The Balance Between Caution and Novel Strategies for Treatment Resistant Depression

Jennifer Dwyer, MD, PhD

The findings of the first randomized placebo-controlled clinical trial of intravenous ketamine in adolescents with depression suggest that ketamine is well tolerated acutely and has significant short-term efficacy in reducing depressive symptoms compared with an active placebo.

In part 2 of this Q&A, Jennifer Dwyer, MD, PhD, Assistant Professor, Co-Director and Co-Founder, Pediatric Depression Clinic, Child Study Center, Yale School of Medicine, New Haven, Connecticut, discusses outcomes and additional research from her randomized, double-blind, placebo-controlled crossover trial study “Efficacy of Intravenous Ketamine in Adolescent Treatment-Resistant Depression.” Noting that this is new and evolving research, clinicians should "feel certain" about their patient's diagnosis and that they are treatment resistant before choosing an experimental treatment option, suggests Dr Dwyer.

In part 1 of this Q&A, Dr Dwyer discussed the impetus for the study, the methods, and most significant findings.

Q: Were any outcomes different than you expected?

A: Since this was the first RCT of ketamine for depression in adolescent patients, there was very little pediatric data available to help set our expectations. While the adult data for ketamine in TRD is compelling, the adolescent brain is undergoing significant changes, and we cannot assume that just because a medication works in adults, that it will work, or work to the same degree, in pediatric patients. We were encouraged to see the rapid antidepressant effect in this adolescent population, and to see the separation between ketamine and the placebo remain significant out to the two-week time point (the longest time point that we assessed in this initial, short-term study).

Q: What are the practical applications of your findings for clinicians treating adolescent patients with depression?  

A: This is a very new area of research, and while we are encouraged by the data from this trial, the main conclusion is that more studies are needed to confirm the findings in a larger number of participants and to gather more safety data. Ketamine is still very much an experimental treatment for adolescent patients, and clinicians should feel certain about the diagnosis and that the patient is truly treatment resistant before moving towards experimental therapies.

It is not infrequent for us to see patients who come with a “treatment resistant” label, but when we look closer, we find that they have not received standard of care depression treatment (that is, they have not received a full trial of a selective serotonin reuptake inhibitor, such as fluoxetine, at a therapeutic dose for at least 6-8 weeks, and a trial of an evidence-based therapy, such as cognitive behavioral therapy (CBT), administered with high fidelity to the therapy principles).

If patients are truly treatment resistant and clinicians are considering ketamine therapy, ideally pediatric patients would have access to a clinical trial, and if not, access to a clinician with significant Interventional Psychiatry experience. There is a real challenge in striking a balance between being sufficiently cautious given the relatively small amount of data available, while being sufficiently aggressive in perusing novel strategies in treatment resistant patients, who lose precious developmental time during their illness and have higher risk for suicide.

Q: Are you conducting any more research in this area, and are there any other studies you feel are needed?  

A: There are several important gaps in our understanding that warrant further study, including clinical trials that look at repeat dosing paradigms and strategies to maintain the benefits for those who experience rapid antidepressant effects. Repeat dosing is a particularly important issue for the pediatric population, as animal studies suggest that younger ages may be more susceptible to neurotoxic effects of chronic ketamine dosing and gathering safety data is very important.

My research group is working on two repeat-dosing pediatric ketamine clinical trials: one that looks at anti-depressant effects in adolescents with TRD (funded by the Klingenstein Foundation and the American Academy of Child and Adolescent Psychiatry) and another that examines anti-suicidal effects in adolescents with TRD and recent suicidal thinking (funded by the NIMH). After receiving ketamine, we follow patients over a series of months while they receive standard of care depression treatment.

NIMH has recently been emphasizing the importance of studying rapid-acting anti-suicidal treatments in youth, and multiple pediatric ketamine studies will likely be up and running soon (see here).

Q: Any final thoughts pertaining to this research? 

A: Pediatric patients deserve evidence-based care and there is still much to learn in the emerging field of pediatric interventional psychiatry. I am encouraged not only by our early results, but also that more research funding and attention is being devoted to evaluating the safety and effectiveness of these new treatments.


Dwyer JB, Landeros-Weisenberger A, Johnson JA, et al. Efficacy of Intravenous Ketamine in Adolescent Treatment-Resistant Depression: A Randomized Midazolam-Controlled Trial. Am J Psychiatry. 2021;178(4):352-362. doi:10.1176/appi.ajp.2020.20010018

Jennifer Dwyer, MD, PhD, is an Assistant Professor at Yale School of Medicine in New Haven, Connecticut, in addition to serving as the Co-Director and Co-Founder or the Pediatric Depression Clinic, Child Study Center. Her study interests include treatment-refectory adolescent depression.