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. 2025 Jun;39(6):609-619.
doi: 10.1007/s40263-025-01180-w. Epub 2025 Apr 26.

Impact of Medical Comorbidities on Ketamine and Esketamine Treatment Effectiveness for Posttraumatic Stress Disorder and Depression: A Clinical Outcomes Analysis from the VA San Diego Healthcare System

Sijia Zhang  1   2 , Houtan Afshar  1   2 , Peter J Colvonen  1   2   3 , Brandon Nokes  1   4 , Jason Compton  1   2 , Jyoti Mishra  1   2   3 , Andrew W Bismark  1   2 , Dhakshin S Ramanathan #  5   6   7 , Miranda F Koloski #  8   9   10
Affiliations

Impact of Medical Comorbidities on Ketamine and Esketamine Treatment Effectiveness for Posttraumatic Stress Disorder and Depression: A Clinical Outcomes Analysis from the VA San Diego Healthcare System

Sijia Zhang et al. CNS Drugs. 2025 Jun.

Abstract

Background: Ketamine and esketamine are increasingly used to manage treatment-resistant depression and have also been shown to reduce symptoms of posttraumatic stress disorder (PTSD). Little is known about how common comorbidities in the veteran population, such as traumatic brain injury (TBI) or obstructive sleep apnea (OSA), may influence ketamine and esketamine treatment outcomes.

Methods: In this retrospective study, we analyzed clinical outcomes from Veterans Affairs (VA) San Diego Healthcare System's ketamine program to assess the relationship between ketamine or esketamine treatment and changes in depression and PTSD symptoms, while also examining how common medical comorbidities influence treatment outcomes. We specifically examined whether a patient's history of TBI or OSA would affect ketamine or esketamine treatment outcomes. Linear mixed-effects models were used to examine how TBI and OSA history interacted with ketamine/esketamine treatment to change PTSD Checklist for DSM-5 (PCL-5) and Patient Health Questionnaire-9 (PHQ-9) scores.

Results: This study included 119 veterans who received eight sessions of ketamine or esketamine treatment at the San Diego VA Medical Center. Using linear effects modeling, we found that repeated ketamine or esketamine sessions were significantly correlated with reductions in both depression (p < 0.005) and PTSD (p < 0.05) symptom scores. However, in veterans with comorbid TBI (n = 38) and severe OSA (n = 9), depression symptoms did not improve over the course of ketamine or esketamine treatment, suggesting this subgroup may require alternative treatments or OSA treatment prior to starting ketamine or esketamine treatment.

Conclusions: Ketamine and esketamine treatment did not improve symptoms of depression in veterans with comorbid TBI and severe OSA. Thus, our findings generally support ketamine and esketamine as effective interventions for depression and PTSD, while emphasizing the consideration of comorbidities such as OSA and TBI.

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Conflict of interest statement

Declarations. Funding: This work is supported by VA Merit (1 I01 RX003623-01) awarded to P.C. and a VA Career Development Award to M.K. (K2BX006125). Conflicts of Interest: The authors report no conflicts of interest. Ethics Approval: This retrospective analysis was approved as an exempt study by the local VA institutional review board (IRB). Consent to Participate: This study was approved by the local VA IRB and was granted an exemption from requiring informed consent owing to its retrospective design and use of deidentified data. Consent to Publish: Not applicable. Availability of Data and Material: The datasets analyzed during the current study are not publicly available owing to ethical and legal restrictions and cannot be shared. Code Availability: No custom code or software was used in this study. Authors’ Contributions: All authors have participated sufficiently in the work to take public responsibility for the content. All authors have contributed to this manuscript in each of the following three ways: (1) made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; (2) drafted the article or revised it critically for important intellectual content; and (3) reviewed and approved the final version to be published. All individuals who qualify for authorship on the basis of the criteria above are listed as authors. All authors have read and approved the final submitted manuscript and agree to be accountable for the work.

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