Low Dose Oral Ketamine as a Treatment for Post-Traumatic Stress Disorder

Grace Forsyth

doi:10.25907/01028

PTSD is a highly complex and debilitating psychiatric condition which creates an array of negative symptomology and impairs crucial neural circuits, significantly affecting an individual’s functioning and overall wellbeing. Despite the individual and economic burden associated with PTSD, current pharmacological and psychological treatments lack efficacy and tolerability. Recent clinical research has identified ketamine, an N-methyl-D-aspartate receptor antagonist, as a rapidly acting treatment for treatment-resistant depression, anxiety and chronic stress. Ketamine has the potential to provide effective symptomatic relief via unique neuroplasticity-enhancing properties and represent a new therapeutic option for PTSD. The present PhD candidature explored this potential, assessing the ability of low-dose oral ketamine to safely provide widespread symptomatic relief and mitigate stress-induced neurobiological damage. Chapter 1 provides a general introduction to relevant research topics, including the progression of PTSD as a psychiatric disorder, developments in our understanding of the neuropathological underpinnings of PTSD. It also describes issues with current pharmacological and psychological treatments, including lack of efficacy, side-effect profiles and tolerability. Ketamine is explored as a drug, presenting current uses, mechanisms of action and associated risks, and use as a novel therapeutic for psychiatric conditions, including preclinical and clinical research. Considering the novelty of oral administration of ketamine, this chapter also presents alternative study designs utilised in previous clinical studies, focusing on dosing and route of administration. Chapter 2 presents the study protocol for the open-label clinical trial, Oral Ketamine Trial for Post-Traumatic Stress Disorder (OKTOP). This research study recruited adult participants from the general community with a diagnosis of PTSD. Eligible participants attended the University of the Sunshine Coast Thompson Institute over 10 weeks, receiving six weeks of low-dose oral ketamine treatment once per week, followed by two follow-up sessions. Participants underwent clinical, biological, cognitive and behavioural assessments at multiple timepoints throughout the trial. These included clinical examinations, safety, tolerability and symptomology questionnaires, magnetic resonance imaging, electroencephalography, cognitive assessment and blood draws. This chapter also explores study design, limitations and future directions. Chapter 3 explores safety and tolerability outcomes following six-weeks of low-dose oral ketamine. The side-effect profile of ketamine is well established and is generally considered safe and well tolerated. Nevertheless, no study to date has examined the safety and tolerability of repeat low-dose oral ketamine administration in adults with PTSD. This chapter reported two forms of analysis, one focusing on dissociated symptoms in the study sample, the second was extracted from a co-authored published paper (European Neuropsychopharmacology) and presented an array of clinical and self-reported side-effect measures. Overall, only a few transient, non-significant changes in clinical observations and dissociation were identified. Any mild to moderate side effects resolved within the trial period. Chapter 4 assessed the effectiveness of low-dose oral ketamine treatment in reducing PTSD and comorbid symptom severity and improving overall wellbeing and functioning. Prior to presenting study findings, this chapter highlights the complexities associated with treating PTSD, particularly surrounding the multifaceted symptomology of PTSD and high rates of comorbidity with other psychiatric disorders. Evidence of the ability of ketamine to produce notable reductions in depression, anxiety and PTSD symptom severity as well as improvements in measures of wellbeing are described. Analysis assessed PTSD, suicidality, depression, anxiety and stress symptom severity, as well as sleep, pleasure, social and occupational functioning and overall well-being using self-reported and clinician-rated behavioural measures following six weeks of ketamine treatment and after three weeks of no treatment. This chapter also presents findings from the paper titled “Low dose oral ketamine treatment on post-traumatic stress disorder (PTSD) (OKTOP): An open-label pilot study”, recently published in European Neuropsychopharmacology. Statistically-significant decreases were found in PTSD, depression, anxiety, stress and suicidality scores, while improvements in sleep, pleasure, overall well-being and social and occupational functioning were observed in both analyses. Chapter 5 presents an overview of PTSD neurobiology, focusing on structural changes in the hippocampus, amygdala, caudate nucleus, putamen, nucleus accumbens and thalamus, and the relationships between PTSD symptomology and brain alterations. The primary aim of this chapter was to determine whether six-weeks of low-dose oral ketamine changed grey matter volumes in subcortical regions in adults with PTSD. The secondary aim of this chapter was to assess the relationship between subcortical grey matter volumes and PTSD symptoms severity scores. While evidence of volumetric changes following ketamine administration was identified, no associations were found between changes in grey matter volume and PTSD symptom severity, as indexed by the PTSD checklist five. Chapter 6 concludes the thesis, providing a consolidation and interpretation of findings, and reflections on the limitations of the present study and considerations for future research. Taken together, my studies demonstrate that repeat administrations of low-dose oral ketamine have promise as a novel, effective and well-tolerated therapeutic for the treatment of PTSD, based on evidenced improvements in symptomology, a low side-effect profile and mitigation of the effects of damage to subcortical regions.

Low Dose Oral Ketamine as a Treatment for Post-Traumatic Stress Disorder

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