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

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

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

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

Six-week oral ketamine treatment for chronic suicidality is associated with increased grey matter volume.

Chronic suicidality has been associated with neuronal atrophy in cortico-striato-limbic regions and is thought to be mediated via a glutamatergic imbalance. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been posited to exert anti-suicidal effects by promoting neurogenesis via modulation of glutamatergic transmission. This voxel-based morphometry study examined the effect of ketamine on whole brain grey matter in adults with chronic suicidality. Grey matter in the periaqueductal grey, nucleus accumbens, putamen, caudate, and thalamus was significantly increased following 6 weeks of low dose oral ketamine treatment. These results support the notion that ketamine rapidly enhances synaptic plasticity within striato-limbic regions.

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

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