Study finds two forms of ketamine therapy can reduce symptom severity in patients with treatment-resistant depression

• Mass General Brigham researchers compared ketamine infusions and esketamine nasal spray in more than 150 patients with severe depression who were treated at McLean Hospital  

• Both treatments reduced depression severity, with IV ketamine showing relatively earlier and greater improvements  

• The authors argue both treatments demonstrated utility and emphasize that careful integration of a broad range of clinical and logistical factors is crucial when considering IV ketamine and esketamine  

A new study led by Mass General Brigham investigators compared the effects of repeated intravenous (IV) ketamine and intranasal (IN) esketamine in patients with treatment-resistant depression. In a retrospective analysis of data from a cohort of 153 adult patients treated at McLean Hospital, a member of the Mass General Brigham healthcare system, researchers revealed that both treatments reduced depression severity, but IV ketamine led to relatively faster and greater improvements in symptoms. The results, published in the Journal of Clinical Psychiatry, may help inform conversations between clinicians and patients about treatment decisions. 

“The results suggest both IN esketamine and IV ketamine are important tools in the evolving neuropsychiatric toolkit,” said study first author Robert Meisner, MD, medical director of the Ketamine Service in the Psychiatric Neurotherapeutics Program at McLean Hospital.  “The differences observed are important, but their substantive meaning is likely contingent on a holistic set of clinical and logistical factors. For some patients, one tool may be more appropriate than the other, and careful and comprehensive consultation is important.”   

Nearly 30% of patients with major depressive disorder fail to respond to two or more antidepressants, necessitating multiple strategies to manage their symptoms. Recently, IN esketamine – a subcomponent of ketamine – has emerged as a promising treatment for this challenging condition and is an FDA-approved antidepressant for adults. By contrast, IV ketamine, initially approved by the FDA as an anesthetic, remains an off-label treatment option despite decades of clinical research that demonstrates its antidepressant effects. 

Researchers evaluated efficacy and rapidity of therapeutic responses in 111 patients who received IV ketamine and 42 patients who received IN esketamine, administered twice weekly over 4-to-5 weeks for a total of eight treatments during the induction treatment phase.   

“We examined data naturally accumulated from patients over the course of clinical work in one of the largest naturalistic comparisons of the two drugs to date,” said corresponding author Shuang Li, MD, PhD, of the Psychiatric Neurotherapeutics Program at McLean Hospital.  

Both groups showed significant overall decreases in depression severity after the final treatment compared to pretreatment baseline. IV ketamine showed greater overall efficacy, with a 49.22% reduction in depression scores by the final dose while IN esketamine resulted in a 39.55% reduction in the same period.  

In addition, IV ketamine was associated with faster responses, with patients exhibiting improved symptoms immediately after the first treatment, whereas IN esketamine led to significant improvements after the second treatment. 

The authors emphasize that differences in clinical contexts, as well as logistical factors like insurance coverage and the accessibility and frequency of appointments, may factor into the decision of which treatment a patient may pursue. They add that risks of ketamine misuse and the proliferation of boutique providers with varying protocols and degrees of regulation necessitate rigorous studies like these. Future randomized clinical trials are needed to confirm comparative efficacy and to eliminate confounding factors such as socioeconomic status, differences in dose, and effects due to other psychiatric treatments.  

“While I believe strongly in the utility of ketamine for the right patient in an appropriate setting, I am also very concerned about the potential for misuse and abuse of this medication,” said Meisner. “We always strive to seek evidence-based, data-driven, safety-first care when we consider these two treatment options.” 

Authorship: In addition to Li and Meisner, Mass General Brigham authors include Brian Boyle, Violeta Valdivia Amanda Sedgewick, Danika Dai, Courtney Miller, Paula Bolton, and Steve Seiner. 

Disclosures: None. 
 
Funding: None 

Paper cited: Meisner R et al. “Comparative Effects of Repeated Ketamine Infusion Versus Intranasal Esketamine in Patients With Treatment-Resistant Depression: A Retrospective Chart Review” J Clin Psych DOI: 10.4088/JCP.25m15789 

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