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

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 an 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. Trial registration: ClinicalTrials.gov NCT03256162 21/08/2017; EudraCT 2016-004764-18 30/11/2016.

Keywords: Adjunctive; Depression; Ketamine; Pilot trial.

Conflict of interest statement

Competing interests: DMM has received speaker’s honoraria from Mecta and Otsuka and an honorarium from Janssen for participating in an esketamine advisory board meeting. The other authors report no conflicts of interest.

Copyright: © 2022 Gallagher B et al.

Figures

Figure 1.. CONSORT flow diagram.

EOT, end of treatment.

Figure 2.. Depression rating scores at end of treatment and follow up timepoints: 24-item Hamilton Rating Scale for Depression (HRSD-24) scores are presented as mean (SD) values.

FU, follow-up. Number of participants at each stage: Baseline - Ketamine n=13, Midazolam n=12; End of treatment - Ketamine n=11, Midazolam n=12; Follow-up at 6 weeks - Ketamine n=9, Midazolam n=9; Follow-up at 12 weeks - Ketamine n=10, Midazolam n=9.

Figure 3.. Depression rating scores throughout the infusion sessions: 24-item Hamilton Rating Scale for Depression (HRSD-24) scores are presented as mean (SD) values.

-60, 60 minutes before infusion begins; 120, 120 minutes post start of infusion; 240, 240 minutes post start of infusion. Number of participants at each infusion: Infusion 1 - Ketamine n=13, Midazolam n=12; Infusion 2 - Ketamine n=9, Midazolam n=12; Infusion 3 - Ketamine n=8, Midazolam n=9; Infusion 4 - Ketamine n=8, Midazolam n=8.

Figure 4.. Patient-rated depression scores at end of treatment and follow up timepoints: 16-item Quick Inventory of Depressive Symptoms, self-report version, (QIDS-SR 16) scores are presented as mean (SD) values.

FU, follow-up. Number of participants at each stage: Baseline - Ketamine n=13, Midazolam n=12; End of treatment - Ketamine n=11, Midazolam n=12; Follow-up at 6 weeks - Ketamine n=9, Midazolam n=9; Follow-up at 12 weeks - Ketamine n=10, Midazolam n=9.

Figure 5.. Patient-rated depression scores throughout the infusion sessions: 16-item Quick Inventory of Depressive Symptoms, self-report version, (QIDS-SR 16) scores are presented as mean (SD) values.

-60, 60 minutes before infusion begins; 120, 120 minutes post start of infusion; 240, 240 minutes post start of infusion. Number of participants at each infusion: Infusion 1 - Ketamine n=13, Midazolam n=12; Infusion 2 - Ketamine n=9, Midazolam n=12; Infusion 3 - Ketamine n=8, Midazolam n=9; Infusion 4 - Ketamine n=8, Midazolam n=8.

Figure 6.. Dissociative symptoms during infusion sessions: The graph shows the total mean (SD) scores for the Clinician-Administered Dissociative States Scale (CADSS) during allocated infusion sessions.

-60, 60 minutes prior to commencement of infusion; 30, 30 minutes post start of infusion: 60, 60 minutes post start of infusion. Number of participants at each infusion: Infusion 1 - Ketamine n=13, Midazolam n=12; Infusion 2 - Ketamine n=9, Midazolam n=12; Infusion 3 - Ketamine n=8, Midazolam n=9; Infusion 4 - Ketamine n=8, Midazolam n=8.