IARS 2024 Mentored Research Award Recipient Interview: Theresa Lii, MD, MS

Opioids Diminish the Placebo Antidepressant Response in an Anesthesia-Blinded Ketamine Trial

Since her anesthesia residency, Theresa Lii, MD, MS, has been inspired to pursue novel topics for research. One such topic she discovered by accident in a trial to investigate whether ketamine could improve postoperative outcomes in patients with major depression with her mentor Dr. Boris Heifets. The trial results uncovered a placebo response as large as the antidepressant effect of ketamine itself. Now an instructor of Anesthesiology, Perioperative and Pain Medicine at Stanford University, Dr. Lii was most fascinated by the placebo response, recognizing that large placebo responses can pose a problem for clinical trials, especially in pain and mental health, and contribute to high failure rates for promising investigational treatments. This initial trial discovery led her to explore predictors of placebo response, hypothesizing that individuals with dysregulated opioid systems might show altered placebo responses — particularly those on prescription opioids. Dr. Lii’s determination for unraveling important research questions led to her receiving the 2024 IARS Mentored Research Award for her research on “Propofol-Enhanced Blinding to Test Psychedelics with Analgesic Potential.” Not content to only uncover answers to one research question, Dr. Lii is also investigating how opioids diminish the placebo antidepressant response in an anesthesia-blinded ketamine trial and will share the outcomes of that research during Poster Session A on Friday, March 21, at the 2025 Annual Meeting, presented by IARS and SOCCA. Below, Dr. Lii reflects on her journey from residency to today, how IMRA has benefitted her, and how presenting at the IARS Annual Meeting will help her to clarify her research story.

Poster Presentation:

Poster Session A, Friday, March 21, 10:00 am – 11:00 am HST, Coral 3, Hilton Hawaiian Village® Waikiki Beach Resort

1. For this research, I am…

Co-Investigator and Lead Author

2. What drew you to this area of research? Has it evolved since your initial research project?

This line of research began during my anesthesia residency, when I set out to investigate whether ketamine could improve postoperative outcomes in patients with major depression. I teamed up with Boris Heifets (my mentor) to design a trial to compare the antidepressant effects of a single dose of ketamine delivered under general anesthesia. To our surprise, we found that the placebo response was as large as the antidepressant effect of ketamine itself. The placebo response was, to me, more interesting than the ketamine response. Digging deeper into individual data, I noticed a large variation in placebo response — some participants had a robust effect, while others had almost none. This led me to explore predictors of placebo response, drawing on Marta Pecina’s work suggesting that the endogenous opioid system plays a key role. I hypothesized that individuals with dysregulated opioid systems might show altered placebo responses — particularly those on prescription opioids. Since our study included both opioid users and nonusers, we were able to test this idea, leading to this work on how opioids influence the placebo antidepressant response.

3. What is the potential impact of your research on the field of anesthesia and patient care?

Large placebo responses are a big problem for clinical trials, especially in pain and mental health, contributing to high failure rates for promising investigational treatments. Notably, placebo effects in US trials have been increasing over time, while patients on chronic opioids — who may have altered placebo responses — are often excluded from these studies. My preliminary findings suggest that including more opioid users in clinical trials might reduce placebo effects and improve ecological validity, potentially improving the ability to detect true drug effects and refining how we evaluate new treatments in anesthesia and pain medicine.

4. What are the benefits of presenting your research at the IARS Annual Meeting?

Every time I prepare a poster or an oral presentation, it forces me to think hard about my data, clarify my story and message, and refine the goals I want to accomplish with my research. Presenting at IARS specifically gives me the opportunity to workshop my research ideas with my peers, who might also be sitting on grant review committees or serve as peer-reviewers for my manuscripts.

5. How has being a 2024 IARS Mentored Research Award recipient affected your research and professional trajectory so far?

The IMRA has given me the opportunity to pursue an interesting and unique line of research — specifically testing propofol sedation as a masking tool — which might be viewed as a less sure-bet by other grant agencies.

6. How is your current research project influenced by your initial IMRA research project?

My latest project is currently funded by the IMRA. For this project, I am studying the analgesic and antidepressant effects of ketamine when administered under nonsurgical propofol sedation.

7. Is there anyone else you wish to acknowledge as part of this research team?

I’d like to thank my two key mentors, Drs. Boris Heifets and Sean Mackey, for helping me get to where I am today. I’d like to thank Dr. Heifets especially for working closely with me to get my first clinical trial off the ground and sharing his lab resources, which allowed me to successfully complete the trial. Dr. Mackey is a senior mentor who has been providing me high-level guidance and advice, especially with regards to planning my current trial examining the therapeutic effects of ketamine given during propofol sedation, in patients with chronic pain and depression.

8. Outside of your research, what might someone be surprised to learn about you?

Contrary to the Bay Area stereotype of having ambitious hobbies like rock-climbing and cycling, I have quiet, unambitious hobbies like gardening and sculpting cute woodland creatures out of wool.