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

This open-label study (n=32) with 6 dosages (weekly) of oral ketamine (35-210mg/70kg) found that it significantly reduced suicidal ideation in those with chronic suicidal thought, with clinically significant lower scores in 69% of participants at the end (which held at 50% 4 weeks later).

Abstract

“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.“

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

Summary

Abstract

32 adults with chronic suicidal thoughts participated in an open-label trial of sub-anaesthetic doses of oral ketamine over 6 weeks. The mean Beck Scale for Suicide Ideation (BSS) 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.

Introduction

Suicide is a significant public health concern worldwide, and is associated with many behavioural, environmental, genetic and neurobiological factors. Chronic suicidality refers to experiencing suicidal ideation over a period of time without the immediate risk implied by acute suicidality.

Antidepressant medications are widely used globally to treat mood disorders and attendant suicidal ideation. However, traditional antidepressant medications do not directly affect the primary excitatory and inhibitory neurotransmitters, and suicidality may be independent from other symptoms in depression and anxiety.

Ketamine, a potent, non-competitive N-methyl-D-aspartate receptor antagonist, has been shown to enhance excitatory (glutamatergic) neurotransmission and increase protein synthesis. It has been shown to reduce depressive and suicidal symptoms within hours, but relapse has also been reported following discontinuation.

Ketamine’s rapid and acute effects on suicidality are partially independent of its effects on mood. Three open-label single-dose studies evaluated the effect of IV ketamine on suicidality in patients with TRD, and another open-label trial reported a steady decrease in suicidal ideation over 6 consecutive weeks.

IV administration of medications is costly and invasive, and must be administered in a hospital setting. An oral form of ketamine is therefore an attractive option.

In a proof-of-concept trial, 57% of patients receiving oral ketamine showed significant improvements in depressive and anxiety symptoms after 2 weeks, whereas in a retrospective study, 32% of participants showed a clinically beneficial response in terms of depression scale ratings.

The present study assessed the potential benefit of oral ketamine in treating adults with chronic suicidal ideation by undertaking an open-label, flexible-dose, 6-week trial of oral ketamine with a 4-week follow-up phase.

Subjects and methods

Ethics approval and consent to participate

This study was approved by the Bellberry Human Research Ethics Committee and ratified by the University of the Sunshine Coast HREC. All participants provided informed written consent.

Participants

Local general practitioners, psychiatrists and psychologists informed patients with chronic suicidality about the trial via phone calls and clinic visits. Adult participants (18+ years) with a Beck Scale for Suicide Ideation (BSS) score of 6 were included in the study.

All participants were assessed as physically healthy and were taking their regular medication regimen as prescribed by their own health professionals. The intervention consisted of 6 weeks of flexible-dose treatment with oral (racemic) ketamine and a 4-week follow-up phase with no ketamine.

Participants received six oral, sub-anaesthetic doses of ketamine over 6 weeks, at one dose per week, and were assessed at nine study visits and via eleven phone assessments between visits. They were supervised immediately post treatment and were advised to avoid activities that required alertness for 12 h post treatment.

Vital signs were recorded at the pre-ketamine visit and three times at the treatment visit. Blood samples were taken at the four main timepoints: pre-ketamine, at the 3rd weekly treatment, post-ketamine and follow-up.

The following rating scales were used to assess primary and secondary trial outcomes: the Beck Scale for Suicide Ideation, Suicidal Ideation Attributes Scale, Montgomery-Asberg Depression Rating Scale, Social and Occupational Functioning Assessment Scale, and World Health Organization Well-Being Index.

Outcome measures

The primary outcome measure was a reduction in suicidality with ketamine treatment, as determined by the BSS. Secondary outcome measures included pre-ketamine to follow-up changes in SIDAS, MADRS, WHO-5 and SOFAS scores.

Safety and tolerability

The following safety and tolerability measures were undertaken 60 min after each ketamine dose: patient rating inventory of side effects, frequency, intensity and burden of side effects rating scale, clinician administered dissociative states scale, young mania rating scale, brief psychiatric rating scale.

Statistical analyses

All statistical analyses were completed using SPSS version 24.0 (IBM Corp 2016). A repeated measures ANOVA was conducted with time as the within-subjects factor and BSS as the dependent variable.

Results

Of 64 participants screened, 40 met the inclusion criteria for the study, and 32 completed 6 weeks of treatment. Of these, 30 returned for the follow-up assessment.

Participants had a mean age of 45.7 years, mean weight at first treatment of 91.1 kg, two-thirds had tertiary level education, 13 participants were married or in a de facto relationship, and all but one participant had secure accommodation.

Primary outcome measure

The mean BSS score was significantly reduced at both post-ketamine and follow-up timepoints when compared to the pre-ketamine timepoint, and the mean BSS score increased from post-ketamine to follow-up, but remained below 50% of the mean pre-ketamine BSS score.

69% of participants responded to ketamine, and 50% responded prolonged. 95% of participants responded at post-ketamine and 80% responded at follow-up.

Secondary outcome measures

The secondary outcome measures decreased significantly from pre-ketamine to follow-up, with a categorical change from ‘high suicidal ideation’ to ‘low suicidal ideation’. The proportion of prolonged antidepressant responders increased from 17.6% to 33.6%.

Adverse events and side effects

No serious adverse events were recorded during the study. Transient changes in vital signs were observed, with maximum elevations in systolic blood pressure occurring at 30 mins post-ketamine. Ketamine treatment was generally well tolerated, with the majority of participants rating their symptoms as mild. The most frequent side effects were decreased energy and fatigue, followed by anxiety, poor concentration, restlessness, general malaise, dry mouth, dizziness and tremors. Participants rated no dissociation symptoms above moderate, and none of the 8 positive-symptom items exceeded a rating of 3 (mild). Only 2 participants had a total YMRS score of 6, and this was due to increased speech rate/amount and irritability.

Discussion

In a pilot study, oral ketamine treatment for chronic suicidality in patients with a range of psychiatric conditions led to a significant decrease in the primary outcome measure (BSS) from pre-ketamine to post-ketamine and from pre-ketamine to a follow-up period during which ketamine had ceased for 4 weeks following the post-ketamine timepoint.

Oral ketamine led to significant short-term and prolonged improvements in suicidal ideation, affective symptoms, well-being and socio-occupational functioning in this sample of adults with a history of chronic suicidality and MDD.

More than two-thirds of participants showed an antisuicidal response to oral ketamine treatment, and half showed a prolonged antisuicidal response. A third of participants did not show a prolonged antisuicidal response, suggesting there may be individual differences in the way suicidal versus broader depressive symptoms may be improved by oral ketamine treatment.

This study assessed the dosing, titration method, and interval timeframes of oral ketamine. It found that oral ketamine was well tolerated, with only temporary side effects such as altered sensorium, dissociative experiences, sedation, dizziness and nausea immediately after the treatment.

This study explored the feasibility, safety and tolerability of oral ketamine treatment in adults with chronic suicidality. While the study has several limitations, the overall findings suggest an overall feasibility and tolerability of oral ketamine in this population thereby providing a foundation for subsequent efficacy and comparative effectiveness trials.

Ketamine, a glutamatergic neurotransmitter, may be used as an antisuicidal agent. More studies are needed to examine the effect of ketamine on suicidal behaviour and suicidal attempts.