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

In this open-label study (n=32) participants with chronic suicidality received oral ketamine (0.5 mg/kg – 3.0 mg/kg) once per week for a total of 6 weeks with a 4-week follow-up phase to assess the effects of ketamine on their stress. It was found that ketamine significantly reduced stress and in some cases, these effects persisted over the 4-week follow-up showing ketamine’s capacity to alleviate symptoms of stress.

“Background: Stress is prevalent in people experiencing suicidality and is a major contributor to the development of mental disorders. Evidence suggests ketamine shows the 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.

Authors: Megan Dutton, Adem T. Can, Denise Beaudequin, Emma Jensen, Monique Jones, Cyrana C. Gallay, Paul E. Schwenn, Jennifer K. Scherman, Cian Yang, Grace Forsyth, Jim Lagopoulos & Daniel F. Hermens

Summary

Thirty two adults with chronic suicidality completed 6 weeks of active treatment, receiving low doses of oral ketamine once per week, with a 4-week follow-up phase. Ketamine showed the capacity to produce a robust and sustained improvement in stress symptoms, in people with chronic suicidality.

1. Introduction

Suicide is a major public health problem worldwide, and stress-induced neurobiological changes are considered major risk factors. Chronic stress can lead to aberrant brain changes, including reduced dendritic length and arborization, reduction of synapses and gray matter volume in the prefrontal cortex and hippocampus. Stress is linked to the pathophysiology of a number of psychiatric disorders, including suicide, regardless of the presence of psychiatric disorder.

There is emerging evidence that suggests stress-induced alterations in glutamate release, re-uptake and glial cell loss are secondary to the observed neurobiological changes in the prefrontal cortex and hippocampus. These alterations are paradoxically maintaining increased levels of extracellular glutamate despite chronic stress-related reductions in neurotransmission.

Ketamine, an NMDA receptor antagonist, has been found to upregulate the expression of neurotrophic factors such as brain derived neurotrophic factor (BDNF), and increase protein synthesis and synaptogenesis, resulting in the restoration of neural connectivity and the reversal of some stress-induced brain changes.

Currently, there are limited treatment options specifically indicated for suicidality. In this study, we investigated the impact of oral ketamine treatment on self-reported measures of stress in people with chronic suicidality, and the relationship between self-reported stress and suicidality responder status.

The study enrolled 40 participants aged 18 years or over, with chronic suicidal ideation and scoring 6 on the Beck Scale for Suicide Ideation. The study concluded in November 2019 with 32 participants completing the six weeks of active treatment and 30 participants completing the full 10 weeks.

The Bellberry Limited Human Research Ethics Committee approved the study and the University of the Sunshine Coast Human Research Ethics Committee ratified it.

2.1. Study design

Participants received a single dose of oral racemic ketamine, weekly for 6 weeks, which was titrated to a maximum dose of 3 mg/kg according to reported tolerability. The ketamine was administered by the psychiatrist, in a compounded oral liquid form which participants drank with apple juice.

2.2. Outcome measures

The self-reported Depression, Anxiety, and Stress Scale – 21 items (DASS) was used to measure psychological distress in patients with chronic suicidality at three timepoints: pre-ketamine, post-ketamine, and follow-up. It has good construct validity and temporal stability.

Each of the three DASS subscales contains seven items and the final score is calculated by summing the scores for the relevant items. Cut-off scores for the various dimensions of severity for the DASS Stress subscale are as follows: ‘Normal’ (0 – 14), ‘Mild’ (10 – 13), ‘Moderate’ (14 – 20), ‘Severe’ (21 – 27) In the OKTOS study, suicidality responder status was defined as 50% improvement in BSS score from pre-ketamine to post-ketamine visit or BSS score 6 at the follow-up visit.

Safety monitoring was undertaken throughout the trial, including blood pressure and heart rate measurements.

2.3. Statistical analyses

ANOVA was conducted with time as the within-subjects factor and DASS Stress, Depression or Anxiety scores as the dependent variables.

Two-way mixed factor ANOVA was conducted with time as the within-subjects factor, with DASS Stress score as the dependent variable. Paired samples t-tests were used to assess changes in blood pressure and heart rate.

3.1. Participant characteristics

The participants had major depressive disorder, chronic suicidality, borderline personality disorder, generalised anxiety disorder, post-traumatic stress disorder and obsessive-compulsive disorder. 72% reported severe or extremely severe stress levels at the pre-ketamine time-point.

3.2. Depression anxiety stress scale outcomes

All three DASS subscales showed significantly reduced scores at the post-ketamine and follow-up timepoints as compared to the scores at the pre-ketamine time-point. However, there were also significant increases in each subscale score observed between the post-ketamine and follow-up time-points.

DASS subscores changed from extreme to moderate to severe across three time-points, with the Depression score remaining at extreme, the Anxiety score dropping to just below the cut-off, and the Stress score dropping below the cut-off.

3.3. Reliable change index

According to the RCI analysis, 78% of participants showed clinically significant change on the DASS Stress subscale, 84% on the DASS Depression subscale, and 63% on the DASS Anxiety subscale.

3.4. Stress according to responder status

The DASS Stress score changed across the three timepoints for responders versus non-responders, with the former showing normal stress levels compared to non-responders at the post-ketamine timepoint, but this difference was lost at the follow-up timepoint.

The mixed ANOVA revealed that prolonged responders had a sustained reduction in DASS Stress levels from post-ketamine to follow-up, whereas prolonged nonresponders relapsed at follow-up. Importantly, prolonged responders maintained lower stress levels between post-ketamine and follow-up.

3.6. Safety

We have previously shown that oral ketamine is generally well tolerated, with the most reported side-effect being dissociation. No serious adverse events were reported throughout the trial, and participants acclimated to the early treatment effects, reporting treatment to be very tolerable with only mild side-effects across the study duration.

4. Discussion

Six single weekly doses of oral ketamine significantly reduced self-reported stress levels in patients presenting with chronic suicidality. However, the mean self-rated depression did not reach a score within the normal range following treatment with ketamine, indicating a greater potential impact of ketamine treatment for stress related symptoms and conditions.

Participants reported that they were able to cope with unexpected stressful events during the trial period in a new and manifestly positive way. This suggests that ketamine may have enhanced coping skills and/or improved resilience, in addition to reducing stress-related symptomatology. A pre-clinical study reported that ketamine can increase resilience to stress and reduce the emergence of psychopathology in mice. The resilience was robust and long lasting, protecting against deleterious stress effects for at least 4 weeks. Six consecutive weekly treatments of ketamine may have conferred some degree of prolonged treatment effect as compared to single ketamine treatments, and may provide hope for improved treatment outcomes in those disorders associated with high levels of suicidality.

Previous efforts to prevent suicide have focused on psychodynamic, cognitive and interpersonal theories. However, recent research has suggested that there are also biological underpinnings to suicidality. The findings of this study provide early support for the use of low dose oral ketamine as a novel agent which may reduce the experience of stress in individuals with chronic suicidality. However, the study had several limitations and may be due to expectancy effects. The results reported here warrant further investigation of oral ketamine as a treatment for stress-related mental disorders and suicidality.

Future studies should consider alternative measures of psychological and physiological stress, such as the HPA axis, which may be a modulator and potential biomarker of suicide risk. The HPA axis appears to play a fundamental role in suicidality, but the extent and mechanisms are still unclear. Epigenetic changes affecting glucocorticoid receptor sensitivity may also be important in understanding suicide risk. Chronic stress emerges as an important factor in increasing suicide risk, and further investigations are required to expand our understanding of the relationships between stress, genes and suicidality, and the role of novel rapid-acting treatments such as ketamine.

5. Conclusion

Ketamine significantly reduces self-reported stress, depression and anxiety, and the improvement in stress levels persisted beyond the ketamine treatment period.