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
In a retrospective case series of 15 veterans with treatment‑resistant depression and comorbid PTSD who switched from intranasal (S)‑ketamine to intravenous racemic (R,S)‑ketamine, IV treatment was associated with larger and statistically significant reductions in PHQ‑9 and PCL‑5 scores while reductions after IN (S)‑ketamine were smaller and not significant. The authors suggest IV racemic ketamine may be a reasonable next step for inadequate responders to IN (S)‑ketamine, but randomised, double‑blind trials are needed.
Authors
- Bentley, S.
- Artin, H.
- Mehaffey, E.
Published
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 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.
Research Summary of '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'
Introduction
Racemic (R,S)-ketamine produces rapid antidepressant effects in randomised trials, and its mechanism is commonly linked to NMDA receptor antagonism. Because the (S) enantiomer is more potent at NMDA receptors and intranasal formulations have only partial bioavailability, a nasal spray of (S)-ketamine (Spravato) was developed and approved for treatment-resistant depression (TRD). Despite this approval, it remains unclear whether intravenous (IV) racemic ketamine provides greater clinical benefit than intranasal (IN) (S)-ketamine, given differences in dosing limits, bioavailability and the potential activity of (R)-ketamine metabolites. Bentley and colleagues conducted a retrospective analysis to examine clinical outcomes in Veterans with comorbid TRD and post-traumatic stress disorder (PTSD) who had received at least six IN-(S)-ketamine treatments and were subsequently switched to IV racemic (R,S)-ketamine. The primary aim was to compare changes in depression (PHQ-9) and PTSD (PCL-5) symptoms across the two formulations, with the hypothesis that IV-(R,S)-ketamine would produce larger symptom improvements than IN-(S)-ketamine. This investigation addresses a practical clinical question about next-step options for patients who do not adequately respond to the FDA-approved intranasal formulation.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- APA Citation
Bentley, S., Artin, H., Mehaffey, E., Liu, F., Sojourner, K., Bismark, A., Printz, D., Lee, E. E., Martis, B., De Peralta, S., Baker, D. G., Mishra, J., & Ramanathan, D. (2022). 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. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 42(3), 272-279. https://doi.org/10.1002/phar.2664
References (6)
Papers cited by this study that are also in Blossom
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Murrough, J. W., Iosifescu, D. V., Chang, L. C. et al. · American Journal of Psychiatry (2013)
Abdallah, C. G., Roache, J. D., Gueorguieva, R. et al. · Neuropsychopharmacology (2022)
Bahji, A., Vazquez, G. H., Zarate, C. A. · Journal of Affective Disorders (2021)
Yoon, G., Petrakis, I. L., Krystal, J. H. · JAMA Psychiatry (2019)
Zhang, J., Hashimoto, K., Li, S. · Pharmacology Biochemistry and Behavior (2014)
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