with varying probabilities (Spurk et al., 2020). The primary aim of this analysis was to explore the heterogeneity in participant characteristics at baseline, which may provide insight into pre-treatment experiences and treatment response patterns. The sample size and number of indicators 31 available in the present research were adequate for LPA, as research has shown that making the sample size larger, using more indicators (measures), or increasing the separation between groups doesn’t necessarily improve the accuracy of the analysis (Tein et al., 2013). When the groups are very similar, with fewer measures, the method often picks one less grouping than it should. On the other hand, when the groupings are very distinct and there are more measures, it sometimes picks one extra grouping (Tein et al., 2013). For model parameterization, variances were assumed to be equal across profiles, and covariances were fixed at zero. This model constraint ensured that the number of estimated parameters remained manageable, enhancing the interpretability of the models as the number of profiles increased (Lubke & Neale, 2006; Vermunt & Magidson, 2002). A series of LPA models were conducted, beginning with a one-profile model and successively adding more profiles until the optimal number of profiles was identified. To determine the best-fitting model, multiple fit indices were evaluated, including the Bayesian Information Criterion (BIC), the Akaike Information Criterion (AIC), the Approximate Weight of Evidence (AWE), the Classification Likelihood Criterion (CLC), and the Kullback Information Criterion (KIC). An analytic hierarchy process (AHP) was applied to balance and prioritize these fit indices in the decision-making process, following the framework outlined by Akogul and Erisoglu (2017). This method helped weigh the different indices and their relative contributions to model fit. The BIC, AIC, and AWE were prioritized based on their lower values, indicating a better model fit, while the CLC and KIC further supported profile validation (Akogul & Erisoglu, 2017). After selecting the optimal number of profiles based on AHP, the class profiles were visually inspected to ensure interpretability and to identify key distinguishing characteristics. 32 Alternative models (e.g., +/- 1 profile) were also visualized to examine pattern differences. This step helped to ensure that the profiles not only had statistical validity but also reflected meaningful differences in patient characteristics. By examining patterns of personality traits and symptoms, the LPA provided insights into both qualitatively and quantitatively different profiles (Zyphur, 2009). This integration of variables allowed for a nuanced understanding of how various factors interact to form distinct subpopulations. Overall, the AHP and model selection criteria enabled a robust approach to identifying meaningful participant profiles at baseline (n = 184), which contributes to a better understanding of individual differences in ketamine treatment response (n = 65). Mean Differences To test for mean differences in mental health scores, paired-sample t-tests were used to compare Baseline data to Follow-up data within individuals. Independent samples t-tests were used to test for differences between naturally occurring groups (e.g., sex assigned at birth). One-way ANOVAs were conducted to evaluate differences in mental health scores across clusters or profile membership groups and demographic categories. Post-hoc comparisons were performed using Tukey’s HSD test. ANOVA is generally robust to unequal sample sizes (unbalanced designs) when the sample sizes are small, provided certain conditions are met. Specifically, robustness is maintained if the assumption of homogeneity of variances (homoscedasticity) is not severely violated and the group sizes are not excessively disproportionate. Unequal sample sizes can slightly affect the Type I error rate, but this effect is mitigated if variances across groups are approximately equal (Field, 2018). Additionally, ANOVA is less sensitive to unequal sizes when the data are approximately normally distributed (Maxwell et al., 2017). However, significant imbalances in sample size can increase the risk of bias in estimating group means and interaction 33 effects, particularly if these imbalances are paired with heterogeneity of variances (Tabachnick & Fidell, 2019). When these assumptions were violated, a more robust version of ANOVA (Welch’s) was employed for analyses. Statistical significance was defined as p < .05, and effect sizes were reported where appropriate to supplement significance testing. Effect sizes were reported using Cohen’s d for t-tests, and eta squared (η²) for ANOVAs. Cohen’s d values of 0.2, 0.5, and 0.8 were interpreted as small, medium, and large, respectively, while η² values of 0.01, 0.06, and 0.14 were considered small, medium, and large effects, respectively (Cohen, 1988). Categorical Differences To examine differences in categorical data, Chi-square tests of independence were used to determine whether profile or cluster membership and demographic variables were associated with key outcomes (Field, 2018). When the assumptions of chi-square (e.g., expected frequencies < 5 in more than 20% of cells) were violated due to small sample sizes, Fisher’s exact test was used as an alternative (Field, 2018). Statistical significance was defined as p < .05, and effect sizes were assessed using Cramér’s V, with values of 0.1, 0.3, and 0.5 indicating small, medium, and large effects, respectively (Cohen, 1988). 34 Chapter 3 Results – Study 1 Descriptive Baseline Statistics Descriptive statistics were calculated to summarize the demographic and baseline characteristics of the overall sample, as presented in Table 1. As shown, the Baseline sample of 184 participants was diverse, with an average age of 47.86 years. The sex distribution was nearly even, with 52.7% identifying as female and 47.3% as male. Most participants had completed post-secondary education (67.4%) and were either employed full-time (31.3%), retired (21.2%), or unable to work due to disability (14.7%). A quarter of the sample was receiving disability. The majority lived with others (72.3%), and over half were in long-term relationships (53.8% married or common-law). Notably, 57.1% reported a history of significant trauma, and 38% experienced significant pain (per the IASP definition of chronic pain: pain that is persistent or intermittent, lasting longer than three months beyond the anticipated time of healing), highlighting physical and psychological challenges within the group. Substance use was common, with 75.5% reporting alcohol use and 40.2% reporting recreational drug use. 35 Table 1 Baseline Data Participant Demographics Variable n (%) or M (SD) Age M = 47.86 years; SD = 14.47 (Min = 20, Max = 81) Sex Assigned at Birth Male 87 (47.3%) Female 97 (52.7%) Gender Man 86 (46.7%) Woman 94 (51.1%) Transgender 2 (1.1%) Non-Binary 1 (0.5%) Self-describe 1 (0.5%) Education (Highest Completed) Less than high school 4 (2.2%) High school 39 (21.2%) Vocational or trade school 15 (8.2%) College 48 (26.1%) University 76 (41.3%) Prefer not to answer 2 (1.1%) Employment Status Unemployed 1 (0.5%) Unable to work due to disability 27 (14.7%) Full-time volunteer 1 (0.5%) Student 3 (1.6%) Homemaker 6 (3.3%) Part-Time 22 (12%) Full-Time 58 (31.3%) Self-employed 27 (14.7%) Retired 39 (21.2%) Receiving Disability Yes 46 (25%) No 138 (75%) Alcohol Use Yes 137 (75.5%) No 47 (25.5%) Recreational Drug Use 36 Variable n (%) or M (SD) Yes 74 (40.2%) No 110 (59.8%) History of Tobacco Use Yes 68 (37%) No 116 (63%) Living with Others Yes 133 (72.3%) No 51 (27.7%) Relationship Status Single 61 (33.2%) Dating 3 (1.6%) Engaged 2 (1.1%) Married/common law 99 (53.8%) Separated/Divorced 15 (8.2%) Widowed 4 (2.2%) Significant Pain Yes 70 (38%) No 112 (62%) History of Trauma Yes 105 (57.1%) No 79 (42.9%) The personality scores of the sample at baseline, as measured by the Mini-IPIP, are presented in Table 2. Agreeableness scores ranged from 6 to 20 (M = 15.57, SD = 3.28), indicating moderately high levels of agreeableness in the group. Conscientiousness scores ranged from 4 to 20 (M = 12.71, SD = 3.86), suggesting moderate levels of conscientiousness with notable variability. Extraversion scores ranged from 4 to 20 (M = 9.94, SD = 4.04), reflecting lower average levels of extraversion. Neuroticism scores ranged from 5 to 20 (M = 15.05, SD = 3.18), suggesting higher levels of neuroticism among participants. Finally, openness scores 37 ranged from 4 to 20 (M = 14.63, SD = 3.50), reflecting moderate levels of openness with observed variability. Table 2 Descriptive Information for Personality Predictor Variables at Baseline Variable Minimum Maximum Mean SD Agreeableness 6 20 15.57 3.28 Conscientiousness 4 20 12.71 3.86 Extraversion 4 20 9.94 4.04 Neuroticism 5 20 15.05 3.18 Openness 4 20 14.63 3.50 The descriptive statistics for insomnia, quality of life (Physical, Psychological and Social domains), anxiety, and depression scores, as reported at baseline, are summarized in Table 3. Insomnia scores, as measured by the ISI, ranged from 0 to 28 (M = 13.31, SD = 7.44), indicating moderate levels of insomnia severity on average. Quality of life scores, derived from the WHOQOL-BREF, varied across domains. Physical QOL scores ranged from 5 to 19 (M = 11.82, SD = 3.33), reflecting moderate mean levels of physical health. Psychological QOL scores ranged from 4 to 19 (M = 9.78, SD = 3.22), suggesting moderately low mean levels of psychological health. Social QOL scores ranged from 4 to 20 (M = 10.98, SD = 3.82), indicating moderate levels of social well-being across the group. Anxiety scores, measured by the GAD-7, ranged from 0 to 21 (M = 11.87, SD = 5.70), indicating moderate anxiety levels. Finally, depression scores, measured by the PHQ-9, ranged from 0 to 27 (M = 14.92, SD = 7.18), reflecting moderate-to-severe levels of depressive symptoms. 38 Table 3 Descriptive Information for Symptom Variables at Baseline Variable Minimum Maximum Mean SD Insomnia 0 28 13.31 7.44 Physical QOL 5 19 11.82 3.33 Psychological QOL 4 19 9.78 3.22 Social QOL 4 20 10.98 3.82 Anxiety 0 21 11.87 5.70 Depression 0 27 14.92 7.18 Latent Profile Analysis (LPA) on Baseline Data Personality LPA. Personality profiles were determined using the The Five-Factor Model of Personality (i.e., Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness to Experience) as indicator variables. Model fit criteria can be found in Table 4. A total of six LPA models were considered, ranging from one to six profile solutions. An analytic hierarchy process based on the fit indices AIC, AWE, BIC, CLC, and KIC (Akogul & Erisoglu, 2017), suggested that the best solution was Model 1 with 3 classes. Based on the analytic hierarchy process and visual inspection of the model, a 3-profile solution was selected as the best-fitting model (Figure 1). 39 Table 4 Fit Indices for Latent Profiles Defined by the Five-Factor Model of Personality Profile AIC AWE BIC CLC KIC Entropy BLRT 1 4960.53 5072.83 4992.68 4942.53 4973.53 1 2 4907.79 5089.18 4959.23 4877.34 4926.79 0.78 0.01 3 4890.00 5139.98 4960.73 4847.46 4915.00 0.73 0.01 4 4883.76 5202.27 4973.78 4829.29 4914.76 0.77 0.1 5 4874.93 5262.07 4984.24 4808.40 4911.93 0.74 0.01 6 4894.66 5350.55 5023.26 4815.97 4937.66 0.65 0.93 Note. Fit indices required for the analytic hierarchy process: Bayesian Information Criterion (BIC), the Akaike Information Criterion (AIC), the Approximate Weight of Evidence (AWE), the Classification Likelihood Criterion (CLC), and the Kullback Information Criterion (KIC). R software determined the weighting of each indicator to conclude a 3-profile solution (bolded). Figure 1. Standardized Personality Profile Means Across Indicator Variables Note. Visual depiction of the mean standardized scores obtained on the personality indicator variables for each of the three profiles. N = 184. 40 Profile 1, titled Easygoing Extrarverts, scored well above average on Extraversion, above average on Agreeableness, average for Conscientiousness, on the higher end of the average range for Openness, and on the lower end of the average range for Neuroticism. Profile 2, titled Average, scored in the average range across all of the five factors of personality. Profile 3, titled Reserved Introverts, scored below average for Extraversion, Conscientiousness, and Openness, well below average on Agreeableness, and at the high end of the average range for Neuroticism. The unstandardized means are presented in Table 5. Most participants fell into the Average profile (n = 117), followed by Reserved Introverts (n = 36), and Easygoing Extraverts (n = 31). Participant profile distribution frequencies for Baseline and Follow-up is presented in Table 6. Table 5 Unstandardized Means of Indicator Variables for the Personality Profiles Variable Easygoing Extraverts Average Reserved Introverts Extraversion 16.10 9.10 7.26 Agreeableness 17.70 16.51 11.01 Conscientiousness 13.31 13.18 10.84 Openness 16.36 14.97 12.15 Neuroticism 14.00 14.98 16.16 Table 6 Frequency Chart of Personality Profiles at Baseline and T1 Profile Name Baseline Data n(%) Follow-up Data n(%) Easygoing Extraverts 31 (16.8%) 9 (13.8%) Average 117 (63.6%) 44 (67.7%) Reserved Introverts 36 (19.5%) 12 (18.5%) Relationship between demographic information and Personality Profiles Sex at birth. A chi-square test of independence was conducted to examine the relationship between sex assigned at birth (male or female) and personality profile membership 41 (i.e., Easygoing Extraverts, Average, and Reserved Introverts). The results indicated a statistically significant association between sex assigned at birth and personality profile membership, χ2(2, N = 184) = 9.465, p = .009. Effect size, Cramér’s V = .160, indicated a small to moderate association between birth sex and personality profiles. This result suggests that personality profile distribution differs based on sex assigned at birth. Specifically, 35.5% of males and 64.5% of females comprised the Easygoing Extraverts profile, while the Average profile comprised 43.6% of males and 56.4% of females. For the Reserved Introverts profile, 69.4% of the individuals were male, whereas 30.6% were female. In other words, more females than expected by chance were associated with Profile 1, and more males with Profile 3. Age. A one-way ANOVA was conducted to determine if there were significant differences in participant ages across the three personality profiles (i.e., Easygoing Extraverts, Average, and Reserved Introverts). The results indicated no statistically significant difference in age between the personality profiles, F(2, 181) = 0.007, p = .993, suggesting that participant age did not significantly vary across the different personality profiles in this sample. The effect size estimates were extremely small, η² = .000, 95% CI [.000 - .000], reinforcing no meaningful variance in age explained by personality profiles. Descriptive statistics showed that the mean ages for each profile were as follows: Easygoing Extraverts (M = 47.77, SD = 14.41), Average (M = 47.95, SD = 14.23), and Reserved Introverts (M = 47.64, SD = 15.70). The overall mean age for all participants was 47.86 years (SD = 14.47). Education. Due to the assumption of 5 or more expected cases per cell being violated, a Fisher-Freeman-Halton exact test (Fisher’s exact Test) was conducted to examine the 42 relationship between personality profile membership (e.g., Easygoing Extraverts, Average, and Reserved Introverts) and the highest level of education achieved. The analysis revealed no significant association between personality profiles and education levels, p = .109. Effect size, Cramér’s V = 0.194, indicated a small-to-moderate association according to Cohen’s (1988) benchmarks. While this may suggest some relationship between the variables, the association was not statistically significant. Although the test did not yield significant results, descriptive trends highlight patterns in the data. The majority (58%) of Easygoing Extraverts reported university as their highest level of education, with a lower proportion (23%) reporting college as their highest level of academic attainment. Those in the Average profile showed a relatively even distribution between university (39%) and college (27%), with a notable proportion reporting high school (21%) as their highest level of education. The Average profile had a high representation in vocational or trade school (9%) compared to other profiles. Reserved Introverts had similar proportions reporting university (33%) and college (25%), and a high percentage reported high school (33%) as their highest level of education compared to the other profiles, with minimal representation in other education categories. Descriptions of Traumatic Events in the Sample As part of the intake questionnaire, participants were asked if they had ever lived through a traumatic event that could be categorized as a Criterion A event (i.e., exposure to a traumatic event that involves actual or threatened death, actual or threatened serious injury, and actual or threatened sexual violence. Exposure may be direct or indirect, depending on the circumstances; DSM-5). Of the 184 individuals in Baseline data, 105 indicated that they had experienced such an event. Those 105 individuals were asked to briefly describe the type(s) traumatic event(s) that 43 they had endured. The events described by patients were categorized into several categories based on the details provided. Many individuals experienced repeated traumas across different categories (e.g., sexual assault, medical trauma, and workplace violence). Similarly, others reported repeated traumas across one category (e.g., multiple sexual assaults). Each category was counted only once per participant. The categories included: Non-consensual Sex Acts ( n = 36; e.g., childhood sexual abuse, sexual assault and rape, and trafficking and confinement); Severe Accidents (n = 30; e.g., car accidents, including fatal ones involving family members, near-fatal accidents such as head-on collisions or near drownings, and workplace-related accidents and incidents such as near plane crashes; Violence (n = 41; e.g., intimate partner/parental violence, assault, or shootings); Loss and Bereavement (n = 29; e.g., Deaths of close family members such as children and partners, suicides of loved ones); Medical Trauma (n = 10; e.g., negligence and adverse outcomes during medical procedures such as overdose, prolonged distress from failed treatments); Childhood Trauma (n = 24; e.g., neglect, non-sexual abuse, abandonment, and endangerment in childhood); Work-Related Trauma (n = 17; e.g., exposure to violence and death such as combat experiences, death threats, accident scenes, and homicide investigations); Natural and Environmental Disasters (n = 7; e.g., present during earthquakes, fires, and tsunamis). Trauma and Personality PTSD. A one-way ANOVA was conducted to examine differences among the three personality profiles (e.g., Easygoing Extraverts, Average, and Reserved Introverts) on PTSD symptoms at baseline. Please note that the PTSD inventory was only administered to those individuals who indicated that they had lived through a traumatic event (n = 105). Results indicated no statistically significant differences in PTSD symptoms across the personality 44 profiles, F(2,102) = 0.560, p = .573 with a small effect size, η² = .011, 95% CI[.000 - .066]. Descriptive statistics for each profile revealed the following mean PTSD scores: Extraverted Easygoing (M = 16.81, SD = 9.55), Average (M = 17.57, SD = 10.12), and Reserved Introverts (M = 19.86, SD = 9.73). The overall mean PTSD score was 17.93 (SD = 9.92). ACEs. Similarly, an ANOVA was conducted to assess differences in Adverse Childhood Events (ACE) scores across personality profiles. The analysis revealed no significant differences in ACE scores among the profiles, F(2,181) = 0.108, p = .898, n = 184, with a very small effect size, η² = .001, 95% CI[.000 - .016]. Descriptive statistics indicated the following mean ACE scores: Extraverted Easygoing (M = 3.26, SD = 2.96), Average (M = 3.15, SD = 2.42), and Reserved Introverts (M = 2.97, SD = 2.74). The overall mean ACE score was 3.13 (SD = 2.57), suggesting that personality profiles were not significantly associated with baseline PTSD or ACE scores. Depression/Anxiety and Personality A series of one-way ANOVAs were conducted to examine differences among personality profiles on depression and anxiety scores at baseline and change scores. For baseline depression scores, there was a statistically significant and large effect of personality profiles, F(2,181) = 11.278, p < .001, η² = 0.111, 95% CI [0.035, 0.195], indicating that personality profiles accounted for 11.1% of the variance in baseline depression scores. A Tukey HSD post hoc test was conducted to explore pairwise differences between personality profiles for depression symptoms. Reserved Introverts (M = 19.22, SD = 6.36) reported significantly higher depression symptoms compared to Easygoing Extraverts (M = 11.52, SD = 7.39), p < .001, with a mean difference of 7.71 (95% CI [3.76, 11.65]). Reserved Introverts also reported significantly higher depression symptoms compared to Average (M = 45 14.50, SD = 6.78), p = .001, with a mean difference of 4.72 (95% CI [1.65, 7.78]). The difference between Easygoing Extraverts and Average was not statistically significant, p = .079. Similarly, a significant and moderate effect of personality profile membership was observed for baseline anxiety scores, F(2,181) = 7.427, p < .001, η² = 0.076, 95% CI [0.015, 0.152]. Personality profile membership explained 7.6% of the variance in anxiety scores. A Tukey HSD post hoc test was conducted to examine pairwise differences between personality profiles for anxiety symptoms. Results indicated that Reserved Introverts (M = 14.39, SD = 4.67) reported significantly higher anxiety symptoms compared to Easygoing Extraverts (M = 9.19, SD = 5.31), p < .001, with a mean difference of 5.20 (95% CI [2.00, 8.39]). Reserved Introverts also reported significantly higher anxiety symptoms compared to Average (M = 11.80, SD = 5.79), p = .039, with a mean difference of 2.59 (95% CI [0.10, 5.07]). The difference between the Easygoing Extraverts and Average did not reach the conventional level of statistical significance, p = .052. In examining the change scores in depression; that is, comparing Baseline data to Follow-up data within individuals’ PHQ-9 scores, there was a significant decrease in scores from Baseline (M = 15.68, SD = 7.19) to Follow-up (M = 12.45, SD = 7.24), t(64) = 4.265, p < .001, with a medium effect size, d = 0.529, 95% CI [0.267, 0.787], indicating an overall significant improvement in depressive symptoms for individuals who received the ketamine infusion. A robust ANOVA (i.e., Welch’s) was employed to determine the differences between the personality profiles due to the unequal group sizes in the small sample. There were no significant differences found among personality profiles for depression change, F(2,17.02) = 0.11, p = 0.899, with a very small effect size. η² = 0.005, 95% CI [0.000, 0.058]. Descriptive statistics for 46 depression change scores were as follows: Extraverted Easygoing (M = 3.00, SD = 5.02), Average (M = 3.02, SD = 5.85), and Reserved Introverts (M = 4.17, SD = 7.98). When examining the change scores in anxiety; that is, comparing Baseline data to Follow-up data within individuals’ GAD-7 scores, there was a significant decrease in scores from Baseline (M = 12.22, SD = 5.88) to Follow-up (M = 10.40, SD = 6.15), t(64) = 2.822, p = .006, with a small effect size, d = 0.350, 95% CI [0.098, 0.599], which indicates a significant overall improvement in anxiety symptoms for individuals who received the ketamine infusion. When employing a robust ANOVA to look for differences between the personality profiles, there were no significant differences found among personality profiles for anxiety change, F(2, 16.55) = 0.42, p = 0.665, also with a very small effect size, η² = 0.015, 95% CI [0.000, 0.093]. For anxiety change scores, Extraverted Easygoing (M = 2.78, SD = 5.72), Average (M = 1.39, SD = 5.11), and Reserved Introverts (M = 2.67, SD = 5.31). Treatment Expectations and Personality A series of one-way ANOVAs were conducted on Baseline data to examine differences in treatment expectancies related to anxiety and depression across personality profiles. For treatment expectancy related to anxiety, the ANOVA indicated no statistically significant differences among personality profiles, F(2,181) = 0.729, p = .484, with a very small effect size, η² = 0.008, 95% CI [0.000, 0.044]. Descriptive statistics revealed that the Reserved Introverts profile had a mean treatment expectancy score of 65.56 (SD = 20.35), the Average profile had a mean of 63.59 (SD = 26.11), and the Extraverted Easygoing profile had a mean of 58.06 (SD = 33.81). The overall mean treatment expectancy score for anxiety was 63.04 (SD = 26.54). 47 Similarly, for treatment expectancy related to depression, the ANOVA showed no statistically significant differences among personality profiles, F(2,181) = 1.387, p = .252, with a small effect size, η² = 0.015, 95% CI [0.000, 0.060]. Descriptive statistics showed that the Reserved Introverts profile had a mean treatment expectancy of 68.06 (SD = 18.18), the Average profile had a mean treatment expectancy score of 64.62 (SD = 24.58), and the Extraverted Easygoing profile had a mean treatment expectancy score 58.06 (SD = 31.98). The overall mean score was 64.18 (SD = 24.97). Symptom LPA. Symptom profiles were determined using six indicator variables, including self-reported Insomnia, Physical Health, Psychological Health, Social Relationships, Anxiety, and Depression. A total of six LPA models were considered, ranging from one to six profile solutions. An analytic hierarchy process based on the fit indices AIC, AWE, BIC, CLC, and KIC (Akogul & Erisoglu, 2017), suggested that the best solution was Model 1 with 5 classes, however, one of the classes contained fewer than 5% of the sample and was therefore not used. Instead, the next best solution, a 4-profile solution, was selected as the best-fitting model according to BIC and BLRT (Table 7). The 4-profile solution is displayed visually in Figure 2. Table 7 Fit Indices for Latent Profiles Defined by Self-Reported Symptoms Profile AIC AWE BIC CLC KIC Entropy BLRT 1 6621.50 6756.65 6660.07 6599.49 6636.49 1 2 6256.21 6471.61 6317.30 6219.99 6278.21 0.89 0.01 3 6176.39 6471.87 6259.98 6126.09 6205.39 0.85 0.01 4 6148.17 6523.72 6254.26 6083.81 6184.17 0.82 0.01 5 6110.81 6566.25 6239.41 6032.56 6153.81 0.88 0.01 6 6108.98 6644.54 6260.08 6016.62 6158.98 0.82 0.17 Note. The fit indices required for the analytic hierarchy process. Bayesian Information Criterion (BIC), the Akaike Information Criterion (AIC), the Approximate Weight of Evidence (AWE), the 48 Classification Likelihood Criterion (CLC), and the Kullback Information Criterion (KIC). A four-class solution (bolded) was selected. Figure 2 Standardized Symptom Cluster Means Across Indicator Variables Note. Visual depiction of the mean standardized scores obtained on the symptom indicator variables for each of the three profiles. N = 184. Cluster 1, titled the Average Group, scored generally in the average range across Insomnia, all three factors of quality of life, depression and anxiety. Cluster Two, titled the Very Well Group, had below-average issues with sleep and anxiety, well below the average range for depression and above-average for all three factors of quality of life. Cluster Three, titled the Very Unwell Group, reported above-average issues with sleep, anxiety and depression and below-average levels across all three domains of quality of life. Cluster Four, titled the Moderately Well Group, scored in the higher end of the average range for issues with sleep, the average range of 49 the physical aspects of quality of life, above average for psychological and social domains of quality of life, the low end of the average range for depression and anxiety. Table 8 presents the unstandardized means. Participants were fairly evenly distributed between the Average Group (n = 54), Very Well Group (n =46), Very Unwell Group (n = 56), and Moderately Well Group (n =28). Participant cluster distribution frequencies for Baseline and Follow-up is presented in Table 9. Table 8 Unstandardized Means of Indicator Variables for the Symptom Clusters Variable Average Group Very Well Very Unwell Moderately Well Insomnia 10.60 6.22 20.37 16.51 Physical QOL 12.64 14.94 8.85 10.83 Psychological QOL 8.69 13.01 6.81 11.99 Social QOL 10.00 13.72 8.24 13.37 Anxiety 12.71 6.83 16.71 9.54 Depression 17.03 5.81 22.37 12.01 Table 9 Frequency Chart of Symptom Clusters at Baseline and Follow-up Profile Name Baseline n(%) Follow-up n(%) Average Group 54(29.3%) 19 (29.2%) Very Well Group 46 (25.0%) 14 (21.5%) Very Unwell Group 56 (30.4%) 23 (35.4%) Moderately Well Group 28 (15.2%) 9 (13.8%) Relationship between demographic information and Symptom Clusters Sex at birth. A chi-square test of independence was conducted to examine the relationship between sex assigned at birth (male or female) and symptom cluster membership (The Average, Very Well, Very Unwell, and Moderately Well Groups). The results indicated no 50 statistically significant association between sex assigned at birth and symptom cluster membership, χ2(3, N = 184) = 0.046, p = .997, V = 0.009, indicating a very weak or negligible association between sex assigned at birth and symptom cluster membership. The distribution of symptom clusters within each sex was nearly equal, with males and females represented similarly across clusters. Specifically, 48.1% of males and 51.9% of females were in the Average Group, 47.8% of males and 52.2% of females in the Very Well Group, 46.4% of males and 53.6% of females in the Very Unwell Group, and 46.4% of males and 53.6% of females in the Moderately Well Group. Overall, the findings indicate that symptom cluster membership does not significantly differ by sex assigned at birth in this dataset. Age. A one-way ANOVA was conducted to determine if there were significant differences in participant ages across the four symptom clusters (e.g., The Average, Very Well, Very Unwell, and Moderately Well Groups). The results indicated no statistically significant difference in age between the symptom clusters, F(3, 180) = 0.368, p = .776. The effect size estimates were very small, η² = .006, 95% CI [.000 - .029], suggesting that patient age did not significantly vary across the different symptom clusters in this sample. Descriptive statistics showed that the mean ages for each cluster were as follows: Average (M = 48.41, SD = 16.03), Very Well (M = 45.91, SD = 12.78), Very Unwell (M = 48.63, SD = 14.59), and Moderately Well (M = 48.46, SD = 14.18). The overall mean age for all participants was 47.86 years (SD = 14.47). Education. A Fisher-Freeman-Halton exact test was conducted due to the assumption of 5 or more expected cases per cell being violated. This test was used to evaluate the association between symptom cluster membership (e.g., The Average, Very Well, Very Unwell, and 51 Moderately Well Groups) and the highest level of education achieved (college, high school, less than high school, prefer not to answer, university, vocational or trade school). The analysis revealed no significant association between symptom cluster membership and education level, p =. 479. Effect size, V = 0.168, indicated a small association that is not significant in the current sample. Trauma and Symptomology PTSD. A one-way ANOVA was conducted to examine differences among the four symptom profiles (e.g., The Average, Very Well, Very Unwell, and Moderately Well Groups). Significant differences in mean PTSD scores were found between the four clusters, F(3,101) = 13.30, p < .001. The effect size measures indicate a moderate effect of cluster membership on PTSD scores, η² = .283, 95% CI [.130 - .397], suggesting that approximately 28.3% of the variance in PTSD symptoms could be attributed to differences in cluster membership. A Tukey HSD post hoc test was performed to examine pairwise differences between symptomology clusters for PTSD scores. The results revealed that the Very Unwell Group (M = 24.82, SD = 8.45) reported significantly higher PTSD symptoms compared to the Average Group (M = 15.24, SD = 8.40), p < .001, with a mean difference of 9.57 (95% CI [4.09, 15.06]). The Very Unwell Group also reported significantly higher PTSD symptoms compared to the Very Well Group (M = 13.33, SD = 9.40), p < .001, with a mean difference of 11.48 (95% CI [5.11, 17.85]). The Very Unwell Group reported significantly higher PTSD symptoms compared to the Moderately Well Group (M = 12.90, SD = 7.99), p < .001, with a mean difference of 11.92 (95% CI [5.77, 18.07]). There were no significant differences between the Average Group and the Very Well Group, p = .878, or between the Average Group and the Moderately Well Group, p = .781, or between the Very Well Group and the Moderately Well Group, p = .999. 52 Adverse Childhood Events. An ANOVA run on Adverse Childhood Experiences (ACE; n = 184) scores across symptomology clusters, revealed no statistically significant differences in ACE scores between the four clusters, F(3,180) = 1.90, p = .132. The effect size measures indicate a small effect of cluster membership on ACE scores, η² = .031, 95% CI [.000 - .081]. Descriptive statistics indicate that Cluster 3 (“Very Unwell”) reported a mean ACE score of M = 3.80, SD = 2.87, Cluster 2 (“Very Well”) reported a mean ACE score of M = 2.91, SD = 2.61, Cluster 1 (“Average”) reported a mean ACE score of M = 2.81, SD = 2.24, and Cluster 4 (“Moderately Well”) reported a mean ACE score of M = 2.75, SD = 2.32). Depression/Anxiety Change Scores and Symptomology ANOVAs were conducted to compare the effect of symptom clusters on changes in depression and anxiety scores among the 65 patients who received ketamine infusions; that is, comparing Baseline data to Follow-up data within those 65 individuals. The four clusters were characterized as follows: Cluster One (Average), Cluster Two (Very Well), Cluster Three (Very Unwell), and Cluster Four (Moderately Well). Depression. A one-way ANOVA approached significance; however, it did not reach a statistically significant effect of cluster membership on changes in depression scores, F(3,61) = 2.428, p = .074, η² = 0.107 95% CI [.000 - .231]. The mean change in depression scores (PHQ-9) varied across clusters, as follows: The Average Group had a mean change score of 3.21 (SD = 6.70), the Very Well Group had a mean -0.21 (SD = 2.78), the Very Unwell Group had a mean of 5.17 (SD = 7.08), and the Moderately Well Group had a mean of 3.67 (SD = 3.94). Anxiety. There was no statistically significant effect of cluster membership on changes in GAD-7 scores, F(3, 61) = 0.40, p = .752, η² = .019, 95% CI [.000 - .083]. The mean change in anxiety scores for the Average Group was a mean change score of 1.74 (SD = 4.32), the Very 53 Well Group had a mean of 0.93 (SD = 6.40), the Very Unwell Group had a mean of 2.70 (SD = 5.72), and the Moderately Well Group had a mean of 1.11 (SD = 3.55). Clinical Change Among the 65 Patients Who Received Ketamine Infusions and Completed Clinical Follow-up. Category Change. The PHQ-9 and the GAD-7 questionnaires are commonly used clinical tools to measure symptoms of depression and anxiety, respectively. These questionaires are often used to categorize symptom severity into clinically meaningful ranges. These categories were applied to the present data and Baseline and Follow-up as shown in Table 10 and Table 11. A “category change” refers to a shift in a participant’s classification from one severity category to another between two assessment time points. For both scales, a change in category often signifies clinically relevant shifts in symptoms (Kroenke et al., 2001; Kroenke et al., 2010; Spitzer et al., 2006). Shifting to a lower severity group may suggest a response to treatment. Conversely, a shift to a higher severity category may indicate a need for intervention or adjustment to the current treatment plan. Table 10 Category Change PHQ-9 Score Label # at Baseline # at Follow-up 0–4 None-minimal depression 4 9 5–9 Mild depression 12 17 10–14 Moderate depression 9 15 15–19 Moderately severe depression 17 10 20–27 Severe depression 23 14 54 Table 11 Category Change GAD-7 Score Label # at Baseline # at Follow-up 0–4 None-Minimal anxiety 8 15 5–9 Mild anxiety 13 14 10–14 Moderate anxiety 17 18 15–21 Severe anxiety 27 18 Category changes in these measures can be helpful as they represent shifts across predefined thresholds of symptom severity (Kroenke et al., 2001; Kroenke et al., 2010; Spitzer et al., 2006). Clinicians and researchers use these changes to evaluate treatment effectiveness, monitor patient progress, and make informed decisions about care. In the present sample, with respect to depression scores, 29 (44.6%) patients improved by one or more categories, 29 (44.6%) demonstrated no change, and 7 (10.8%) deteriorated. Similarly, with respect to anxiety scores, 23 (35.4%) patients improved by one or more categories, 33 (50.8%) demonstrated no change, and 9 (13.8%) deteriorated. Caseness Threshold Among the 65 Patients Who Received Ketamine Infusions In addition to category assignment, there is evidence that recovery can be evaluated using the concept of ‘caseness,’ which indicates that a patient’s symptoms are severe enough to be classified as a clinical case. Using caseness criteria, an individual is considered to have recovered if the patient was classified as a clinical case at the beginning of treatment (based on their baseline assessment score) and is no longer classified as such at the end of treatment (based on the most recent assessment score). Caseness in this study is defined as ≥ 8 on the GAD-7 and ≥ 10 on the PHQ-9 (Porter et al., 2024). PHQ-9 scores of  10 have demonstrated an 88% specificity and 88% sensitivity for major depression (Kroenke et al., 2001). Similarly, GAD-7 55 scores of  8 have demonstrated a 76% specificity and 92% sensitivity for generalized anxiety (Kroenke et al., 2007; Plummer et al., 2016). In this sample of 65 patients who received ketamine infusions at baseline, the number of patients who transitioned from clinical to “recovered” at follow-up for depression was 13 (20%). With respect to Anxiety, the number of patients who transitioned from clinical to “recovered” at follow-up one week after treatment was 12 (18.5%). Reliable Change Index for PHQ-9 Among the 65 Patients Who Received Ketamine Infusions The Reliable Change Index represents the degree of change on a measure that an individual must exhibit to exceed the variation attributable to measurement error. The Reliable Change Index provides a threshold for categorizing individuals as showing reliable improvement, deterioration, or no significant change based on their raw change scores (Blampied, 2022). Reliable change for the PHQ-9 has been defined as a change in score ≥ 6 (National Collaborating Centre for Mental Health, 2024). In this sample, 3 (4.6%) demonstrated reliable deterioration, 45 (69.2%) exhibited no change, and 17 (26.2%) demonstrated reliable improvement. Relationships Between Demographics and Reliable Change Outcomes in Depression Among the 65 Patients Who Received Ketamine Infusions Personality and Reliable Change Index Scores in Depression. A Fisher’s exact test was conducted to examine the relationship between personality profile membership (Easygoing Extraverts, Average, and Reserved Introverts) and reliable change in depression scores (Reliable Deterioration, No Change, Reliable Improvement) among the 65 participants who received ketamine. This test was conducted due to the assumption of 5 or more expected cases per cell 56 being violated. The analysis revealed no significant association between personality profile membership and reliable change in depression scores, Fisher-Freeman-Halton exact test, p = 1.000, with a small effect size, V = 0.116 (Cohen, 1988), indicating a negligible effect of personality in reliable change index scores. Symptom Clusters and Reliable Change Index Scores in Depression. A Fisher’s exact test was conducted to evaluate the association between symptom profile membership (Average Group, Very Well Group, Very Unwell Group, and Moderately Well Group) and reliable change in depression scores (Reliable Deterioration, No Change, Reliable Improvement) among the 65 participants who received ketamine. The Fisher-Freeman-Halton exact test approached significance but did not reach the conventional level of statistical significance, p = .056, with a medium effect size, V = 0.268 (Cohen, 1988). These results suggest a moderate relationship between symptom profile membership and reliable change in depression scores, though the lack of statistical significance limits the strength of this conclusion. In the Average Group 10.5% of participants experienced reliable deterioration, 57.9% reported no change, and 31.6% demonstrated reliable improvement. The Very Unwell Group presented no cases of reliable deterioration, 65.2% of participants with no change, and 34.8% with reliable improvement, possibly reflecting the impact of treatment on those with more room for improvement at baseline and the inability to deteriorate sufficiently to reach the threshold. Individuals in the Very Well had 7.1% of participants with reliable deterioration, 92.9% with no change, and no cases of reliable improvement, potentially reflecting the opposite of the Very Unwell Group (i.e., insufficient room to improve). Finally, the Moderately Well showed no cases of reliable deterioration, 66.7% of participants with no change, and 33.3% with reliable improvement. 57 History of Trauma and Reliable Change Index Scores in Depression. A Fisher’s exact test was conducted to assess the relationship between a history of a traumatic event (Yes or No) and reliable change in depression scores (Reliable Deterioration, No Change, Reliable Improvement) among the 65 participants who received ketamine. The analysis revealed a significant association between a history of a traumatic event and reliable change in depression scores, Fisher-Freeman-Halton exact test, p = .008, with a medium effect size, V = 0.355. This finding suggests a moderate relationship between the variables such that participants with a history of a traumatic event were more likely to experience reliable improvement in depression scores compared to those without such a history. Specifically, among participants without PTSD symptoms, 4.5% experienced reliable deterioration in depression symptoms, 90.9% showed no change, and only 4.5% demonstrated reliable improvement. In contrast, participants with PTSD symptoms exhibited different patterns: 4.7% experienced reliable deterioration, 58.1% showed no change, and 37.2% demonstrated reliable improvement. Reliable Change Index for GAD-7 Among the 65 Patients Who Received Ketamine Infusions A reliable change for the GAD-7 has been defined as a change in score ≥ 4 (National Collaborating Centre for Mental Health, 2024). Using this criterion, in this sample, 7 (10.7%) demonstrated reliable deterioration, 41 (63.1%) exhibited no change, and 17 (26.2%) demonstrated reliable improvement. Relationships Between Demographics and Reliable Change Outcomes in Anxiety Among the 65 Patients Who Received Ketamine Infusions Personality Profiles and Reliable Change Index Scores in Anxiety. A Fisher’s exact test was conducted to evaluate the relationship between personality profile membership 58 (Easygoing Extraverts, Average, Reserved Introverts) and reliable change in anxiety scores (Reliable Deterioration, No Change, Reliable Improvement) among the 65 participants who received ketamine. The results revealed no significant association between personality profiles and reliable change in anxiety, Fisher-Freeman-Halton exact test p = .756, with a small effect size, V = 0.130, indicating a negligible effect of personality in reliable change index scores. Symptomology and Reliable Change Index Scores in Anxiety. A Fisher’s exact test was conducted to examine the relationship between symptom cluster membership (Cluster One: Average, Cluster Two: Very Well, Cluster Three: Very Unwell, Cluster Four: Moderately Well) and reliable change in anxiety scores (Reliable Deterioration, No Change, Reliable Improvement) among the 65 participants who received ketamine. The Fisher-Freeman-Halton exact test was applied, and the results revealed no significant association between symptom cluster membership and reliable change in anxiety, p = .997, with a very small effect size, V = 0.070, indicating a negligible association between the variables. History of Trauma and Reliable Change Index Scores in Anxiety. A Fisher’s exact test was conducted to examine the relationship between the history of a traumatic event (Yes or No) and reliable change in anxiety scores (Reliable Deterioration, No Change, Reliable Improvement) among the 65 participants who received ketamine. The Fisher-Freeman-Halton exact test revealed a statistically significant association, p = .047, with a medium effect size, V = 0.301, indicating a medium-strength association between history of traumatic events and reliable change in anxiety (Cohen, 1988). Reliable deterioration in anxiety was more prevalent among individuals without a history of trauma, comprising 57% of this group, suggesting they may be more susceptible to worsening anxiety. Conversely, individuals with a history of trauma were significantly more likely to experience reliable improvement, accounting for 88% of 59 improvements, indicating a strong association between trauma history and positive outcomes in anxiety treatment. Stability, or no change in anxiety levels, was most common among individuals with a trauma history, representing 61% of this group, aligning with the larger group size. These findings highlight that deterioration is more typical among those without trauma history, while improvement is strongly linked to those with traumatic experiences. Stability remains prominent among individuals with trauma, reflecting the group’s overall composition. Reliable Recovery Among the 65 Patients Who Received Ketamine Infusions Reliable recovery is achieving both recovery (i.e., no longer scoring above the caseness threshold for the measure) and reliable change (i.e., meeting the reliable change index score for the measure; Porter et al., 2024). Among the 65 patients who received ketamine, with respect to depression, 10 (15.4%) individuals achieved reliable recovery at follow-up one week following treatment. Using the same criteria, 1 (1.5%) individual’s depression reliably deteriorated at follow-up. With respect to anxiety, 8 (12.3%) individuals achieved reliable recovery, while 4 (6%) reliably deteriorated. Descriptive Analyses of 65 Patients Who Received Ketamine Infusions As mentioned earlier, when comparing Baseline data to Follow-up data within individuals’ PHQ-9 scores, there was a significant decrease in scores, t(64) = 4.265, p < .001, which indicates a significant improvement in depressive symptoms for those individuals who received the ketamine treatment. Similarly, there was also a significant decrease in scores on the GAD-7, t(64) = 2.822, p = .006, which indicates a significant improvement in anxiety symptoms for those individuals who received the ketamine treatment. For the physical domain of quality of life, no statistically significant difference was found in scores from baseline to follow-up, t(64) = −1.245, p = .218, and the effect size was negligible, 60 d = −0.154, 95% CI [-0.398, 0.091]. This suggests no significant change in the physical domain of quality of life. For the psychological domain of quality of life, there was a statistically significant increase in scores from baseline to follow-up, t(64) = −2.190, p = .032, with a small negative effect size, d = −0.272, 95% CI [-0.518, -0.023]. This indicates a significant improvement in the psychological domain of quality of life for those individuals who received the ketamine treatment. Exploratory Paired t-tests for Change in Depression Scores among the 65 Patients who received Ketamine Treatment History Of Trauma. For depression change scores, there was a statistically significant difference between participants with and without a history of trauma, t(63) = −2.803, p = .007 (two-sided), with those with a history of trauma showing a greater reduction in depression scores. The effect size was moderate, d = −0.735, 95% CI [-1.262, -0.203], indicating that the history of trauma had a moderate association with the change in depression scores. Mean scores and standard deviations are presented in Table 12. Presence of Significant Pain. For depression change scores, there was no statistically significant difference between participants with and without significant pain, t(63) = −1.589, p = .117 (two-sided). The effect size was small, d = −0.421, 95% CI [-0.945, 0.105], indicating that the presence of significant pain had minimal impact on depression change scores. Mean scores and standard deviations are presented in Table 13. Sex at Birth. For depression change scores, there was no statistically significant difference between participants based on sex at birth, t(63) = 1.147, p = .256 (two-sided). The 61 effect size was small, d = 0.285, 95% CI [-0.206, 0.774], indicating a minimal effect of sex at birth on depression change scores. Means and standard deviations are presented in Table 14. Exploratory Paired t-tests for Change in Anxiety Scores among the 65 Patients who received Ketamine Treatment History Of Trauma. For anxiety change scores, the difference between the groups approached significance but did not reach the conventional level of statistical significance in a two-sided test, t(63) = −1.796, p = .077. The effect size was small to moderate, d = −0.471, 95% CI [-0.989, 0.051], suggesting that, while there was a trend for greater improvement among those with a history of trauma, the result was not statistically robust. Mean scores and standard deviations are presented in Table 12. Presence of Significant Pain. For anxiety change scores, no statistically significant difference was found between the groups, t(63) = 0.108, p = .915 (two-sided). The effect size was negligible, d = 0.029, 95% CI [-0.491, 0.548], suggesting that significant pain did not meaningfully impact anxiety change scores. Means and standard deviations are presented in Table 13. Sex at Birth. For anxiety change scores, no statistically significant difference was found between the groups, t(63) = 0.839, p = .404 (two-sided). The effect size was small, d = 0.209, 95% CI [-0.281, 0.697], suggesting a negligible influence of sex at birth on anxiety change scores. Mean scores and standard deviations are presented in Table 14. Exploratory Paired t-tests for Change in Quality of Life Scores among the 65 Patients who received Ketamine Treatment History Of Trauma and Physical Quality of Life. For quality of life change scores in WHOQOL domain 1 (Physical), there was a statistically significant difference between the two 62 groups, t(63) = 2.047, p = .045 (two-sided). The effect size was moderate, d = 0.537, 95% CI [0.012, 1.057], indicating that individuals with a history of trauma experienced greater improvement in this quality-of-life domain than those without a history of trauma. Mean scores and standard deviations are presented in Table 12. History Of Trauma and Psychological Quality of Life. In WHOQOL domain 2 (Psychological), approached significance but did not reach the conventional level of statistical significance, t(63) = 1.858, p = .068 (two-sided), with a small to moderate effect size, d = 0.487, 95% CI [-0.036, 1.006]. This suggests a possible trend for quality-of-life improvement in this domain among those with a trauma history, although the result did not reach conventional significance. Mean scores and standard deviations are presented in Table 12. Presence of Significant Pain and Physical Quality of Life. For quality of life change scores in WHOQOL domain 1 (Physical), there was no statistically significant difference between the two groups, t(63) = 1.247, p = .217 (two-sided). The effect size was small, d = 0.331, 95% CI [-0.194, 0.852], suggesting only a slight, non-significant improvement in quality of life for those with significant pain in this domain. Means and standard deviations are presented in Table 13. Presence of Significant Pain and Psychological Quality of Life. For WHOQOL domain 2 (Psychological), no statistically significant difference was found between the groups, t(63) = 1.090, p = .280 (two-sided). The effect size was small, d = 0.289, 95% CI [-0.234, 0.810], indicating that significant pain was not associated with notable changes in this quality-of-life domain. Mean scores and standard deviations are presented in Table 13. Sex at Birth and Physical Quality of Life. For quality of life change scores in WHOQOL domain 1 (Physical), there was also no statistically significant difference between the 63 two groups, t(63) = −1.083, p = .283 (two-sided). The effect size was small, d = −0.269, 95% CI [-0.758, 0.222], indicating a minor and non-significant difference in quality-of-life change scores based on sex at birth. Mean scores and standard deviations are presented in Table 14. Sex at Birth and Psychological Quality of Life. For WHOQOL domain 2 (Psychological), no statistically significant difference was found between the groups, t(63) = −1.400, p = .167 (two-sided). The effect size was small, d = −0.348, 95% CI [-0.838, 0.145], suggesting a slight, non-significant effect of sex at birth on changes in this quality-of-life domain. Mean scores and standard deviations are presented in Table 14. Table 12 Mean Change Scores in Variables for History of Trauma No Tramaa Traumab Variable M SD M SD Depression .41 3.75 4.67 6.60 Anxiety .23 5.51 2.63 4.87 Physical QOL .36 1.94 -.62 1.80 Psychological QOL .10 1.48 -.90 2.22 Note. a n = 22, b n = 43. Table 13 Mean Change Scores in Variables for the Presence of Significant Pain No Paina Painb Variable M SD M SD Depression 2.41 5.58 4.95 6.92 Anxiety 1.86 4.25 1.71 6.87 Physical QOL -.09 1.63 -.71 2.35 Psychological QOL -.36 1.69 -.95 2.64 Note. a n = 44, b n = 21. 64 Table 14 Mean Change Scores in Variables for Sex Assigned at Birth Malea Femaleb Variable M SD M SD Depression 4.17 6.73 2.43 5.49 Anxiety 2.4 5.79 1.31 4.63 Physical QOL -.57 2.19 -.06 1.59 Psychological QOL -.93 2.43 -.23 1.59 Note. a n = 30, b n = 35. 65 Chapter 4 Method – Study 2 The Ketamine Experience Survey was sent to all 65 patients who received ketamine infusions and adhered to their clinical follow-up one week after treatment from Study 1. There were no additional inclusion or exclusion criteria for participation. Of those 65 patients, 31 voluntarily completed the Ketamine Experience Survey; consequently, Study 2 is based on the responses from those 31 participants. The survey aimed to comprehensively understand their personal experiences with, and perspectives on, this treatment. Data Collection After reviewing the letter of initial contact and consent form, participants were asked if they consented to complete a brief (i.e., approximately 20-30 minutes) online survey (Appendix 2). The anonymous survey employed a convergent mixed-method design, meaning that participants were asked quantifiable questions (e.g., responses on a Likert scale or VAS) and open-ended questions that allowed them to describe their experiences (Creswell & Creswell, 2018). In general, the survey asked participants to recall their experiences over the course of their ketamine journey. All survey data was collected on Qualtrics (Qualtrics, Provo UT). Analytic Procedure Survey responses were summarized using descriptive statistics (i.e., frequencies and percentages for categorical variables and means and ranges for continuous variables). Quantitative analyses were performed in SPSS v29. Responses to the open-ended question were analyzed using thematic analysis to identify the impact of the treatment on participants’ lives that may not have been captured in the closed-ended questions (Braun & Clark, 2006). In line with a framework from Braun and Clarke (2006), the qualitative data were analyzed using the following steps: familiarizing with the data, generating initial codes, organizing codes into themes, 66 reviewing and refining the themes, naming the themes, and presenting the final themes. No quantitative approach was taken in the thematic analysis, and each open-ended question was independently coded (Braun & Clark, 2006). Preliminary codes were derived inductively (Frith & Gleeson, 2004). Coding involved a semantic approach whereby explicit statements were described and interpreted to arrive at initial themes. Themes were then examined and refined to achieve parsimony in the results. A connecting approach was used to link the qualitative and quantitative portions of the study, which allowed for an expansion of the qualitative data (Creswell & Creswell, 2005). 67 Chapter 5 Results – Study 2 Pre-Treatment Considerations Quantitative. Participants reported various pre-treatment considerations related to their conditions and costs associated with treatment (Table 15). Depression was the most frequently reported primary condition, followed by trauma and pain. The most endorsed secondary reasons for seeking ketamine treatment included anxiety and depression. Participants reported an average of 3.45 additional conditions (SD = 2.45, Range = 1 – 8) alongside their primary condition. There were no participants who endorsed having only one condition prior to treatment. The mean severity of symptoms before treatment, including primary and accompanying conditions, was in the severe range (8.2/10). Participants also reported trying multiple pharmacological options, with the vast majority attempting four or more medications to treat their symptoms, including over a quarter of individuals who reported trying ten or more. Cost was a significant barrier for just over 80% of participants, who indicated that finances affected their ability to initiate treatment. 68 Table 15 Descriptive Information of Pre-Treatment Considerations Variable n(%)/M, SD Primary Condition Depression 15 (48.4%) Anxiety 2 (6.5%) Trauma 5 (16.1%) Disordered eating 1 (3.2%) Pain 6 (19.4%) Suicidal thoughts 2 (6.5%) Additional Condition(s) Depression 17 (54.8%) Anxiety 24 (77.4%) Stress 17 (54.8%) Trauma 14 (45.2%) OCD 8 (25.8%) Disordered eating 6 (19.4%) Pain 8 (25.8%) Suicidal thoughts 13 (41.9%) Average number of conditions M = 3.45, SD = 2.45 Symptom Severity before treatment M = 8.2, SD = 1.6 Number of medications before ketamine 1 2 (6.5%) 2 to 3 4 (12.9%) 4 to 6 11 (35.5%) 7 to 9 5 (16.1%) 10+ 9 (29.0%) Cost affected ability to initiate treatment Yes 25 (80.6%) No 6 (19.4%) Note.n = 31 Open Ended Responses. Patients were asked to describe how they felt before their first treatment. Mental Health Struggles were commonly discussed. Many participants expressed depression and anhedonia by conveying feelings of sadness, hopelessness, and helplessness, with 69 phrases like “no positive outlook on life,” “joyless,” “low mood,” and “nothing good about life.” Likewise, an inability to experience joy or pleasure was commonly reported, with phrases like “profoundly anhedonic,” “joyless,” and “emotionally flat.” Depictions of anxiety were also frequently reported, including statements about “panic attacks” and “anxiousness to the point of sometimes being immobilized.” Suicidal thoughts and ideation were common, with several participants explicitly mentioning persistent thoughts of suicide, such as “I was ready to die” and “I would go to sleep at night hoping to never wake up.” Participants also frequently conveyed dealing with cognitive impairments and mentioned issues such as “poor focus,” “lack of mental sharpness,” “difficulty thinking clearly,” and “memory problems.” Multiple individuals relayed experiences with Physical Pain and Limitations. Specifically, mentions of chronic pain conditions, including fibromyalgia, rheumatoid arthritis, and somatoform disorders, were cited as contributing factors to their distress. Participants also described pain-related limitations in mobility, sleep disruptions, and an overall reduction in quality of life. Several individuals mentioned past Traumatic Experiences and dealing with PTSD and CPTSD. Symptoms described included “night terrors,” “intrusive thoughts,” and feeling “revved up and worried” when considering previous trauma exposures. Several participants depicted the theme of Desperation and Exhaustion with statements such as “desperate to feel different,” “given up hope,” “completely exhausted,” “bleak and hopeless,” and “mentally and physically fatigued.” In contrast to the desperation and exhaustion felt by many, a minority of responses reflected hope and openness, with some participants feeling 70 optimistic about the potential for ketamine therapy to help with statements such as “open and hopeful” and “excited” about treatment. The general tone of responses was negative and overwhelmingly reflected profound distress, characterized by severe emotional, cognitive, and physical challenges. The most prominent themes include depression, anxiety, chronic pain, and trauma, often intertwined in complex ways. While the predominant tone is one of despair and struggle, a few participants conveyed cautious optimism, suggesting a readiness for change and potential recovery through ketamine-assisted therapy. Treatment Considerations Quantitative. Participants reported a variety of experiences with treatment (Table 16). Most participants in the study indicated that they had undergone fewer than three sessions; however, there was a broad range of ketamine use experience. On average, participants reported that they were comfortable during the treatment, with scores ranging from not comfortable at all to completely comfortable. Despite their reported comfort, nearly half of the participants (45.2%) reported experiencing negative side effects as part of the treatment, with nausea, disturbing sensory perceptions, and negative emotional states being the most common. Symptom relief following treatment was reported as falling into the moderate range. Importantly, the vast majority of participants (87.1%) indicated that costs associated with treatment impacted their ability to continue treatment. 71 Table 16 Descriptive Information of Treatment Considerations Variable n(%)/M, SD Number of sessions in total 1 10(32.3%) 2 to 3 11(35.5%) 4 to 6 6(19.4%) 7 to 9 3(9.7%) 10+ 1(3.2%) Comfort during session M = 7.7, SD = 2.6 Reported side effects Yes 14 (45.2%) No 17 (54.8%) Side effects endorsed Nausea without vomiting 3 (9.7%) Nausea with vomiting 4 (12.9%) Physical discomfort 3 (9.7%) Overheating 1 (3.2%) Disturbing sensory perceptions 4 (12.9%) Negative emotional state 7 (22.6%) Other 5 (16.1%) Symptom relief after treatment M = 4.7, SD = 3.7 Cost affected ability to continue treatment Yes 27 (87.1%) No 4 (12.9%) Note. n = 31. Open Ended - Relief. Participants were asked to describe the relief they experienced from treatment. Many participants described holistic Relief and Improvements. Several participants who experienced mental health relief described feeling less rigid in their thinking, more connected to themselves and others, and able to “zoom out” and gain new perspectives. Some mentioned feeling a reconnection to joy or happiness. Similarly, a subset of participants experienced physical and cognitive improvements, such as reduced chronic pain, better sleep, 72 increased mobility, and mental clarity or sharpness. Mental and physical relief was tied to improved functionality, including the increased ability to engage in daily tasks, work, and social interactions, which were highlighted by some participants, indicating meaningful functional gains. Many participants who conveyed improvements also expressed gratitude for their improvements and optimism about the future. Several participants described Re-evaluation and Perspective Shifts. Participants noted positive changes in how they related to their emotions and relationships, often describing a newfound curiosity about themselves or an ability to let go of unhelpful relationships. A few mentioned the psychedelic experience offering valuable insights, such as seeing life from a new angle or recognizing what they would miss during moments of suicidal ideation. Despite many participants achieving some relief or improvements, many participants noted that they experienced Short-Lived Benefits, with relief fading after a few weeks or months. Similarly, some participants mentioned that they experienced only Partial Treatment Success in that while ketamine provided certain benefits (e.g., reduced pain or improved clarity), it fell short of what they would consider comprehensive relief. A subset of responses conveyed Treatment Failure and Unmet Expectations, with participants noting that ketamine was not the “magical cure” they had hoped for. Frustration with the High Cost of Treatment was a recurring theme. Financial barriers were frequently mentioned, with participants expressing that more frequent or longer treatment regimens might have led to better outcomes. Likewise, participants who expressed little treatment success described the impact of the high cost for no to minimal benefit. In sum, the open-ended responses related to relief revealed a complex picture of the relief experienced through ketamine-assisted therapy. While some participants described meaningful 73 and transformative improvements, others reported only temporary or partial benefits, often accompanied by frustration with the high cost or unmet expectations. Themes of emotional growth, re-evaluated perspectives, and increased functionality emerged among those who benefited. Disappointment and frustration were reflected for those who experienced minimal to no effects. Open Ended - Benefits. Additionally, participants were asked about the specific symptoms or issues they felt ketamine-assisted therapy helped with the most. Many participants reported significant improvements in anxiety and depression, often describing it as “gone” or “reduced.” Several responses highlighted diminished or eliminated thoughts of self-harm or suicide. Improved Cognitive Abilities was also a recurring theme, with participants noting “better focus,” “mental sharpness,” and “the ability to concentrate” as commonly cited benefits. Neuroplasticity was also articulated as a benefit, with participants emphasizing the potential long-term benefits of ketamine’s neuroplasticity effects, such as creating “new neural connections” and helping the brain move past the “default mode network.” Many participants described Perspective Shifts and Transformation, and these shifts related to their self-view and worldview. For example, some noted increased confidence, finding a sense of purpose, newfound resilience, rediscovering a sense of self, and moving beyond past traumas, indicating shifts in self-perception. Similarly, some individuals mentioned the psychedelic experience as pivotal, allowing them to break free from entrenched thought patterns or realize that their state was not permanent. The psychedelic “trip” was noted as a meaningful and positive experience, helping participants access new mental states and perspectives. 74 Some participants reported Relief from Chronic Pain and Improved Physical Functioning including decreased flare-ups, reduced pain intensity, and improved management of physical conditions. Likewise, some responses included mentions of enhanced mobility, reduced reliance on pain medication, and increased ability to exercise. While most participants focused on what benefitted most from treatment, there was a theme that emerged around Negative Experiences. A few participants expressed frustration that ketamine therapy did not help them or caused uncomfortable side effects. Similarly, others conveyed that they experienced only minor benefits, such as “taking the edge off” but not providing sufficient relief. In sum, the responses reveal a spectrum of experiences with ketamine-assisted therapy, ranging from profound relief to little or no benefit. The most notable improvements were in mental health (reduced anxiety, depression, and suicidal ideation), cognitive clarity, and physical pain relief. Participants highlighted the transformative potential of ketamine’s effects on perspective and emotional growth, with some crediting it for reshaping their sense of self and purpose. However, mixed outcomes and the presence of negative or minimal results underscore the variability of individual responses to the therapy. The overall tone was largely hopeful, with moments of gratitude and empowerment, though tempered by frustration from those who did not benefit. Open Ended – No Improvement or Worsening. Approximately half of the participants in the survey indicated that there were aspects of their mental health or well-being that Ketamine-Assisted Therapy did not improve or worsened. The primary theme that arose was Financial Difficulties Associated with Treatment. The high cost of ketamine-assisted therapy was repeatedly mentioned as a significant barrier, adding 75 stress and frustration. Many participants described financial strain as exacerbating their mental health challenges. Participants also expressed frustration that effective treatments were often only available to wealthier individuals, creating inequity in mental health care. Another theme that emerged was Adverse Effects or Worsening Symptoms, with several participants reporting feeling worse after the treatment. For some, specific symptoms such as dissociation, depression, suicidality or pain severity worsened after the treatment. Others described negative physical side effects, including heart palpitations, motion sickness, and bladder issues, which in some cases persisted for extended periods. Disappointment and Loss of Hope was also a recurring theme, with some participants indicating that ketamine therapy did not meet expectations. For instance, some participants described feeling no significant/temporary improvement in symptoms or only experiencing short-lived relief. Many participants expressed a profound sense of despair after ketamine failed to provide relief, particularly if they had viewed it as a last-resort option. Some noted that the failure of ketamine therapy deepened their discouragement, leaving them feeling that no treatment could help. Some participants described Negative or Dark Experiences during the ketamine sessions themselves, particularly in subsequent treatments. A limited number of patients felt they had inadequate clinical support, compounding the negative experience. Responses on the topic of challenges and negative outcomes associated with ketamine-assisted therapy highlighted the struggles faced by some individuals. Themes of financial stress, unmet expectations, and worsening symptoms dominated the feedback. Many participants felt disillusioned, describing increased depression and suicidality, short-lived relief, or no benefits at all. Adverse physical side effects and challenging clinical environments compounded their 76 dissatisfaction. Despite these challenges, a few individuals noted temporary benefits or insights into their conditions, but these were overshadowed by pervasive frustration and despair. The responses underline the need for more accessible, supportive, and individualized approaches to mental health treatments and a better understanding of ketamine’s limitations. Post-Treatment Considerations Quantitative. Participants reported varied success with ketamine (Table 17). Most participants (74.2%) reported at least minimal medication effectiveness and endorsed that treatment improved their daily functioning to some degree. Following treatment, just over half of the participants reported returning to baseline, while the remaining participants stated they continued to feel at least some of the benefits of treatment. Time since the most recent treatment varied, with nearly half reporting more than six months since their last session. At the time of the survey, participants ranked their symptom severity as 57.5 (SD = 28.5). The mean difference in symptom severity before and after treatment (i.e., from the pre- and post-treatment considerations section of the survey) was 24.03 (SD = 28.74), representing a significant retrospective self-reported reduction in symptoms as a result of undergoing ketamine-assisted therapy, t(30) = 4.66, p < .001 with a large effect size, d = .836 [CI .421-1.241]. 77 Table 17 Descriptive Information of Post-Treatment Considerations Variable n (%)/M, SD Effectiveness Rating Not effective at all 8 (25.8%) Slightly effective 5 (16.1%) Moderately effective 6 (19.4%) Very effective 6 (19.4%) Extremely effective 6 (19.4%) Return to the baseline Yes, I returned to baseline 16 (51.6%) No, I still feel benefits of treatment 15 (48.4%) Time since most recent treatment Less than 30 days 2 (6.5%) 1-2 Months 7 (22.6%) 2-4 Months 5 (16.1%) 4-6 Months 2 (6.5%) More than 6 months 15 (48.4%) Present symptom severity M = 5.8, SD = 2.9 Note. n = 31. Open Ended—Life Impacted. Participants were asked to share how treatment had affected their lives. They were prompted that the effects may be positive, neutral, or negative. Many individuals highlighted Positive Life Changes. Within the theme of Positive Life Changes was Improved Mental Health. In this area, participants highlighted reduced anxiety, depression, and suicidal ideation. Phrases like “no longer want to kill myself” and “I feel hopeful/optimistic” conveyed the types of changes they experienced. Enhanced Quality of Life also emerged as a theme, with participants noting improvements in family dynamics, relationships, productivity, and personal growth, describing a “profound” impact. Enhancements were attributed to increased confidence, better communication, and the ability to engage in 78 meaningful activities were emphasized by some participants. Downstream Positive Effects also arose as a theme, with positive outcomes noted not only for individuals but also for their families and support networks. Another Positive Life Change included Physical Benefits and Pain Reduction, with some experiencing relief from chronic pain, leading to improved functionality and the ability to perform daily tasks or pursue goals. Cognitive Improvements were the final positive change noted. Participants reported improvements in clarity, decision-making, and focus. Conversely, some participants relayed Negative Outcomes. Worsened Mental State, such as deepened depression, increased anger, or diminished hope, particularly when treatment was ineffective or unaffordable, emerged. Adverse Physical Effects such as motion sickness, bladder issues, memory loss, and phantosmia were reported, sometimes lasting months after treatment. Financial Burden was also a negative outcome for many. The high cost of treatment was frequently mentioned, contributing to stress, anger, and a feeling of being “teased” by incomplete or inaccessible relief. Financial Burden was often compounded by Short-Lived or Marginal Benefits, with some participants reporting initial improvements, these were often short-lived or very minor improvements, leading to frustration and a sense of futility. Responses to post-treatment considerations reveal a broad spectrum of experiences, with participants describing both significant positive changes and deep frustrations. For some, ketamine-assisted therapy was life-changing, reducing pain, anxiety, and depression, and fostering personal growth and engagement. Others, however, experienced negative physical effects, worsened mental health, or disappointment from the treatment’s high cost and limited efficacy. While the tone ranged from hopeful to despairing, the financial strain of treatment and its uneven outcomes were recurring themes, highlighting the need for more accessible and 79 consistent approaches to mental health care. For many, the therapy served as either a transformative intervention or a stepping stone toward further treatments. 80 Chapter 6 – General Discussion The present research explored the personality and symptom profiles, as well as early treatment outcomes, of individuals undergoing ketamine-assisted therapy for treatment-resistant psychological conditions. Utilizing LPA, distinct personality and symptom profiles were identified at baseline, and their associations with mental health outcomes were examined. A key focus was understanding how individual differences—such as trauma history, symptom severity, and personality traits—varied at baseline and influenced treatment effects. Study 1 concentrated on quantitative analysis, identifying personality and symptom clusters, clinical differences, and group-level analyses; whereas, Study 2 employed a mixed method approach to more deeply explore patient-reported experiences, providing a holistic view of the impact of ketamine-assisted therapy. Together, these studies contribute to the growing body of literature on personalized approaches to mental health interventions, underscoring ketamine’s potential to address complex and comorbid psychological disorders. Study 1 – Clinical Data Personality Profiles The LPA, using a measure of the Five-Factor Model of personality, identified three distinct personality profiles: Easygoing Extraverts, Average, and Reserved Introverts. These profiles were characterized by unique configurations of the Big Five personality traits. Specifically, the Easygoing Extraverts scored in the above-average range for Extraversion and Agreeableness, in the average range for Conscientiousness and Openness, and at the low end of the average range for Neuroticism. The Averages scored in the average range across all five factors of personality. The Reserved Introverts scored below average for Extraversion, 81 Conscientiousness, Openness, and Agreeableness and at the high end of the average range for Neuroticism. Demographics and Personality. There were no meaningful differences on personality profile membership based on age or education level. The relationship between sex assigned at birth and personality profile, however, emerged as significant. Males were more likely to belong to the Reserved Introvert profile, while females were more frequently categorized within the Easygoing Extraverts and Average profiles. The presence of sex differences in personality traits is well established; specifically, females have been found to typically exhibit higher levels of neuroticism, agreeableness, extraversion, and conscientiousness, while males typically score higher in openness to experience (Goodman & Gotlieb, 2004). Previous research has found that these sex differences in personality traits appear to play an important role in mental health outcomes (e.g., Serrano et al., 2022). Higher openness to experience has been linked to an increased likelihood of subthreshold depressive symptoms in females and to the persistence or recurrence of such symptoms in males (Serrano et al., 2022). Openness, may also predispose individuals to depressive symptoms when encountering stressful events (Khoo & Simms, 2018; Wolfenstein & Trull, 1997). Conscientiousness, on the other hand, seems to offer some protection against depression, but its effects differ between genders. For men, having lower conscientiousness has been linked to more frequent and earlier signs of mild depression and major depressive episodes. For women, lower conscientiousness is related to continuing or recurring mild depression symptoms (Serrano et al., 2022). High conscientiousness has been posited to promote effective coping strategies that mitigate the negative impact of stressful life events, reducing the risk of depression (Weiss et al., 2009). Finally, increased levels of agreeableness and extraversion have been found to reduce the risk of subthreshold depressive 82 symptom onset and the recurrence of probable major depressive episodes, respectively, but only in males (Serrano et al., 2022). The significant relationship between sex assigned at birth and personality profile in Study 1 offers unique insight into patterns of personality that emerge in those seeking ketamine-assisted therapy, whichprovides a unique opportunity to tailor pre-ketamine aspects of care to support patients according to their personality profile and sex. Depression, Anxiety, and Personality. Significant differences were observed in baseline depression and anxiety symptoms across personality profiles. Reserved Introverts reported significantly higher levels of both depression and anxiety compared to Easygoing Extraverts and the Average profile. The Reserved Introverts profile maps on closely to prior research, which has found similar personality configurations (i.e., characterized by high neuroticism, low extraversion, and low conscientiousness) and has been dubbed "vulnerable personality" (Wardenaar et al., 2014) or the "misery triad" (Miller, 1991). The Reserved Introverts profile, marked in this research by low extraversion, low-average conscientiousness, and high-average neuroticism, corresponds with evidence suggesting that introverted and emotionally unstable traits are closely linked to increased depression and anxiety symptoms (Lyon et al., 2021; Widiger & Oltmanns, 2017). A meta-analysis of 175 correlational studies further supports this association, demonstrating that neuroticism is positively correlated with generalized anxiety disorder and major depressive disorder, while extraversion and conscientiousness are negatively correlated with these affective disorders (Kotov et al., 2010). The observed differences in baseline depression and anxiety symptoms across personality profiles may be partly explained by variations in emotion regulation strategies commonly employed by varying personality types. Emotion regulation is the ability to modulate emotions, 83 both in terms of expression and experience, through specific strategies aimed at achieving emotional goals (McRae & Gross, 2020; Tamir et al., 2020). Emotion regulation strategies shape how individuals experience and manage their emotions, and difficulties in this process have been implicated as a mechanism underlying various forms of psychopathology and clinically relevant behaviours (Gratz & Tull, 2010). For example, higher neuroticism is often associated with maladaptive emotion regulation strategies, such as rumination and avoidance, and lower use of adaptive strategies, such as reappraisal and mindfulness (Barańczuk, 2019; Eisenberg & Fabes, 1994; Kim et al., 2017). This relationship may be further amplified in individuals who experience less supportive emotion socialization processes, leading to persistent difficulties in managing emotions (Eisenberg et al., 1996; Kochanska et al., 2004). In contrast, higher extraversion is linked to greater use of adaptive strategies, including problem-solving, mindfulness, and acceptance, and lower use of maladaptive strategies, such as worry and suppression (Barańczuk, 2019). These adaptive strategies may act as protective factors, reducing the likelihood of heightened depression and anxiety symptoms in individuals with high extraversion. The differences in emotion regulation strategies observed across personality traits highlight the role of personality in influencing psychological vulnerability and resilience. Research suggests that the strength of these relationships may vary depending on sex, clinical status, and the context in which emotion regulation is assessed (Barańczuk, 2019). The interplay between personality traits and emotion regulation underscores its relevance as a transdiagnostic construct. Emotion regulation difficulties are prevalent across various psychological disorders and provide a framework for healthcare providers to address maladaptive behaviors and promote healthier emotional responses in patients (Menefee et al., 2022; Sloan et al., 2017). For individuals with high neuroticism and low extraversion, 84 therapeutic interventions focusing on enhancing adaptive emotion regulation strategies may be particularly beneficial in mitigating depression and anxiety symptoms. By considering personality profiles and their associated emotion regulation patterns, pre-treatment interventions can be tailored to address the unique psychological needs of individuals. Changes in Depression and Anxiety Following Treatment. Ketamine-assisted therapy resulted in significant improvements in both depression and anxiety for patients. However, the absence of significant differences in change scores for depression and anxiety between the identified personality profiles suggests that while personality influences baseline symptom severity, it does not appear to significantly affect the short-term therapeutic response to ketamine. The lack of differences in short-term treatment response highlights the broad efficacy of ketamine treatment, irrespective of individual differences in personality traits. The lack of variation in treatment response across personality profiles aligns with prior research, indicating that ketamine’s rapid antidepressant and anxiolytic effects are effective for diverse patient populations (Zarate et al., 2006). Personality traits such as neuroticism, extraversion, and conscientiousness are typically associated with variability in emotional regulation and coping strategies, which often contribute to differences in mental health outcomes (Widiger & Oltmanns, 2017; Barańczuk, 2019). However, ketamine’s mechanism of action, which includes modulation of the glutamatergic system and synaptic plasticity, may exert therapeutic effects that are strong enough to minimize the impact of personality-related differences (Krystal et al., 2013). This pattern may also reflect ketamine’s capacity to target core neurobiological dysfunctions shared across individuals with depression and anxiety, regardless of personality traits. The results suggest that ketamine may be uniquely suited as a transdiagnostic treatment, 85 addressing underlying mechanisms that contribute to symptomatology across diverse patient subgroups. Personality traits may play a role in determining the severity of baseline symptoms, but ketamine’s effectiveness appears to transcend these individual differences, providing significant benefits across a wide range of patients. While there was no effect of personality in the short-term follow-up, additional research would be required to explore whether differences emerge over longer-term treatment courses. This would help clarify whether personality traits influence sustained treatment effects, or specific aspects of recovery, following ketamine-assisted therapy. Trauma and Personality. The lack of significant differences in baseline PTSD and ACE scores across the identified personality profiles suggests that trauma, whether experienced in childhood or adulthood, does not vary based on personality characteristics. This contrasts with previous research suggesting that personality profiles may influence the development of posttraumatic responses (Chung et al., 2005) or that traumatic experiences may shape personality over time (Widiger, 2011). The current finding implies that personality traits may play a limited role in shaping the initial presentation of trauma-related symptoms. Research has indicated that personality profiles are associated with different comorbidities in individuals with PTSD. Veterans with PTSD and an internalizing personality profile tend to experience internalizing symptoms such as anxiety and depression, while those with an externalizing profile are more likely to exhibit externalizing symptoms such as substance abuse and aggression (Kotov et al., 2010). While the present study did not find significant differences in trauma scores across personality profiles, the influence of personality on the types of comorbid symptoms observed in trauma-exposed individuals is well-documented. This 86 highlights the importance of assessing individual personality traits to understand the manifestation of both clinical and subclinical PTSD symptoms. The association between personality traits and the presentation of PTSD symptoms may help clinicians predict patterns of co-occurring symptoms in trauma-affected individuals. For instance, subclinical symptoms such as alcohol misuse, aggression, or depression often occur alongside one another, even when full diagnostic criteria for PTSD are not met. The inclusion of personality assessments in clinical evaluations may, therefore, offer valuable insights into symptom clusters, which could improve personalized treatment approaches (Campbell et al., 2021). Understanding these patterns could help clinicians better address the interconnected nature of trauma-related symptoms and comorbidities, potentially enhancing both diagnostic accuracy and therapeutic outcomes. Symptom Clusters The LPA on symptom data revealed four distinct profiles: the Average, Very Well, Very Unwell, and Moderately Well Groups. These groups highlight the diversity in symptom presentations among individuals seeking ketamine treatment and emphasize the multidimensional nature of treatment resistance, with symptom variability reflecting key domains such as sleep difficulties, psychological distress, and quality of life. The differences in baseline symptomology found in Study 1 align with previous research highlighting the heterogeneity in symptom presentations among patients with treatment-resistant conditions (Jones & Carter, 2019; Smith et al., 2020). Symptoms and Demographic Factors. Analyses showed no significant associations between symptom profiles and sex assigned at birth, age, or education, diverging from earlier studies that often link demographic factors to differences in symptom presentation (Nolen- 87 Hoeksema, 2012; Carstensen et al., 2011; Mirowsky & Ross, 2015). This lack of association may reflect the shared experience of treatment resistance within this population, or the limitations of demographic predictors when symptoms are analyzed as multidimensional profiles. Trauma and Symptomology. Baseline PTSD scores were significantly associated with symptom cluster membership, with individuals in the Very Unwell cluster exhibiting the highest levels of symptom severity, suggesting that those with more severe symptom profiles are likely to experience greater trauma-related distress. PTSD has been found to trigger or aggravate various psychiatric issues (Bryant, 2022). The findings from Study 1 indicating a relationship between symptom severity and PTSD severity is consistent with previous research linking elevated levels of psychopathology, such as depression and anxiety, to increased PTSD symptomatology (Campbell et al., 2021; Cloitre et al., 2010). Shared features across these conditions, including emotional numbing, dysphoria, hypervigilance, and sleep disturbances, may account for their strong associations with PTSD (Gros et al., 2012). The link between symptom clusters and PTSD underscores the importance of evaluating symptom severity when assessing trauma-related conditions. Individuals with high PTSD symptomatology often experience cascading effects on other mental health domains. Previous studies suggest that PTSD can contribute to the onset or exacerbation of other psychiatric disorders, including major depressive disorder and anxiety disorders, emphasizing the need for targeted PTSD treatment (Bryant, 2022; Smoler, 2016). Addressing PTSD symptoms may yield broader benefits, improving mental health outcomes across a range of related conditions (Bryant, 2022; Smoler, 2016). Despite the strong association between PTSD and symptom cluster membership, no significant differences in ACE scores were observed across clusters. This finding suggests that 88 the impact of early adversity on adult symptomatology may be offset by individual differences in resilience or coping mechanisms (Kalmakis & Chandler, 2015; Poole et al., 2017). Furthermore, the lack of differences in ACE scores across clusters may reflect the possibility that certain types or degrees of early adversity do not directly correspond to symptom severity in adulthood. Instead, factors such as the nature of the adversity, the presence of protective influences, or variations in individual susceptibility may moderate the relationship between early life stress and adult trauma responses. Taken together, the findings related to PTSD, ACEs, and symptomology highlight the complex interplay between early adversity, individual resilience, and adult trauma-related distress. Understanding these dynamics could inform the development of more targeted and effective interventions for individuals experiencing PTSD and comorbid conditions. Changes in Depression and Anxiety Post-Treatment. No significant differences in change in depression or anxiety scores were observed between symptomology clusters following ketamine-assisted therapy, suggesting that while symptomology clusters indicated differences in baseline symptoms, they do not appear to be related to early treatment responses for depression and anxiety. The minimal impact of symptomology clusters on treatment response may reflect the robust antidepressant and anxiolytic effects of ketamine, which could override individual differences in symptom severity, mapping onto existing literature highlighting the broad efficacy of ketamine in reducing depressive and anxious symptoms, thus providing consistent benefits across patient groups with limited predictors of outcomes (Price et al., 2022; Zarate et al., 2006; Grunebaum et al., 2018). Clinical Change and Reliable Change Index. Analysis of clinical change revealed that nearly half of participants experienced reliable improvements in depression scores following their ketamine treatement, while over a third showed reliable reductions in anxiety. Categorical 89 analysis of reliable change index scores (i.e., reliable responders, reliably stable, or reliable deteriorators) underscored the importance of trauma history: individuals with trauma histories were more likely to demonstrate reliable improvements in both depression and anxiety, aligning with research indicating that ketamine’s dissociative and rapid antidepressant effects may alleviate trauma-related dysregulation (Dore et al., 2019). Patients without trauma histories, however, were more likely to experience a deterioration in anxiety, suggesting that a history of trauma could play a role in improving outcomes for those undergoing ketamine-assisted therapy. Symptom severity was also associated with reliable change index scores. Individuals in the Very Unwell cluster derived greater benefits, reflecting ketamine’s established efficacy in addressing severe depression and anxiety (Sanacora et al., 2017). It is promising that the results indicate that those who are most symptomatic are experiencing reliable positive change. Personality profiles were not significantly associated with reliable changes in mental health outcomes, suggesting that ketamine’s effects may operate independently of baseline personality traits despite the Reserved Introverts having lower scores at baseline. Improvements in Depression and Anxiety. Ketamine-assisted therapy was associated with significant reductions in both depressive and anxiety scores, consistent with existing research on its rapid and robust antidepressant and anxiolytic effects (e.g., Zarate et al., 2006; Grunebaum et al., 2018). The improvements in psychological symptoms align with ketamine's proposed mechanisms, including modulation of glutamate neurotransmission and enhanced synaptic plasticity (Duman et al., 2019) and add to the growing evidence supporting ketamine as a viable intervention for treatment-resistant mood and anxiety disorders. Quality of Life Changes. Significant improvements were observed in the psychological domain of quality of life following ketamine treatment but not in the physical domain. The 90 improvement in psychological quality of life may reflect the alleviation of mood and anxiety symptoms, as quality of life is closely tied to psychological well-being (Browne et al., 2017). The lack of significant changes in physical quality of life may suggest that ketamine’s effects are more pronounced in mental health domains, and additional interventions might be required to address physical health concerns. Similarly, the route of administration, dose, and duration of infusion may play an important role in the physical domains – as such, the intramuscular route used in the present research may not have been sufficient for treating physical challenges (Noppers et al., 2010; Orhurhu, et al., 2019; Schwartzman et al., 2011; Sigtermans et al., 2009). History of Trauma. A history of trauma was associated with greater reductions in short-term follow-up depression scores and significant improvements in the physical quality of life domain, suggesting that individuals with trauma histories may derive greater benefit from ketamine in these areas. The greater improvements in depression and physical quality of life scores may potentially be due to ketamine’s ability to rapidly alleviate trauma-related emotional distress (Feder et al., 2014). Likewise, the overlap in symptoms between depression and PTSD (Gros et al., 2012) and the cyclical worsening between pain and depression (Sheng et al., 2017) may account for the significant changes in these areas. While improvements in anxiety scores and psychological quality of life for those with a history of trauma approached significance, they did not meet the threshold. The positive findings in depression and physical quality of life highlight the potential for ketamine to address trauma-related psychopathology and enhance physical functioning in this population. Presence of Significant Pain. The presence of significant pain was not associated with changes in depression or anxiety scores, nor did it meaningfully impact quality of life improvements, aligning with prior research indicating that while chronic pain may exacerbate 91 mood symptoms, it does not necessarily influence response trajectories to ketamine treatment (Michaels et al., 2018). As stated earlier, the ketamine administration technique may not be the most effective means for improving pain symptoms, which would account for the minimial treatment differences between the pain and no pain groups (Noppers et al., 2010; Orhurhu, et al., 2019; Schwartzman et al., 2011; Sigtermans et al., 2009). Sex at Birth. Sex at birth did not significantly affect changes in depression, anxiety, or quality of life scores. This suggests that ketamine’s efficacy is broadly consistent across sexes, supporting prior research indicating no significant sex differences in treatment response (Wilkinson et al., 2017). Study 2: Patient Experiences and Perceptions Study 2 provided qualitative and quantitative insights into patient experiences with ketamine-assisted therapy. The sample was a subset of those who had completed at least one round of ketamine-assisted therapy at the participating clinic. Most participants reported subjective improvements in emotional well-being and satisfaction with treatment. The introspective and dissociative effects of ketamine were described as facilitating emotional release, self-awareness, and relief from psychological burden, aligning with prior research on altered states of consciousness in psychedelic therapy (Carhart-Harris et al., 2018). Many participants who discussed trauma histories noted ketamine’s capacity to address long-standing emotional dysregulation, further supporting its role in treating trauma-related conditions (Feder et al., 2014). While participants relayed overall positive benefits of ketamine, significant and meaningful barriers to treatment emerged. Specifically, financial constraints and logistical challenges, including lack of coverage and high costs for treatment, travel, and post-treatment 92 support, were reported. The findings relating to financial challenges were unexpected within the context of the open-ended questions and warrant in-depth follow-up. Most participants in Study 2 endorsed that cost was a significant hurdle in initiating and continuing treatments. Participants in Study 2 also noted the lack of integration with other extended therapeutic modalities limited the sustainability of their treatment benefits. Taken together, these views reflect systemic inequities in mental health care and highlight the need for comprehensive care models that address both clinical and practical aspects of treatment delivery (Moroz et al., 2020). Findings related to financial difficulty in accessing treatment particularly apply to those of lower financial means who have been found to make decisions contrary to medical advice to conserve resources (Rojas, 2023). For example, due to the financial pressures associated with treatment, patients may limit therapy, or maximize the dosage, of the medication in an attempt to maximize the effect--despite these approaches being counter to recommendations (Rojas, 2023). Strengths and Limitations Strengths. This research employed a comprehensive real-world sampling approach, significantly enhancing the ecological validity of its findings. Integrating LPA allowed for a nuanced exploration of individual differences present at baseline, thus providing a richer context for understanding participant variability. Further, the application of a reliable clinical change index analysis resulted in robust metrics for effectively assessing changes in clinical outcomes over time. By combining quantitative data with qualitative patient-reported outcomes, this research offered a holistic understanding of the impact of ketamine-assisted therapy on individuals suffering from mental health challenges. The focus on patients' trauma histories and their moderating effects represents a more novel contribution to the existing literature, particularly by 93 emphasizing the importance of trauma-informed care within the context of psychedelic-assisted therapies. This alignment not only helps in recognizing the diverse trajectories of recovery but also underscores the need for tailored therapeutic approaches that consider the unique experiences of each patient. Limitations. The observational and retrospective design of the present research inherently limited control over several potentially confounding variables. Notably, factors such as concurrent changes in medication and variations in therapy adherence were not strictly monitored, introducing potential biases into the findings. Furthermore, the lack of a placebo control group significantly constrains our ability to draw strong causal inferences about the specific effects of ketamine in this context. Despite these limitations, there exists a robust body of clinical trial literature that investigates and supports the efficacy of ketamine across various domains, including its applications in treating depression and PTSD (e.g., Feder et al., 2014; Peyrovian et al., 2020; Wan et al., 2014). The relatively short follow-up period of only one-week post-infusion poses challenges in gaining deeper insights into long-term outcomes associated with ketamine treatment. It is noteworthy that evidence suggests a correlation between early treatment success and longer-term positive outcomes (Lipsitz, 2021). It is also important to highlight that patients in this study were not asked to repeat all measures at follow-up. This omission ruled out certain change-score analyses, limiting the ability to assess significant changes in areas such as pain levels or PTSD symptoms over time. Moreover, the sample used for this study was geographically and socioeconomically limited, which further restricts the generalizability of the findings to broader populations. 94 Lastly, the small sample sizes for specific analyses diminished the statistical power of the results (e.g., comparisons of subgroups). The small sample size also excluded meaningful analysis of gender, largely due to the under-representation of those who identify differently than the sex they were assigned at birth in this sample. Collectively, these issues underscore the need for further research with larger, more diverse populations to better understand and validate the effects of ketamine treatments. Implications Clinical Implications. The overall findings from the present research, combined with previous research, highlight the broad general effectiveness of ketamine-assisted therapy for those struggling with treatment-resistant psychological conditions. Study 1 revealed the treatment was particularly effective for individuals with severe symptoms and trauma histories. Trauma-informed approaches, such as enhanced preparatory counselling and structured integration sessions, could optimize outcomes for trauma-affected patients. Likewise, findings that personality (e.g., Reserved Introverts) can influence symptom severity at baseline suggest that pretreatment considerations may yield beneficial outcomes for patients and provide them with tools for downstream success in line with other research (e.g., emotion regulation approaches; Barańczuk, 2019; Menefee et al., 2022). Symptom severity should also inform treatment planning, with more intensive protocols and accelerated triaging approaches recommended for patients resembling those in the Very Unwell cluster. Larger, multi-site, samples that include more diverse symptom indicators could be useful in extending this line of research. eHealth solutions could also benefit from the LPA findings of the present research. It may be useful to generate personality and symptom profiles for individual patients to provide a 95 holistic therapeutic picture for clinicians, providing them with evidence-based approaches to tailor components of their patients’ ketamine-assisted therapy treatment. Study 2 revealed that patients did not always find therapeutic alignment with their provider, indicating room for improvement in the therapeutic relationship with their therapist. Research suggests that patients are more likely to continue with treatment if they feel understood and supported by their therapist (Norcross & Wampold, 2019). In contrast, if patients feel misunderstood, judged, or overstimulated, particularly when dealing with highly sensitive trauma-related material, they are more likely to disengage from therapy (Berk & Parker, 2009; Norcross & Wampold, 2019). Understanding these dynamics is crucial for developing more effective, patient-centered approaches to treatment. To improve the overall quality of life in those seeking ketamine-assisted therapy, several tools may be integrated into care planning. Extended psychological care, such as ongoing cognitive-behavioural therapy, emotion regulation strategies, or mindfulness-based therapies--which have shown promise in improving quality of life by addressing maladaptive thought patterns and promoting adaptive coping strategies--could enhance patient outcomes (Hofmann et al., 2010). Likewise, positive psychology interventions, which have been demonstrated to effectively enhance well-being and reduce depressive symptoms, contributing to improved quality of life, may be introduced to those who are open to exploring them over the course of treatment (Bolier et al., 2013). Peer support interventions have also been associated with improved mental health outcomes and quality of life by providing social support and shared experiences (Repper & Carter, 2011); thus, building peer networks within the clinic may create a sense of community. Building these networks would align with findings from Study 2, which indicated that some participants felt that they would have benefitted from an ongoing 96 relationship with the clinic following the intervention protocol. Creating effective ketamine-based interventions underscores the complex interplay between biopsychosocial factors and their impact on well-being, which highlights the need for comprehensive, ongoing, and tailored interventions to improve quality of life (Karunamuni et al., 2021; Price et al., 2022b; Wilkinson et al., 2017b). For those living with chronic pain, the interconnectedness of chronic pain and mental health can influence one another’s onset and progression (Sheng et al., 2017). The high comorbidity between chronic pain and major depressive disorder necessitates a holistic approach to treatment that addresses both the physical and psychological dimensions of these conditions. The mean differences between baseline and follow-up indicate that, overall, ketamine has a positive impact on psychological well-being, which may have downstream effects for those who also live with chronic pain. Specifically, the cyclical worsening of the conditions may be interrupted by ketamine-assisted therapy. The limited benefits seen in the physical domain of this study may reflect the nature of the chronic pain presentation. For example, if a patient is presenting with chronic pain as their sole complaint (i.e., no psychological symptoms), intramuscular ketamine infusion may not be as helpful as hoped. Future research and clinical practice should continue to explore integrated treatment modalities that aim to improve outcomes for individuals suffering from chronic pain and mood disorders. Policy Implications. Findings from Study 1, in line with a wide body of previous research, indicated that the ketamine treatment was broadly and rapidly effective (Zarate et al., 2006). Specifically, Study 1 determined that effectiveness was not related to the symptom or personality profiles, but did show particular benefits for those with trauma histories and severe baseline symptoms. Based on this broad effectiveness, it may be argued that this medication 97 should not be reserved for treatment-resistant patients who have tried and failed multiple other approaches; rather, it could instead serve as a first-line defence. Doing so may help bridge the time period required for traditional approaches (e.g., therapy and antidepressants; Hollon et al., 2014) to take effect. The findings from Study 2, which largely indicated difficulty affording to initiate and continue treatment, support the need for expanded insurance coverage and public funding for ketamine-assisted therapy. Addressing financial barriers through subsidies or sliding-scale payment models could democratize access to this innovative therapy. Policymakers should prioritize the development of standardized clinical guidelines, including protocols for screening, dosing, and post-treatment integration, to ensure safe and equitable treatment delivery. Canadians living with mental illness are a particularly vulnerable population due to the large discrepancy in earnings between those with mental illness and those without (Statistics Canada, 2023). Canadians with mental illness miss more time at work and earn 31% less than their non-disabled peers (Canadian Psychological Association, 2024; Statistics Canada, 2023). Ensuring equitable and timely access can reduce the burden of living with a treatment-resistant psychological condition. Mental illness can range in severity and have dire consequences, including death (e.g., suicide), and should be treated with the urgency and parity of physical health. In March of 2027, Canadians with mental illness as their sole medical condition will be able to request medical assistance in dying (MAID; Government of Canada, 2021; Bastidas-Bilbao et al., 2023). It is, therefore, incumbent upon policymakers and politicians to consider that the costs associated with ketamine treatment are prohibitive for a large proportion of Canadians, and to ensure that all Canadians have equitable access to this potentially life-saving treatment. 98 Future Directions. Future research could explore whether personality moderates other aspects of treatment outcomes, such as durability of response or side-effect profiles. Likewise, looking at sub-facets of key personality traits (e.g., Vulnerability in Neuroticism) may yield deeper insights into susceptibility and treatment. Trauma-related investigation of internalizing (anxiety/depression) vs externalizing (aggression/substances) improvements with ketamine may similarly provide valuable insights. Incorporating measures of emotional regulation and coping strategies, which are closely tied to personality, could provide further insights into the nuanced interplay between personality and mental health treatment outcomes. Future research may also benefit from investigating the mechanisms underlying personality-related findings, particularly the role of resilience, coping strategies, and biological markers in moderating treatment outcomes. Larger sampled multi-site studies that collect extended follow-ups would help assess the durability of ketamine’s effects and identify predictors of sustained recovery. Investigating the interplay between personality traits and altered states of consciousness could further elucidate the mechanisms underlying ketamine’s efficacy, particularly the role of openness to experience in moderating therapeutic outcomes (Carhart-Harris et al., 2019). Longitudinal studies examining the durability of ketamine’s effects across symptomology clusters may also provide insights into optimizing treatment protocols for diverse patient populations. Conclusion This research advances the understanding of ketamine-assisted therapy by elucidating the roles of personality and symptomology in shaping treatment outcomes. The findings demonstrate that ketamine-assisted therapy significantly improves depression, anxiety, and psychological quality of life, particularly for individuals with trauma histories and severe baseline symptoms. 99 While personality profiles are associated with baseline depression and anxiety symptoms, they appear to play a limited role in moderating the effectiveness of ketamine-assisted therapy. Similarly, symptomology clusters, although associated with baseline PTSD severity, have limited predictive value for changes in depression and anxiety following treatment. This research highlights ketamine’s broad efficacy in reducing mood and anxiety symptoms and improving quality of life, with relatively uniform benefits across subgroups. Notably, the lack of differences in treatment response across symptomology clusters suggests that ketamine may serve as a universally effective intervention for depression and anxiety. This research also provides insights into patient experiences, highlighting the many challenges faced by individuals who seek this treatment, including suffering from multiple mental health disorders, attempting numerous medications, and rating their symptoms as extremely severe. While those who underwent ketamine-assisted therapy typically experienced benefits, the financial cost associated with treatment was extremely restrictive, if not prohibitive, for many individuals. 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Academy of Management Perspectives, 23(4), 6-17. https://doi.org/10.5465/amp.2009.45590147 137 APPENDICES Appendix 1 Intake (7 days before treatment) Follow up (7 days after treatment) PHQ-9 (Depression) * PHQ-9 ~ GAD-7 (Anxiety) * GAD-7 ~ WHOQOL-BREF (Quality of Life; Subscales 1, 2, and 3) * WHOQOL-BREF (Subscales 1 and 2) ~ NSESSS-PTSD (PTSD) ~ - ACE (Adverse Childhood Events) ~ - ISI (Sleep) * - Significant Pain ~ - Treatment Expectations ~ - Mini-IPIP (Personality; 5 Subscales) ^ - List of questionnaires deployed at baseline (i.e., 7 days before treatment) and at follow-up (i.e., 7 days after Treatment). * denotes questionnaires used in the symptom LPA, ^ denotes the questionnaire used for the personality LPA, and ~ denotes questionnaires used in other analysis. 138 Appendix 2 Ketamine Experience Survey Pre-treatment considerations. What condition did you primarily seek Ketamine Assisted Therapy for? a) Depression b) Anxiety c) Stress d) Trauma e) OCD f) Disordered eating g) Pain h) Suicidal thoughts i) Other _____________ In addition to the primary reason listed above, did you experience any of the following [check all that apply]: a) Depression b) Anxiety c) Stress d) Trauma e) OCD f) Disordered eating h) Suicidal thoughts i) Other _____________ Please use the space below to tell us how you felt BEFORE undergoing Ketamine Therapy: ____________________________________________________________________________ How many medications did you try to alleviate your symptoms BEFORE trying Ketamine? 1 2-3 4-6 7-9 10+ How severe were your symptoms before treatment? (Not at all severe to Extremely severe; 1-10 VAS) Did the cost of ketamine treatment affect your ability to initiate treatment? 139 (Yes, No) Treatment Considerations How comfortable were you during your treatment session? (Not at all to Extremely; 1-10 VAS) How much symptom relief did you feel immediately after treatment? (No Relief to Complete Relief; 1-10 VAS) Is there anything you'd like to tell us about the relief you experienced? __________ What specific symptoms or issues do you feel ketamine treatment helped with the most? (Open-ended; potential options for analysis: depression, anxiety, sleep, concentration, etc.) Were there any aspects of your mental health or well-being that ketamine treatment did not improve or worsened? (Yes or No) o If Yes, please describe ______________ Did the cost of ketamine treatment affect your ability to continue treatment? (Yes, No) Did you experience any negative side effects from ketamine treatment? (Yes or No) o If Yes: Check all that apply: Nausea without vomiting Nausea with vomiting Physical discomfort Overheating Disturbing sensory perceptions Negative emotional state Other How many Ketamine infusions have you had in total? 1 2-3 4-6 7-9 10+ Prefer not to answer 140 Post-Treatment Considerations How would you rate the overall effectiveness of ketamine treatment in managing your symptoms? Not effective at all Slightly effective Moderately effective Very effective Extremely effective How long has it bees since you most recent treatment? Less than 30 days 1-2 Months 2-4 Months 4-6 Months More than 6 months did you return to the baseline Yes No How severe are your symptoms since treatment? (Not at all severe to Extremely severe; 1-10 VAS) Please describe how this treatment has affected your life (the effects may be negative, positive, or neutral) ______________.
Thesis/Dissertation
eng
Psychology
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Davies, Paul G.
Personalized approaches to mental health interventions : effectiveness of ketamine-assisted therapy for treatment-resistant psychological conditions
Text