Study Design and MethodoBreaking the Cycle: Repeated Ketamine Infusions Show Promise for Chronic PTSD
In the pivotal study A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder by Feder et al. (2021), researchers investigated the impact of multiple ketamine infusions on individuals living with long-term PTSD. The findings mark a significant advancement in the treatment landscape for trauma-related disorders—especially for those unresponsive to standard interventions.
Using a rigorous double-blind, randomized design, the study found that repeated doses of intravenous ketamine not only reduced PTSD symptoms significantly but also improved depressive symptoms, with a strong response rate and good tolerability. This research adds a crucial piece to the evolving puzzle of how to treat chronic PTSD effectively and quickly.
logy
The trial enrolled 30 individuals diagnosed with chronic PTSD and randomly assigned them to receive:
- Ketamine (0.5 mg/kg) or
- Midazolam (0.045 mg/kg) as an active placebo
Each participant received six infusions over two consecutive weeks, and outcomes were measured using:
- Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)
- Montgomery–Åsberg Depression Rating Scale (MADRS)
Assessments were conducted 24 hours after the first infusion and at weekly intervals, providing a thorough timeline of symptom trajectory.
Significant Symptom Reduction
By the end of the two-week infusion protocol, 67% of patients in the ketamine group met response criteria, compared to just 20% in the midazolam group. The mean CAPS-5 total score was 11.88 points lower in the ketamine group, reflecting a large effect size (Cohen’s d = 1.13).
Moreover, the antidepressant effects were also pronounced: MADRS scores showed significant improvement alongside PTSD symptom relief. These dual benefits are particularly important, as comorbid depression is common in chronic PTSD.
Duration of Response
Among those who responded to ketamine, the median time to relapse was 27.5 days following the last infusion. This suggests that while the effect is not permanent, it may offer a valuable window of symptom remission that can be leveraged with adjunctive therapy or follow-up treatments.
These results align with previous trials in depression and PTSD, which also highlight ketamine’s rapid but transient effects, necessitating strategies for maintaining long-term gains.
Safety and Tolerability
Despite concerns about the dissociative properties of ketamine, the treatment was well tolerated:
- No serious adverse events occurred
- Side effects diminished over the course of the infusions
- The dissociative experience was transient, peaking soon after administration and resolving within a few hours
This favorable safety profile is encouraging for broader clinical use, especially given the treatment resistance typically seen in chronic PTSD populations.
The Role of Midazolam as a Control
Midazolam served as a psychoactive placebo, helping to maintain blinding while controlling for expectancy effects. The large difference in outcomes between groups underscores that ketamine’s benefits are pharmacologically driven, not just the result of receiving an active substance.
This methodological strength adds credibility to the conclusion that ketamine directly improves PTSD symptoms—not merely mood or general well-being.
Implications for Clinical Practice
This study is the first randomized controlled trial to demonstrate the efficacy of repeated ketamine infusions for PTSD. For clinicians, it suggests several takeaways:
- Ketamine may offer a breakthrough option for patients with severe, chronic PTSD who have failed conventional treatments
- Repeated administration can lead to significant and sustained symptom relief
- Careful monitoring and relapse planning are essential to extend benefits
Given these promising results, ketamine could be incorporated into integrated care plans, possibly alongside psychotherapy or other pharmacologic strategies.
Remaining Questions and Future Research
While the outcomes are compelling, several important questions remain:
- How can response be maintained longer? Investigating booster doses or maintenance protocols is crucial.
- What mechanisms drive ketamine’s effects in PTSD? Functional imaging and biomarker studies could shed light.
- Can certain patients be identified in advance as responders? Personalized treatment algorithms are needed.
Further trials with larger sample sizes, longer follow-up, and active psychotherapeutic support will help clarify how ketamine fits into PTSD treatment over the long term.
Conclusion
The study A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder adds to a growing body of evidence that ketamine can rapidly and meaningfully reduce PTSD symptoms, even in individuals with severe, treatment-resistant forms of the disorder. With a good safety profile and measurable antidepressant benefits, ketamine is poised to become a vital tool in the psychiatric armamentarium for trauma-related conditions.
As we move toward a new era of precision mental health care, ketamine may not just offer relief—but restore hope to those for whom other treatments have failed.
References
- Feder A, Costi S, Rutter SB, et al. A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder. Am J Psychiatry. 2021;178(2):193–202. https://doi.org/10.1176/appi.ajp.2020.20050596
- Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012;338(6103):68–72. https://doi.org/10.1126/science.1222939
- Krystal JH, Abdallah CG, Sanacora G, et al. Ketamine: A paradigm shift for depression research and treatment. Neuron. 2019;101(5):774–778. https://doi.org/10.1016/j.neuron.2019.02.005
- Abdallah CG, Averill CL, Akiki TJ, et al. Ketamine treatment and global brain connectivity in PTSD and major depression. Neuropsychopharmacology. 2017;42(6):1210–1219. https://doi.org/10.1038/npp.2016.186
- Liriano F, Hatten C, Schwartz TL. Ketamine as treatment for post-traumatic stress disorder: a review. Drugs Context. 2019;8:212305. https://doi.org/10.7573/dic.212305
