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Ketamine Treatment in TRD Should Last 4 Weeks or More for Antidepressant Benefit
In this exclusive Q&A, Managing Editor of Psych Congress Network, Meagan Thistle, spoke with Colleen Loo, MBBS, FRANZCP, MD, the lead researcher of a groundbreaking study on the use of subcutaneous racemic ketamine for treatment-resistant depression (TRD), a subset of major depressive disorder (MDD), not responding to 2 or more depression treatments. Previous trials hinted at the efficacy of intravenous racemic ketamine, but phase 3 trials were required to substantiate the findings.
The study, published in the British Journal of Psychiatry, aimed to assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine among participants with TRD. Conducted at multiple centers in Australia and New Zealand, the double-blind, randomized, active-controlled trial found that subcutaneous ketamine is a practical and safe treatment for TRD.
Here, Dr Loo, professor of psychiatry at the University of New South Wales, Sydney, Australia, shares the rationale behind the study, its major findings, practical implications, and more.
Editor’s note: Responses have been lightly edited for clarity.
Meagan Thistle, Psych Congress Network: What is the rationale behind choosing racemic ketamine and midazolam as the active control drug in this study, and how do they compare in terms of efficacy and safety?
Colleen Loo, MBBS, FRANZCP, MD: Smaller studies had shown marked antidepressant effects for racemic ketamine, and we wanted to conduct a larger clinical trial to provide definitive evidence of efficacy and safety when a course of ketamine treatments are given to treat depression.
We chose midazolam to improve blinding, as this was a double-blind study. Ketamine has the characteristics of sedative and mind-altering effects, and midazolam captures some of these effects. Prior studies have shown that it is harder to find a difference between ketamine and control when midazolam is used instead of a control drug or substance with no effects on mental state. Thus, the efficacy of ketamine was tested in relatively tougher conditions, but still came through strongly.
Thistle, PCN: The study used a flexible response-guided dosing approach for cohort 2. Can you explain how this dosing approach was determined and why it was implemented?
Dr Loo: Prior smaller studies1 at our centre over the last decade had suggested that an individualized dosing approach, with flexible response guided dosing, was optimal, as each person receives a higher dose if needed for efficacy but not higher than needed so as to minimize side effects. For this multisite trial, we initially started with a simpler fixed-dose approach, but the data safety monitoring board noted that no one in the first cohort remitted, and advised we revise the dosing approach.
Thistle, PCN: In cohort 1 (fixed-dose), racemic ketamine did not show a statistically significant difference in remission rates compared to midazolam. What do you think could be the reasons for this outcome?
Dr Loo: It was clear that the dose was insufficient in cohort 1. Prior studies have already shown that efficacy is dose-related.
Thistle, PCN: How did the study assess the acute and cumulative safety of repeated racemic ketamine treatments over a 4-week period? Were there any notable safety concerns or adverse events?
This is a really important aspect of the study. Our study used a very comprehensive and detailed approach to monitor safety. Many studies have reported on the safety of ketamine in the 2 hours after each treatment, but our study also examined for cumulative effects over multiple treatments—this is important because the longer-term effects (eg, on the bladder lining) are different from short-term effects in the 2 hours after dosing.
The safety approach we used was a prototype of the Ketamine Side Effect Tool (KSET), which has since been published2, is freely available, and we recommend it for use in ketamine clinics and research studies. There were no notable safety concerns in our study.
Thistle, PCN: The study showed that the antidepressant efficacy of racemic ketamine was evident only in cohort 2 (flexible-dose) and not in cohort 1 (fixed-dose). What factors might have contributed to this difference in efficacy between the 2 cohorts?
Dr Loo: This finding shows the following:
- The importance of having an adequate dose; and
- The usefulness of individualized, response-guided dosing.
Though the majority of participants needed escalation to the highest dose, not everyone did. For example, an individualized approach meant each person received the optimal dose for them.
The study highlights the importance of ongoing treatment to maintain antidepressant effects.
Thistle, PCN: Can you discuss the practical implications of these findings for clinicians treating patients with MDD and TRD and the potential long-term use of racemic ketamine as a treatment for treatment-resistant depression?
Dr Loo: Yes, we built in a 4-week follow-up period without treatment to establish this important finding—that most people with TRD will need ongoing treatment for more than 4 weeks to maintain antidepressant benefits. As we still have limited data on the longer-term effects of ongoing ketamine treatment, it is important we monitor people carefully and collect data on the effectiveness and safety of longer-term use.
References
Colleen Loo, MBBS (Hons), FRANZCP, MD (research doctorate), is a clinical psychiatrist and professor of psychiatry at the University of New South Wales and the Black Dog Institute, Sydney, Australia. She is an internationally recognized clinical expert and researcher and has published over 300 peer-reviewed papers. Dr Loo has received grant funding from the Australian NHMRC, MRFF, US-based NARSAD and Stanley Foundations, UK NHS/MRC, Singapore NMC and the Ramsay Hospital Research Foundation.
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Any views and opinions expressed are those of the author and/or participants and do not necessarily reflect the views, policy, or position of Psych Congress Network or HMP Global, their employees, and affiliates.
