Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial
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Abstract
This study tested the efficacy of repeated intravenous ketamine doses to reduce symptoms of posttraumatic stress disorder (PTSD). Veterans and service members with PTSD (n = 158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n = 54), low dose (0.2 mg/kg; n = 53) or standard dose (0.5 mg/kg; n = 51) ketamine. Participants were assessed at baseline, during treatment, and for 4 weeks after their last infusion. Primary analyses used mixed effects models. The primary outcome measure was the self-report PTSD Checklist for DSM-5 (PCL-5), and secondary outcome measures were the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and the Montgomery Åsberg Depression Rating Scale (MADRS). There were no significant group-by-time interactions for PTSD symptoms measured by the PCL-5 or CAPS-5. The standard ketamine dose ameliorated depression measured by the MADRS significantly more than placebo. Ketamine produced dose-related dissociative and psychotomimetic effects, which returned to baseline within 2 h and were less pronounced with repeated administration. There was no evidence of differential treatment discontinuation by ketamine dose, consistent with good tolerability. This clinical trial failed to find a significant dose-related effect of ketamine on PTSD symptoms. Secondary analyses suggested that the standard dose exerted rapid antidepressant effects. Further studies are needed to determine the role of ketamine in PTSD treatment. ClinicalTrials.gov identifier: NCT02655692.
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In a randomized, placebo-controlled, multicenter trial, repeat-dose ketamine (eight infusions twice weekly) had no effect on PTSD-associated symptoms in 158 individuals with treatment-resistant PTSD.
“a recent, randomized, placebo-controlled (saline), multicenter clinical trial found that repeat-dose ketamine (eight infusions, given twice per week) had no effect on PTSD-associated symptoms in 158 individuals with treatment-resistant PTSD”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [104]
The Abstract describes 158 veterans and service members who had not responded to previous antidepressant treatment, randomized to eight twice-weekly infusions of ketamine or placebo. It reports no significant difference between groups in PTSD symptom outcomes, and the Discussion says ketamine failed to demonstrate significant efficacy compared with placebo. That does not establish that ketamine had *no effect* on PTSD symptoms; the claim states the null finding too categorically. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPlacebo response rates are high in depression and suicidality research, as well as in trials with rapid-acting antidepressants.
“placebo response rates are high in depression and suicidality research, as well in trials with rapid-acting antidepressants [104]”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [104]
The Discussion (page unavailable) reports an unexpectedly large placebo effect in this ketamine trial and says high placebo response is not uncommon in the field. The trial studied PTSD symptoms in veterans and active-duty military personnel; these passages do not establish high placebo response rates specifically in depression or suicidality research, or across rapid-acting antidepressant trials generally. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn that trial, repeat-dose ketamine significantly decreased depressive symptoms.
“however, repeat-dose ketamine significantly decreased depressive symptoms [104]”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [104]
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Ketamine and rapid antidepressant action: New treatments and novel synaptic signaling mechanisms
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- Authors
- Abdallah, C. G., Roache, J. D., Gueorguieva, R., Averill, L. A., Young-McCaughan, S., Shiroma, P. R., Purohit, P., Brundige, A., Murff, W., Ahn, K.-H., Sherif, M. A., Baltutis, E. J., Ranganathan, M., D’Souza, D., Martini, B., Southwick, S. M., Petrakis, I. L., Burson, R. R., Guthmiller, K. B., López-Roca, A. L., Lautenschlager, K. A., McCallin, J. P., Hoch, M. B., Timchenko, A., Souza, S. E., Bryant, C. E., Mintz, J., Litz, B. T., Williamson, D. E., Keane, T. M., Peterson, A. L., & Krystal, J. H.
- Affiliations
- Michael E. DeBakey VA Medical Center (US)
- The University of Texas at San Antonio Health Science Center (US)
- Yale University (US)
- University of Minnesota (US)
- United States Department of Veterans Affairs (US)
- Brown University (US)
- Brooke Army Medical Center (US)
- University of Southern California (US)
- Boston University (US)
- Durham VA Health Care System (US)
- Corresponding author
- Abdallah, Chadi G.
- ORCID
- Abdallah, Chadi G.
- Roache, John D.
- Gueorguieva, Ralitza
- Averill, Lynnette A.
- Shiroma, Paulo R.
- Brundige, Antoinette
- Sherif, Mohamed A.
- Ranganathan, Mohini
- D’Souza, Deepak
- Southwick, Steven M.
- Petrakis, Ismene L.
- McCallin, John P.
- Hoch, Matthew B.
- Mintz, Jim
- Litz, Brett T.
- Williamson, Douglas E.
- Keane, Terence M.
- Peterson, Alan L.
- Krystal, John H.
- Venue
- Neuropsychopharmacology
- Published
- 2022-01-19
- Volume
- 47
- Issue
- 8
- Pages
- 1574-1581
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC8767037
- OpenAlex
- W4226063380
- Cited by
- 111
- References
- 25
- Citations by year
- 2026: 18 · 2025: 33 · 2024: 20 · 2023: 32 · 2022: 7 · 2021: 1
- FWCI
- 20.98
- Type
- journal article
- Language
- en
- Update notices
- correction (2022-05-11)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuropsychopharmacology (publishedVersion)
- medRxiv (acceptedVersion, cc-by-nc)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- U.S. Department of Defense (W81XWH-13-2-0065)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Keywords
- ketamine, post-traumatic stress disorder, antidepressant-resistant depression, dose-response relationship, intravenous infusion, veterans, military personnel, dissociative effects, psychotomimetic effects, treatment tolerability, rapid antidepressant effects
- MeSH terms
- Antidepressive Agents, Double-Blind Method, Humans, Ketamine, Military Personnel, Stress Disorders, Post-Traumatic, Veterans, Treatment Outcome
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