Ketamine as an adjunctive therapy for major depression – a randomised controlled pragmatic pilot trial (Karma-Dep Trial)

This trial (n=25) compared the effects of ketamine infusion (n=13, 35mg/70kg) to midazolam (n=12, 3.1mg/70kg) administered once-weekly to people experiencing a depressive episode. There were no major differences between groups as measured using the Hamilton Rating Scale for Depression (HRSD-24).

Abstract

“Background: Depression is a common psychiatric disorder that has become the leading cause of disability worldwide. The standard medical care for depression over the past 50 years has focused on monoamine neurotransmitters. These treatments can take weeks to take effect, highlighting the need for novel treatment strategies. One such approach may be ketamine. Ketamine acts as an antagonist of the N-methyl-D-asparate receptor and thus targets the excitatory amino acid neurotransmitter glutamate. Interestingly, at sub-anaesthetic doses, a single infusion of ketamine can elicit a rapid, though transient, antidepressant response. 

Methods: The aim of this study was to conduct a pragmatic randomised controlled pilot trial of four once-weekly ketamine infusions as adjunctive therapy for depression. The main objective was to assess trial procedures to inform a future definitive trial. The primary clinical outcome was the 24-item Hamilton Rating Scale for Depression (HRSD-24). Trial participants were patients admitted to St Patrick’s Mental Health Services for treatment of a depressive episode. They underwent usual inpatient care as prescribed by their treating team. Consented participants were randomly allocated to a four-week course of either once-weekly ketamine (0.5mg/kg) or midazolam (0.045mg/kg) infusions given over 40 minutes and with 12 weeks follow-up. 

Results: In total, 1581 admissions to St Patrick’s Hospital were assessed for eligibility over nine months, with 125 (8%) meeting criteria, with 25 (20%) providing consent. In total, 13 were randomly assigned to the ketamine arm and 12 to the midazolam arm. There were no major differences in HRSD-24 scores between the two groups. The infusions were generally safe and well-tolerated. 

Conclusions: This is the first pragmatic pilot trial of adjunctive serial ketamine infusions for hospitalised depression, an important possible use of ketamine. This study suggests that a definitive trial of adjunctive ketamine is feasible.”

Authors: Bronagh Gallagher, Meabh Foley, Claire M. Slattery, Gabriele Gusciute, Enda Shanahan & Declan M. McLoughlin

Summary

Ketamine is an antagonist of the N-methyl-D-asparate receptor and thus targets the excitatory amino acid neurotransmitter glutamate. Ketamine can elicit a rapid, though transient, antidepressant response.

Abbreviations

A brief review of the main terms and acronyms used in this article include: Brief Psychiatric Rating Scale, Clinician-administered Dissociative States Scale, DSM-5, ICH, MADRS, MINI, MoCA, MSMTRD, NICE, PRISE, QIDS-SR-16, TRD, YMRS.

Introduction

Depression is a common psychiatric disorder that causes significant disability, is a major contributor to the global burden of disease, and lowers life expectancy by approximately 10 years in depressed patients compared with the general population.

Over the past 60 years, pharmacological treatment for depression has focused on drugs targeting monoamine neurotransmitters. These treatments can take up to six weeks to have an effect, and are slow-acting.

Ketamine is a dissociative anaesthetic that acts as a non-competitive antagonist of the N-methyl-D-asparate (NMDA) receptor and thus targets the excitatory amino acid neurotransmitter glutamate. It may also have other potential mechanisms of action.

Ketamine has been shown to have rapid-acting but short-lived antidepressant effects. A single slow intravenous infusion over 40 minutes of low dose subanaesthetic ketamine improves depressive symptoms with efficacy onset within one hour post infusion, peak effect sizes occur at 24 hours and last up to 8 days13.

Ketamine has short-lived physical, psychotomimetic, neurological and psychiatric side-effects. Limited use of ketamine is safe with side-effects being transient, but chronic high-dose ketamine use can cause uropathy and dependency.

Three trials have used repeated serial dosing of intravenous ketamine to prolong its antidepressant effect, but the results are not conclusive. Ketamine may not be superior to placebo in reducing depression scores, and the positive effects of serial infusions therefore currently remain uncertain.

Intranasal esketamine has shown promising results as an adjunctive treatment for depression, and serial ketamine infusions have a rapid antidepressant effect.

We wished to investigate ketamine as an adjunctive treatment for depression in patients hospitalised with depression. We conducted a pragmatic randomised controlled patient- and rater-blinded pilot trial to assess trial procedures to inform a future definitive trial.

Study design and participants

A randomised controlled pragmatic pilot trial of four once-weekly ketamine infusions compared to midazolam infusions as an adjunctive therapy in hospitalised depressed patients was conducted at St Patrick’s University Hospital.

This clinical trial was approved by two hospitals, the Health Products Regulatory Authority and the Research Ethics Committee. It was registered with ClinicalTrials.gov.

Eligible participants were inpatient ages 18-24, suffering from an acute depressive episode, and met DSM-5 criteria for major depressive disorder or bipolar affective disorder. They were also required to score 21 on the 24-item Hamilton Rating Scale for Depression.

Randomisation and blinding

Block randomisation was performed by another researcher within St Patrick’s University Hospital and a protocol was in place to allow emergency unblinding.

The raters, participants and regular treating teams were blinded to the study treatment assignment. The anaesthetist administering the ketamine/midazolam infusions was not blinded but was not involved in assessments or data analysis.

Assessments

This study used the 24-item Hamilton Rating Scale for Depression (HRSD-24) as the primary clinical outcome measure. HRSD-24 scores were obtained 60 minutes before the infusion began (0 mins) and at 120 and 240 minutes after the start of the infusion.

Response to treatment was defined as a 60% decrease from baseline HRSD-24 and a score of 16, remission as a 60% decrease from baseline HRSD-24 and a score of 10, and relapse as a 10 point increase in HRSD-24 compared to responders’ end of treatment score and a score of 16.

We used a number of instruments to capture side-effects such as dissociative effects and psychotomimetic effects, including the Clinician-Administered Dissociative States Scale (CADSS)34 and the Young Mania Rating Scale (YMRS; mood item)36.

Heart rate, blood pressure, pulse oximetry, and ECG were recorded before and during infusions and for a further 200 minutes. Infusions were discontinued if haemodynamic changes persisted after beta-blocker therapy.

The Patient-Rated Inventory of Side Effects (PRISE) was used to document other general adverse events by patients before, during, and after infusions.

Interventions

Ketamine and midazolam were made up as 50 ml colourless saline solutions and administered as slow infusions over 40 minutes using an infusion pump. Patients were monitored for heart rate, blood pressure, pulse oximetry and ECG before, during and after infusions.

Statistical analysis

Baseline clinical and demographic characteristics are presented using descriptive statistics. 95% confidence intervals for the differences between the groups at the end of treatment phase are calculated using IBM SPSS Statistics, version 24.0 (IBM Corp, Armonk, NY).

Participants

In a nine-month period, 125 patients were assessed for eligibility to participate in a trial. 13 patients were randomly assigned to the ketamine arm and 12 to the midazolam arm, and 16 participants completed all four infusions.

Participants discontinued after one infusion in the ketamine group, and after two infusions in the midazolam group. Of these, two dropped out due to dissociative side-effects, one chose to do a therapeutic programme and could no longer attend the infusion clinics, and one had improved sufficiently to be discharged from hospital.

Depression outcomes

The HRSD-24 scores were similar in the ketamine and midazolam groups at end of treatment and follow up at weeks six and 12. The QIDS-16 SR scores followed a similar pattern to the HRSD-24 scores.

There were no responders or remitters in either group during the first infusion session. At the 12-week follow-up, there were 7/10 responders and 4/9 remitters, respectively.

Safety and tolerability

Participants receiving ketamine tended to score higher than those receiving midazolam during the first infusion, but declined with each subsequent infusion session and returned towards pre-infusion levels at the +60 minute time point for each of the four infusion sessions.

The most common new-onset side-effects in the ketamine group during the first infusion session were anxiety, dizziness, restlessness, fatigue, poor co-ordination and dry mouth. These symptoms became less prevalent in subsequent infusion sessions, and were considered to be tolerable.

The most common side-effects reported during the first infusion session in the midazolam group were sleeping too much and fatigue. There were no obvious differences in terms of new onset physical symptoms between the two groups.

Vital signs were monitored and recorded throughout each infusion session. Ketamine caused a higher change in SBP than midazolam did.

Nine participants had an increase in SBP of 20% from baseline during the first infusion session, three participants had an increase in SBP of 20% from baseline during the second infusion session, and two participants had an increase in SBP of 20% from baseline during the fourth infusion session.

Discussion

This is the first pragmatic trial of adjunctive serial ketamine infusions for hospitalised depression. Most participants completed all four once-weekly infusions, with some discontinuing due to side effects, ECT, or being discharged from hospital before all four infusions were complete.

Ketamine and midazolam infusions were safe and well tolerated in our small patient sample. Ketamine caused more dissociative side-effects than midazolam, but with each subsequent infusion, dissociative symptoms diminished.

The most common physical side-effects reported in the ketamine group were anxiety and dizziness, which lessened with subsequent infusions. In the midazolam group, the most commonly reported symptom was fatigue, which was maintained as the treatment course continued.

Previous studies have shown that ketamine has a fast acting antidepressant effect which is superior to placebo13. However, this pilot trial did not observe the superior antidepressant effect of ketamine and further research is required to establish the possible sustained antidepressant effect of serial ketamine infusions.

Most previous trials using subanaesthetic doses of ketamine in the treatment of depression have used saline as the placebo. The Karma-Dep trial used midazolam as an active comparator, therefore potentially helping with blinding and establishing an accurate treatment effect.

This pilot trial has several limitations, including that it was restricted to inpatients at St Patrick’s University Hospital and that participants were not permitted to continue with the infusion clinics if discharged early from hospital.

Conclusions

This study suggests that ketamine and midazolam infusions are well tolerated in the treatment of persons hospitalised for a depressive episode.

Underlying data

Access to raw data is restricted under Research Ethics Committees approval, and researchers must provide a written proposal on how the data will be used in research before access is granted.