In this open-label study (n=30) participants received six oral sub-anaesthetic doses of ketamine, one dose a week over six weeks. The initial dose was 35mg/70kg which increased to a max of 210mg/70kg by week six. Although restoration of function and wellbeing did improve, these effect sizes were smaller than for suicidality and depression outcomes suggesting that reduction in these outcomes may not be necessary for full restoration of function and wellbeing.

Abstract

“Recovery of functioning is integral to successful treatment outcomes in depressive illness. Optimal antidepressant treatment results in both symptomatic remission and functional recovery. Oral ketamine rapidly reduces suicidality and depression; however, reports of functional and wellbeing outcomes are lacking. This study examines participants’ social and occupational functioning and wellbeing outcomes in the Oral Ketamine Trial on Suicidality (OKTOS). Thirty adults with chronic suicidality participated in the trial over 10 weeks. Functional recovery and wellbeing were assessed using the Social and Occupational Functioning Scale (SOFAS) and World Health Organization Well-Being Index (WHO-5). Suicidality and depressive symptoms were assessed using the Beck Scale for Suicidal ideation (BSS) and Montgomery-Asberg Depression Rating Scale (MADRS). Relationships between the four treatment outcomes were analysed. Forty-three percent of participants achieved healthy function (SOFAS ≥ 80) and 27% reported healthy wellbeing (WHO-5 > 60%) at the four-week post-treatment follow-up. Wellbeing was revealed as the data-derived treatment endpoint for the sample. Effect sizes for functioning and wellbeing outcomes were smaller than for suicidality and depression outcomes. Results suggest that reduction in depressive symptoms and suicidal ideation may be necessary but not sufficient for full restoration of function and wellbeing in antisuicidal and antidepressant therapy, including clinical trials.”

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

Summary

Thirty adults with chronic suicidality participated in the Oral Ketamine Trial on Suicidality (OKTOS). Forty-three percent achieved healthy function (SOFAS > 80) and 27% reported healthy wellbeing (WHO-5 > 60%) at the four-week post-treatment follow-up.

Introduction

Suicide is a leading cause of death globally, and ketamine has been shown to reduce suicidal ideation and depressive symptoms. There is a significant gap in evidence however, characterising the effect of ketamine treatment on positively valenced outcomes.

Individuals with suicidal ideation or attempting suicide have extremely low wellbeing, indicated by the World Health Organization Well-Being Index (WHO-5). Traditional treatments for mental health disorders have focused on alleviating the presence of negative affects.

The Oral Ketamine Trial on Suicidality (OKTOS) was completed in November 2019. The data was used with machine learning to develop a tool to support clinical decisionmaking for ketamine treatment candidacy.

1.1. Bayesian networks

Bayesian networks are used to weigh the joint predictive power of multiple variables, especially clinical characteristics, in studies with limited samples. These networks can be used to observe patterns of interaction between postulated domains of psychopathology.

Methods

OKTOS was approved by several ethics committees and registered with the Australian Clinical Trials Registry. All participants provided informed, written consent.

2.1. Participants

Adult participants with MDD who had experienced suicidal ideation for more than six months were referred to OKTOS. Exclusion criteria included the presence of psychosis, mania or hypomania, and acute suicidality requiring an urgent psychiatric intervention.

2.2. Trial design and treatment

A ten-week trial was conducted at the Thompson Institute, Queensland Australia, using oral ketamine at one dose per week for six weeks. No significant adverse effects or tolerability concerns were observed.

2.3. Variables examined in the current study

The Social and Occupational Functioning Assessment Scale (SOFAS) and the WHO-5 were used to assess positively valenced outcomes, and the Beck Scale for Suicidal Ideation (BSS) and the Montgomery-Asberg Depression Rating Scale (MADRS) were used to assess negatively valenced outcomes at follow-up. A 21-item clinical research instrument was used to assess suicidal ideation, and a ten-item questionnaire was used to measure severity of depressive symptoms.

The BSS, WHO-5, MADRS and SOFAS were self-rated by participants, and the trial was followed up four weeks after the last ketamine treatment.

2.4. Data collection

Participants completed a clinical rating scale and demographic questions using a touch screen tablet, and data was prepared using SPSS.

2.5. Statistical analyses

Exploratory analyses were performed using SPSS version 26.0 (IBM Corp 2016) on data from 32 participants. Non-parametric methods were employed and significance was set at p 0.05.

The OKTOS clinical trials team developed a series of simple, discrete BN featuring the four treatment outcome variables with differing edge formations. The BN was evaluated using established validation procedures, and the highest conformation was chosen.

A primary feature of BN modelling is the ability to model multivariate scenarios. These scenarios are quantified by the percent change in each response node state.

3.1. General characteristics of the study population

Of 64 participants screened, 40 met inclusion criteria for OKTOS, and of these 16 were female and had a mean age of 45.7 14.2 years. All participants experienced clinically significant suicidal ideation and had moderately or seriously impaired function prior to commencing treatment.

3.2. Treatment outcomes

Pre-post analyses showed that 43% of participants had healthy functioning at the follow-up time-point, and 6% had good wellbeing at the follow-up time-point. Seven participants had lower wellbeing scores at follow-up from baseline.

3.4. Bayesian modelling

Simple, four-node BNs comprising outcome variables of functioning, depression, suicidality and wellbeing had accuracies of 70%, 77%, 90% and 97%, respectively, and the highest accuracy was achieved by a model with wellbeing as the outcome variable.

3.5. Scenarios

The results of multivariate and univariate scenario modelling show that having no depression or suicidality after ketamine treatment increases the chance of good wellbeing and healthy functioning, and that having moderate difficulty functioning despite ketamine treatment decreases the chance of good wellbeing and healthy functioning.

Discussion

This study explores the interactions between positively and negatively valenced outcomes in a clinical trial of oral ketamine for chronic suicidality, demonstrating the complexity of interplay between these four outcome variables.

The absence of correlations between positively and negatively valenced measures at baseline may have reflected a small sample variance due to the inclusion criteria. However, the emergence of strong negative correlations between positively and negatively valenced outcomes suggests ketamine may have affected outcome scores.

While most participants improved during the trial, the treatment effect differed across measures at follow-up, with positively valenced outcomes showing smaller effect sizes than negatively valenced outcomes. Furthermore, evidence suggests that depression symptom severity contributes to functional impairment both directly and through mediating mechanisms of cognitive interpretation of symptom experience.

The iterative Bayesian modelling and validation process indicated that wellbeing should be the ultimate outcome measure of interventions in MDD, and that the maintenance and quality of symptomatic remission, long-term duration of treatment and patient adherence may also be contributing factors in functional recovery.

BN modelling provides a visual, interactive means for studying the “problems of living” using the network theory of mental disorders, and can be used to identify causal networks and treatment endpoints from multiple trial outcome variables.

4.1. Limitations

This study has several limitations, including a small sample size, a lack of a control arm, a non-specific measure of functioning, and a short length of follow-up. Future studies should test whether functional gains observed with oral ketamine treatment are able to be sustained over longer time periods.

This study indicates that ketamine may improve positively valenced outcomes in depressive disorders, but the results should be viewed with caution given the study limitations.

Authors’ contributions

JL, AC, MD, MJ, JS, PS, CG, CY, GF and EJ procured funding, designed the trial, gathered data, performed analyses and numerical simulations, and drafted the manuscript.