Treatment Response Following Repeated Low-Dose Oral Ketamine in Adults with Chronic Suicidality

Cyrana Gallay

doi:10.25907/01124

Suicide is an urgent public health concern and a leading cause of death, globally. Chronic suicidality may be described as persistent or recurrent suicidal ideation presenting over periods of months to years. While suicidality is associated with a complex range of proximal and distal risk factors, there is no single set of clinical features accurately able to predict development. Limited pharmacological interventions exist for the treatment of suicidality. However, a growing body of pre-clinical and clinical research suggests that low-dose ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, may produce an anti-suicidal treatment effect. In the present thesis, the term low-dose oral ketamine, consistent with terminology used in the OKTOS literature, refers to sub-anaesthetic, flexible-dose oral ketamine administered at 0.5–3.0 mg/kg. This PhD thesis aimed to elucidate the clinical outcomes associated with low-dose oral ketamine as a treatment for suicidal ideation. A description of the empirical data chapters comprised in this thesis are as follows: Chapter 2 introduces the Oral Ketamine Trial for Suicidality (OKTOS). This open label, flexible dosing, upwards titration, pilot study examined low-dose oral ketamine as a treatment for chronic suicidal ideation. During the six-week active treatment phase, participants (n = 32) received six weekly doses of low-dose oral ketamine, delivered once per week (six doses total) in liquid oral form. Participants underwent two follow-up assessments (week 7, week 10). Adult participants (aged 18 years or older) experiencing chronic suicidality were eligible to participate in the study. Participants were screened for chronic suicidality, which was defined as persistent or recurrent suicidal ideation over time, without imminent risk requiring psychiatric intervention. Key inclusion criteria included acute suicidality requiring urgent psychiatric intervention, history of psychosis, mania, or hypomania, recent drug or alcohol abuse, psychiatric history of bipolar disorder, schizophrenia, or personality disorder. A history of cardiovascular disease states (i.e., stroke, hypertension), brain damage, or previous reaction to ketamine were contraindicated. Additional exclusionary criteria included clinically important findings on physical examination (i.e., resting heart blood pressure >150/100), neuroimaging scans (i.e., presence of brain legions, tumours), and urinalysis (atypical liver function test results, urinary infection, pregnancy) and blood tests. Participants who were pregnant or breastfeeding were excluded from the trial. The primary aim of this chapter was to determine whether low-dose oral ketamine produced anti-suicidal effect in adults with chronic suicidal ideation. Additional aims included the evaluation of safety, tolerability, and behavioural treatment outcomes. Results of this chapter found that low-dose oral ketamine was associated with a reduction in suicidal ideation in 69% of participants and was associated with safe and tolerable treatment outcomes across the study duration. Interestingly, no positive dose-related increase in patient-rated side effects were found. Across the 10-week period, a moderate to strong relationship was found between change in suicidal ideation and depression symptomology, though suicidal ideation was minimally associated with change in anxiety symptomology and change in six behavioural domains including somatic concern, guilt, hostility, self-neglect, blunted affect, and emotional withdrawal symptom domains. Chapter 3 explored whether an early clinical response to oral ketamine treatment (defined as clinically significant response achieved by treatment three), is able to predict overall treatment response (defined as a clinically significant response achieved by week 6) to the six-week oral ketamine treatment protocol. The secondary aims of this chapter explored whether early clinical response was associated with increased likelihood of achieving extended treatment response at the follow-up assessment phase, and whether participants who were unable to achieve early response within the first three weeks were more likely to be non-responders across the duration of the study. Analyses from chapter 3 demonstrated that early clinical response by week three was a strong predictor of subsequent outcomes, and that early responders were more likely to achieve long-term treatment outcomes, in-comparison to early non-responders. Chapter 4 examined whether low-dose oral ketamine was associated with rapid treatment response in adults experiencing suicidal ideation. In this chapter, rapid treatment response was defined as a clinically significant response from pre-treatment (30 minutes before participant receives ketamine) to post-treatment (90 minutes, 24-hours, and 72-hours post-treatment). Data from treatment weeks one, two, and three were explored. The secondary aims of this chapter were to assess whether participant characteristics (age, gender, weight, and baseline suicidal severity scores) correlated with rapid treatment response. Analyses from Chapter 4 found that low-dose oral ketamine was associated with rapid improvement in suicidal ideation within a 90-minute period, with additional improvements observed at subsequent time points (24 hours and 72 hours post-treatment). Chapter 5 explored the neurobiological correlates of treatment response. In this chapter, an exploratory, whole-brain neuroimaging technique was utilised to determine whether low-dose oral ketamine was associated with structural brain volume change from baseline (week 0) to follow-up 1 (week 7). A subsequent region of interest analysis was conducted to identify whether differences in structural brain volumes exists between responders an non-responders at baseline, and whether the structural brain volumes of responders changed differently, as a consequence of ketamine treatment, from baseline to follow-up 1. Analyses from Chapter 5 found that six weeks of low-dose oral ketamine was associated with increased structural grey matter volumes in the putamen, thalamus, caudate, nucleus accumbens, and periaqueductal grey. No statistically significant differences were observed between responders and non-responders at baseline. Structural brain volumes were not shown to change differently between responders and non-responders from baseline to follow-up 1. Overall, findings from my thesis suggest that repeated low-dose oral ketamine is associated with robust and rapid clinical improvements in suicidal ideation (as presented in chapters two, three and four) and is associated with changes in structural grey matter volumes in striato-limbic brain regions. However, ketamine-induced neuroplasticity may not be associated with clinical response status (as presented in chapter 5). This research responds to the urgent need for safe, effective, and rapid-acting anti-suicidal treatments for adults experiencing suicidality.

Treatment Response Following Repeated Low-Dose Oral Ketamine in Adults with Chronic Suicidality

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