Response to intravenous racemic ketamine after switch from intranasal (S)-ketamine on symptoms of treatment-resistant depression and post-traumatic stress disorder in Veterans: A retrospective case series

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 are no data directly comparing outcomes on depression or other comorbidities 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 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 ( across 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 = 0.1) and by an average of 5.6 +/- 1 after IV-ketamine treatments (p = 0.0003) compared to pretreatment 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 = 0.03) compared to pretreatment baseline 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, randomized controlled trials are warranted to assess whether IV racemic ketamine is more effective than IN-(S)-ketamine.