Combining Ketamine and Internet-Based Cognitive Behavioral Therapy for the Treatment of Posttraumatic Stress Disorder: Protocol for a Randomized Controlled Trial

Background Over one third of patients with posttraumatic stress disorder (PTSD) do not respond to current interventions. Ketamine presents a potential treatment option; however, its effects are temporary. Administering ketamine alongside psychotherapy is one potential means of prolonging its effects; however, only a few studies have investigated this treatment method to date, and none have tested ketamine with internet-based or electronically delivered cognitive behavioral therapy (e-CBT). Objective This open-label randomized controlled trial aims to assess the efficacy of a combined treatment method of subanesthetic intravenous ketamine and e-CBT for treating patients with PTSD. Methods In total, 20 patients with refractory PTSD recruited from a community clinic will be randomly assigned to either an experimental group (n=10), receiving a combination of ketamine and therapist-administered e-CBT over 14 weeks, or a waitlist control group (n=10), receiving the experimental treatment after 14 weeks. Both groups will be assessed for the symptoms of PTSD and comorbid disorders before treatment, at two midway points, and at the end of the experiment. Results PTSD symptoms of participants in the experimental group are expected to improve significantly more than those of participants in the waitlist control group (P=.05) with a large effect size (η2=0.14). Conclusions This is the first study to assess the relationship between e-CBT and ketamine and their combined ability to treat refractory PTSD. If successful, this study will open web-based, asynchronous therapeutic options for patients with PTSD and will provide new insights into the functional role of glutamate in trauma-related disorders as well as in learning, memory, and fear extinction. Trial Registration ClinicalTrials.gov NCT04771767; https://clinicaltrials.gov/ct2/show/NCT04771767. International Registered Report Identifier (IRRID) PRR1-10.2196/30334

1) Excellent and timing proposal that will provide rapid information on the combined approach using ketamine and e-CBT for PTSD 2) Team with expertise to successfully conduct the study 3) Ketamine treatment for MDD and bipolar as one of the research strengths at Queen's.
1) The proposal could be clear in general. Abstract should be more comprehensive, with brief introduction, hypothesis, aims and objectives, as well as a last paragraph describing the impact. The Introduction could present a better flow of ideas and the hypothesis should be clearly stated. This is such an important project that is easy to sell and there is room for improvements in each section when preparing a CIHR proposal. It is important to spell it out to the reviewers why this work is so unique and important. Impact section could be improved by putting it in context with other similar combined approaches (specifically ketamine + psychotherapy-augmentation) tested or currently being tested in depression, bipolar, and of course PTSD.
2) In methodology it is not clear if after the completion of the study, and after control patients complete treatment, the results will be analyzed altogether.
Adjudication Scale (Research impact and Research Applicant(s)) 4.5-4.9 Extremely significant impact appropriate team 3.0-3.4 Moderate impact and/or poor team 4.0-4.4 Very significant impact ,appropriate team 2.5-2.9 Limited impact and/or poor team 3.5-3.9 Significant impact, appropriate team 0.0-2.4 Negligible impact and/or poor team 1) PI has appropriate training and expertise to recruit and assess patients and to oversee study progress.
2) Team with complementary expertise to develop the proposal. Dr. Vasques experience in treating mood disorders patients with ketamine. This is such an important.
3) Dr. Alavi developed the OPTT TF-CBT program and will oversee the e-CBT therapy.
4) New combined approach using Ketamine and e-CBT for PTSD with chances for rapid and effective results. Very good 3.5 -3.9 Acceptable, but low priority 3.0 -3.4

May or May Not be Fundable
Needs revision 2.5 -2.9 Needs major revision 2.0 -2.4 Seriously flawed 1.0 -1.9 Rejected 0.0-0.9 Overall Adjudication Score: 4.5 Comments: Evidence from literature supports the hypothesis that the combination of a ketaminebased pharmacological approach with psychotherapeutic treatment may significantly improve symptoms in treatment resistant PTSD. This is a timing and relevant project that may lead to a muchneeded rapid and effective new approach to treat PTSD. The ketamine project led by Dr. Vasques is leading to many new collaborations among Queen's researches and fostering new ideas. It has great chances to become a competitive CIHR proposal. Improvements in the text (as suggested) will help to make this a strong proposal.
Budget is appropriate. Great mix of young and established researchers with complimentary expertise. Comments:

Title of Grant
• Several different types of CBT exist for PTSD, including Prolonged Exposure (e.g., Foa) and Cognitive Processing Therapy (e.g., Monson) -should distinguish this in proposal regarding evidence base and re: nature of eCBT -more specifics of treatment. What is the role of exposure, trauma processing in TF-CBT? How will those be delivered asynchronously? • Literature on combination of eCBT with medications (not just cbt + medications)? Literature on combo of ketamine with face-to-face CBT? Need to include this to speak to importance/novelty of study. Very good 3.5 -3.9 Acceptable, but low priority 3.0 -3.4

Comments:
This study has a number of strengths, as identified above. With some changes to the methodology it has the potential to provide very interesting and clinically relevant data on novel approaches to the treatment of PTSD. Before funding, however, the research team should address the areas outlined above. The critical change is to add two study groups to the design (and consider sample size) to allow for meaningful interpretation of the findings. Specifically, instead of just Treatment A + Treatment B vs. Control, the 2 groups Treatment A and Treatment B should be added for cross comparison. I would also consider exploring the value of eCBT vs in person CBT in combination with ketamine (although that might be a separate study.)