RESUMO
Background: (S)-ketamine is a glutamatergic drug with potent and rapid acting effects for the treatment of depression. Little is known about the effectiveness of intranasal (S)-ketamine for treating patients with comorbid depression and post-traumatic stress disorder (PTSD). Methods: We performed a retrospective case series analysis of clinical outcomes in 35 Veterans with co-morbid depression and PTSD who were treated with intranasal (S)-ketamine treatments at the VA San Diego Neuromodulation Clinic between Jan 2020 and March 2021. Veterans were not randomized or blinded to treatment. The primary outcome measured was a change in patient health questionnaire-9 (PHQ-9) and PTSD Checklist for DSM-5 (PCL-5) scores across the first 8 treatments (induction period) using a repeated measures analysis of variance (ANOVA). In a smaller sub-group (n = 19) of Veterans who received at least 8 additional treatments, we analyzed whether intranasal (S)-ketamine continued to show treatment effects. Finally, we performed a sub-group and correlation analyses to understand how changes in PHQ-9 and PCL-5 scores were related across treatments. Findings: During the induction phase of treatment there was an absolute reduction of 5.1 (SEM 0.7) on the patient health questionnaire-9 (PHQ-9) rating scale for depression, from 19.8 (SEM 0.7) at treatment 1 to 14.7 (SEM 0.8) at treatment 8 (week 4) (F(7238) = 8.3, p = 1e-6, partial η2 = 0.2). Five Veterans (14%) showed a clinically meaningful response (50% reduction in PHQ-9 score) at treatment 8. There was an absolute reduction of 15.5 +/- 2.4 on the patient checklist 5 (PCL-5) rating scale for PTSD, from 54.8 (SEM 2) at treatment 1 down to 39.3 (SEM 2.5) at treatment 8 (F(7238) = 15.5, p = 2e-7, partial η2 = 0.31). Sixteen Veterans (46%) showed a clinically meaningful response (reduction in PCL-5 of > 30%) in PTSD. Change in PHQ-9 correlated with change in PCL-5 at treatment 8 (r = 0.47, p = 0.005), but a decrease in PTSD symptoms were observable in some individuals with minimal anti-depressant response. Interpretations: While this is an open-label retrospective analysis, our results indicate that both depression and PTSD symptoms in Veterans with dual-diagnoses may improve with repeated intranasal (S)-ketamine treatment. The effects of (S)-ketamine on PTSD symptoms were temporally and individually distinct from those on depression, suggesting potentially different modes of action on the two disorders. This work may warrant formal randomized controlled studies on the effects of intranasal (S)-ketamine for individuals with co-morbid MDD and PTSD. Funding: VA Center of Excellence in Stress and Mental Health, VA ORD (Career Development Award to DSR), Burroughs-Wellcome Fund Award (DSR), NIMH (EL).
RESUMO
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.
