A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression

This randomized active placebo-controlled between-subjects study (n=54) compared the antidepressant efficacy of administering six consecutive ketamine infusions (35 mg/70kg) versus consecutive five midazolam infusions (3.15 mg/70kg) followed by a single ketamine infusion, over twelve days. While acute repeated ketamine showed greater antidepressant efficacy to midazolam after five infusions, there was no significant difference in depression scores after the control grouped had received a single ketamine infusion.

Abstract

“Introduction: The strategy of repeated ketamine in open-label and saline-control studies of treatment-resistant depression suggested greater antidepressant response beyond a single ketamine. However, consensus guideline stated the lack of evidence to support frequent ketamine administration.

Methods: We compared the efficacy and safety of single vs. six repeated ketamine using midazolam as active placebo. Subjects received either six ketamine or five midazolam followed by a single ketamine during 12 days followed by up to 6-month post-treatment period. The primary end point was the change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) score at 24 h after the last infusion.

Results: Fifty-four subjects completed all six infusions. For the primary outcome measure, there was no significant difference in change of MADRS scores between six ketamine group and single ketamine group at 24 h post-last infusion. Repeated ketamine showed greater antidepressant efficacy compared to midazolam after five infusions before receiving single ketamine infusion. Remission and response favored the six ketamine after infusion 4 and 5, respectively, compared to midazolam before receiving single ketamine infusion. For those who responded, the median time-to-relapse was nominally but not statistically different (2 and 6 weeks for the single and six ketamine group, respectively). Repeated infusions were relatively well-tolerated. Repeated ketamine showed greater antidepressant efficacy to midazolam after five infusions but fell short of significance when compared to add-on single ketamine to midazolam at the end of 2 weeks.

Discussion: Increasing knowledge on the mechanism of ketamine should drive future studies on the optimal balance of dosing ketamine for maximum antidepressant efficacy with minimum exposure.”

Authors: Paulo R. Shiroma, Paul Thuras, Joseph Wels, C. Sophia Albott, Christopher Erbes, Susannah Tye & Kelvin O. Lim

Summary

A study compared the efficacy and safety of single vs. six repeated ketamine using midazolam as active placebo. The study found that repeated ketamine showed greater antidepressant efficacy compared to midazolam after five infusions but fell short of significance when compared to add-on single ketamine to midazolam at the end of 2 weeks.

Introduction

Ketamine, a glutamate receptor – blocking drug, has been shown to improve mood within a few hours in some patients with treatment-resistant depression. However, a two-arm, randomized, active placebo-controlled trial compared the efficacy and safety of six IV ketamine versus a single IV ketamine among patients with TRD.

Study design and patients

The study was conducted at the Minneapolis Veterans Affairs Medical Center on outpatients with major depressive disorder. Previous antidepressant treatment was assessed on all available information including VA pharmacy, and community-based records.

Patients with post-traumatic stress disorder, mild to moderate traumatic brain injury, psychosis-related disorder, bipolar disorder, or any Axis I disorder other than MDD were excluded from the study.

Study procedures

Patients received six infusions of ketamine or midazolam on a Monday-Wednesday-Friday schedule over a 12-day period. The last infusion consisted of ketamine for both arms, but the dose of ketamine was kept undisclosed to subjects and raters of antidepressant outcomes at 24 h.

Patients arrived at the infusion unit after fasting for at least 8 h. They were monitored for vital signs and mental status during the ketamine infusion and were discharged with written instructions about potential side effects of sedatives and several measures to improve recovery at home.

Outcomes

The primary outcome was change in depression severity measured by the clinician-administered Montgomery – sberg Depression Rating Scale score (MADRS)13 at 24 h (T+24) after the last infusion. Other secondary outcomes included clinical global impression severity and improvement measures, self-reported numeric rating scale for pain, Beck anxiety inventory, and credibility and expectancy questionnaire.

Side effects were measured with the patient rated inventory of side effects (PRISE), the Brief Psychiatric Rating Scale (BPRS+), the Clinician-Administered Dissociative States Scale (CADSS), and the Young Mania Rating Scale (YMRS), respectively.

Statistical analysis

A power analysis was performed for MADRS score using compound symmetric covariance matrix, 5% significance level, and repeated measures ANOVA. 21 patients per group were needed to detect a 10-point difference in change of MADRS score between the single versus repeated ketamine group.

Study participants

One hundred seventy-eight subjects were pre-screened for eligibility, and 58 were randomized to treatment. All 54 subjects with baseline assessment, initiated study interventions, and completed primary outcome end point.

Participants were mostly middle aged, unemployed or retired, married, white males, with a history of mood disorder among first-degree relatives. They had a chronic history of depression and a history of suicidal attempt.

Primary outcome

There was no significant difference in MADRS score between single and six ketamine treatments at T+24 after the end of treatment. However, there was a significant change in MADRS score by groups over time when including all MADRS measures.

Response and remission rates

After six infusions, there was no significant difference in response rates between groups, but there was a significant difference in remission rates after infusion 4 (six ketamine versus midazolam).

Other secondary outcomes

There was no significant difference between groups in anxiety, self-rated pain, credibility, or expectancy of treatment as measured by CEQ scores at the end of treatment. However, there was a significant improvement in CGI for subjects in both groups, midazolam plus single ketamine and six ketamine.

Durability of response

MADRS scores were used to determine time-to-relapse among patients who achieved response after the last infusion. The median time-to-relapse was 2 weeks for midazolam plus single ketamine and 6 weeks for midazolam plus six ketamine.

Adverse events

During infusion phase, the most common side effects for ketamine were general malaise, decreased energy, increased blood pressure, headaches, fatigue, nausea/vomiting, anxiety, and poor concentration.

Vital signs

There were 25 and 17 cases of mild and moderate adverse events during infusion phase, respectively. The ketamine group had higher blood pressure at T+40m and T+100m compared to midazolam, but no significant difference in heart rate.

Dissociative, psychomimetic, and mania

Ketamine caused significantly greater dissociation than midazolam, and all patients receiving ketamine had complete resolution of dissociative side effects within the 2-h monitoring period. There was no significant change within or between groups regarding psychotic or elevated mood symptoms at any time point throughout infusions.

Serious adverse events

There were two cases of serious adverse events that required IRB report: one patient complained of headaches after post-infusion MRI and another patient reported mild headaches during second infusion.

Blinding

Subjects guessed incorrectly about treatment allocation prior to and after the last infusion in 6.3% of midazolam cases and 50.0% of ketamine cases, respectively. Raters incorrectly guessed treatment assignment in 20.8% of midazolam cases and 7.1% of repeated ketamine cases.

Discussion

A single center study of Veterans with moderate-to-severe, recurrent, TRD showed that repeated ketamine showed greater antidepressant efficacy compared to midazolam after five infusions before receiving single ketamine as the last infusion.

The prospect of repeated dosing of ketamine for treatment of TRD is critical as frequent use of ketamine could lead to cognitive impairments, dissociation, and poor impulse control. Additionally, medical, legal, and ethical concerns have been raised regarding the use of repeated ketamine.

Our findings support the idea that repeated ketamine further reduces the severity of depression in TRD, but the antidepressant improvement through six ketamine treatments was not significantly different when compared to a single ketamine. However, the clinically significant difference was sufficient to support the use of repeated infusions.

In our study, participants correctly guessed treatment assignment in more than 90% of cases even before exposure to ketamine at the last infusion. However, an optimal comparator that mimics the dissociative and psychomimetic side effects of ketamine is still missing.

Serial ketamine had greater side effects as compared to midazolam plus single ketamine, but dissociation was the most common side effect and was not associated with antidepressant response.

Among those who responded to either assigned treatment after six infusions, multiple ketamine prolonged the response for a median of 6 weeks compared to 2 weeks of midazolam plus single ketamine. This suggests that repeated ketamine in combination to conventional anti-depressants may be a feasible strategy to maintain treatment response.

Ketamine’s immediate and delayed antidepressant effects may be based on different mechanisms, including non-competitive antagonist action on the NMDA receptor and subsequent activation of AMPA receptors driving acute antidepressant effect37,38, and modulation of synthesis and release of brain-derived neurotrophic factor and enhancement of synaptic plasticity via activation of molecular targets.

Limitations of the study

A total of 54 participants were enrolled in the study, which was underpowered to detect a difference of 4 points in MADRS score between groups at end of six infusions. However, a single ketamine infusion as the last infusion provided further antidepressant gains and erased any statistical difference in favor of six ketamine up until that point.

The study allowed concomitant psychiatric medication regimen on stable dosages for at least 6 weeks prior to study onset, but could not rule out the impact of concurrent medications. The population studied was predominantly male and older (average age of 53-years old), and 20% had sub-syndromal PTSD.

Conclusion

Acute repeated ketamine showed greater antidepressant efficacy than midazolam after five infusions, but this difference fell short of significance when a single ketamine was added as the last infusion.