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.


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

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Study details

Compounds studied

Topics studied
Treatment-Resistant Depression PTSD

Study characteristics
Case Study

15 Humans

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