Response to Intravenous Racemic Ketamine After Switch From Intranasal (S)-ketamine on Symptoms of Treatment-Resistant Depression and PTSD in Veterans: a Retrospective Case Series

This study retrospectively analyzed clinical outcomes in 15 veterans with comorbid treatment-resistant depression (TRD) and PTSD who initially received intranasal ketamine treatment before sitting to treatment with IV racemic ketamine. Both treatments led to significant reductions in measures of TRD and PTSD however, treatment with IV racemic ketamine led to greater reductions, suggesting that off-label use of IV racemic ketamine may be useful for those who do not respond adequately to FDA-approved intranasal ketamine.

Abstract

“Background: Racemic (R,S) ketamine is a glutamatergic drug with potent and rapid-acting antidepressant effects. An intranasal formulation of (S)-ketamine was recently approved by the US Food and Drug Administration (FDA) to be used in individuals with treatment-resistant depression (TRD). There is no data directly comparing outcomes on depression or other co-morbidities between these two formulations of ketamine. However, recent meta-analyses have suggested that IV racemic ketamine may be more potent than IN-(S)-ketamine.

Methods: We retrospectively analyzed clinical outcomes in 15 Veterans with comorbid treatment-resistant depression (TRD) and post-traumatic stress disorder (PTSD) who underwent ketamine treatment at the VA San Diego Neuromodulation Clinic. All Veterans included in this analysis were given at least 6 intranasal (IN)-(S)-ketamine treatments prior to switching to treatment with IV racemic ketamine.

Results: Veterans receiving ketamine treatment (including both IN-(S)-ketamine and IV-(R,S)-ketamine), showed significant reductions in both the Patient Health Questionnaire-9 (PHQ-9), a self-report scale measuring depression symptoms (rm ANOVA F(14,42) = 12.6, p < 0.0001) and in the PTSD- Checklist for DSM-5 (PCL-5), a self-report scale measuring PSTD symptoms (rm ANOVA F(13,39) = 5.9, p = 0.006). Post-hoc testing revealed that PHQ-9 scores were reduced by an average of 2.4 +/- 1.2 compared to baseline after (S)-ketamine treatments (p=0.18) and by an average of 5.6 +/-1 after IV ketamine treatments (p=.0003) compared to pre-treatment baseline scores. PCL-5 scores were reduced by an average of 4.3 +/- 3.3 after IN (S)-ketamine treatments (p = 0.6) and 11.8 +/- 3.5 after IV ketamine treatments (p = 0.02) compared to pre-treatment base-line scores.

Conclusions: This work suggests that off-label IV (R,S)-ketamine could be considered a reasonable next step in patients who do not respond adequately to the FDA-approved IN (S)-ketamine. Further double-blinded, randomised-controlled trials are warranted to assess whether IV racemic ketamine is more effective than IN-(S)-ketamine.”

Authors: S. Bentley, H. Artin, E. Mehaffey, F. Liu, K. Sojourner, A. Bismark, D. Printz, E. E. Lee, B. Martins, S. De Peralta, D. G. Baker, J. Mishra & D. Ramanathan

Summary

Racemic (R,S)- ketamine is a glutamatergic drug with potent and rapid acting antidepressant effects. There are no data directly comparing outcomes between IV and IN- ketamine.

1 | INTRODUCTION

Racemic ketamine has rapid antidepressant effects, and an intranasal formulation of (S)- ketamine was developed based on this theory. This formulation was demonstrated to have clinically significant antidepressant effects for treatment- resistant depression.

There are no head- to- head or cross- over studies that compare effects between IV racemic ketamine and IN- (S)- ketamine for treatment- resistant depression. However, a recent meta- analysis suggests that the effect size of IV racemic ketamine may be about twice as strong as those observed from IN- (S)- ketamine.

In this paper, we retrospectively analyzed patient outcomes from 15 Veterans who were first given intranasal (S)- ketamine and were then switched to IV racemic ketamine. The results showed that IV- ketamine showed a larger effect in clinical symptoms than IN- (S)- ketamine.

2.1 | Study design

A retrospective chart review was conducted of Veterans who received at least six IN (S)- ketamine treatments and then received at least two IV- ketamine treatments in the VA San Diego neuromodulation program.

2.2 | Treatment

In-(S)- ketamine treatments were offered to Veterans with a PHQ- 9 score of at least 15 and a failure to respond to at least two antidepressants. IV-(R,S)- ketamine treatments were offered after discussion with clinician based on initial treatment response.

15 Veterans received ketamine treatment at the VA San Diego Medical Center Neurostimulation Clinic, with a variability in how quickly they were switched from IN- (S)- ketamine to IV- (R,S)- ketamine.

Ketamine doses were increased in the clinic for these Veterans by 56 mg on the first day, 0.75 mg at the second treatment, and 1 mg/kg on the third treatment.

2.3 | Clinical assessments

Veterans were administered a Patient Health Questionnaire- 9 (PHQ- 9) and a PTSD Checklist for DSM- 5 (PCL- 5) prior to each treatment to track depression and PTSD symptoms.

We reviewed medical records for Veterans with PTSD to determine diagnostic history, comorbidities, and treatment history, including past trials of ketamine, ECT, and adequate/inadequate antidepressant trials. We did not systematically collect or review chart data on side effects of the ketamine treatments.

2.4 | Data analyses

We conducted four main analyses to understand the relative efficacy of IV- ketamine. A repeated- measures ANOVA was performed on both PCL-5 and PHQ-9 at 4 key time- points. Three individuals stopped IV- ketamine treatment prior to the 6th treatment, so we used a last- observation carried- forward (LOCF) method to account for the missing data. A repeated- measures ANOVA model with a LOCF approach was used to estimate the effects over time. We performed a paired t-test to measure the change in PCL- 5/PHQ-9 scores after IN- (S)- ketamine and IV- (R,S)- ketamine.

The effects of IV ketamine on skin sores were assessed using a paired t-test and an ANOVA. The data supporting these findings are available from the corresponding author upon reasonable request.

3.1 | Dosages

All Veterans received 81 mg of IN (S)- ketamine after their first treatment, which equates to 44 mg of IV (R,S)- ketamine. The effective IN (S)- ketamine dose would be 9,10, roughly comparable to the 44 mg of IV (R)- ketamine patients were given on average.

3.2 | Depression outcomes

We performed a repeated measures ANOVA analysis of PHQ-9 scores prior to first intranasal (S)- ketamine treatment, last intranasal (S)- ketamine treatment, and 6th IV- ketamine treatment. We found that treatment reduced PHQ-9 scores from severe to moderately severe on average.

Nine Veterans showed a reduction of at least 6 points in PHQ-9 scores after IV- (R,S)- ketamine treatments, compared to the baseline pre- IN time- point. This resulted in a large effect size for IV- (R,S)- ketamine compared to IN- (S)- ketamine alone.

After the initial six IV-ketamine treatments, significant improvements in PHQ-9 scores were observed in 11 Veterans. These improvements remained stable between the 6th- IV treatment and the last IV treatment.

3.3 | PTSD outcomes

We examined changes in PCL5 scores in 15 Veterans with PTSD after IN- (S)- ketamine treatments. We found that PCL5 scores were reduced an average of 4.3 3.4 (mean/SEM) points after IN- (S)- ketamine treatments, but were 11.8 3.5 (mean/SEM) points lower at the 6th- IV- ketamine treatment.

After switching to IV- (R,S)- ketamine, Veterans showed significantly greater change in symptoms compared to IN- (S)- ketamine alone, with 8 Veterans showing at least a 10- point reduction in PCL- 5 scores.

Post-traumatic stress disorder (PTSD) is often broken into four major clusters of symptoms, including re- experiencing symptoms, avoidance symptoms, mood and cognition symptoms, and hyperarousal symptoms.

We analyzed changes in symptom cluster scores using a paired t- test and found that clusters B, D, and E responded significantly to IV- (R,S)- ketamine treatments.

We performed repeated- measures ANOVA on PCL 5 summary scores measured across the first 6- IV treatments and found a significant reduction in PCL 5 scores across treatments, though post hoc Tukey’s HSD test did not reveal a significant difference between pretreatment and any IV- ketamine time- point.

4 | DISCUSSION

This retrospective case series focused on whether IV- (R,S)-ketamine would show any additional effect on depression or PTSD symptoms in Veterans who had a suboptimal response to intranasal (S)-ketamine treatments.

The antidepressant response to IV- (R,S)- ketamine treatments occurred relatively rapidly and was stable, whereas the effects on PTSD symptoms seemed to take longer and continued even during the switch to maintenance dosing.

The starting IV dosage was 0.5 mg/kg, but a significant change in symptoms was observed only after a slightly higher dose (0.75 mg/kg). This suggests that individuals who did not respond to IN- S- ketamine may require slightly higher than average dosing of ketamine. Prior data have not revealed clear dose- dependent effects of ketamine on average, but it seems plausible that some individuals may require higher dosages to achieve an efficacious response.

The added benefit of IV- ketamine may be related to the presence of the (R)- enantiomer in the IV racemic ketamine formulation we used, or to the fact that it may produce antidepressant effects via AMPA- receptor modulation instead of NMDA receptor modulation.

Our data suggests that IV- (R,S)- ketamine is more effective than IN- S- ketamine, but we did not blind Veterans ahead of time.

Although this case series reflects a relatively small and very specific sample of patients, it is possible that IV- R,S- ketamine is more effective than IN- ketamine, and that a double- blinded randomized controlled trial comparing the two treatment options would be needed to determine this. We cannot conclude that IV- ketamine is more effective than IN- (S)- ketamine, but we believe the data provides initial support for this hypothesis.

In sum, we found some evidence that IV- (R,S)- ketamine significantly improves depression and PTSD symptoms more than intranasal (S)- ketamine alone, and that it may be a reasonable option for some individuals.

ACKNOWLEDGEMENTS

This work was supported by the Department of Veterans Affairs, Veterans Health Administration, and the National Institute of Mental Health.