Breaking Barriers in Depression Care: Comparing rTMS and Esketamine for Treatment-Resistant Depression

What is treatment-resistant depression? 

Treatment-resistant depression (TRD) is a form of depression that doesn't improve after several different medication and psychotherapy treatments (typically ≥2 different treatments). It’s more common than people might think and is often harder to treat, with symptoms lasting longer and feeling more intense than non-resistant depression. One major study showed that if two treatments don’t work, there's less than a 15% chance a third will help. This makes TRD especially challenging to treat and highlights the urgent need for more effective treatments. 

What motivated this research? 

In recent years, two new treatments — rTMS and intranasal esketamine — have emerged as effective options for people with resistant depression. rTMS uses magnetic pulses to stimulate brain regions linked to depression, while esketamine is a fast-acting nasal spray that works by increasing levels of certain neurotransmitters. Both are approved and have been shown to help when standard treatments fail, but they work differently, involve different care settings, and have different side effect profiles. Until now, no study had directly compared them. To fill this gap, we analyzed data from two major clinical trials to compare rTMS and intranasal esketamine head-to-head, with the aim of generating evidence to help patients and doctors make more informed treatment choices. 

What was the most important finding of this study, in your opinion? 

We found that both rTMS and intranasal esketamine were more effective at reducing depression symptoms than switching to a new antidepressant in people with treatment-resistant depression. After four weeks, patients who received either of these new treatments had less severe depression than those who took a new antidepressant medication. When comparing rTMS and intranasal esketamine directly, neither stood out as clearly better; however, rTMS was slightly better, though the difference was not statistically significant. Overall, the study shows that both treatments are good options, and rTMS may work just as well — or even slightly better — than intranasal esketamine for people whose depression hasn’t responded to typical treatments. 

How does this change service delivery in the future? 

This study suggests that when standard depression treatments don’t work, doctors should consider rTMS or intranasal esketamine as effective next steps instead of trying more antidepressants. Both rTMS and intranasal esketamine have been shown to help when typical medications fail, which might lead to earlier referrals to specialized clinics and better outcomes for patients. Since rTMS is at least as effective as esketamine—and may have fewer side effects or safety concerns—it might become the preferred option for many. These findings could also encourage the expansion of health system access to these treatments, which may meaningfully improve the lives of individuals suffering from tough-to-treat depression. 

Any next steps? 

While this study offers important insights, it also highlights the need for further research—especially a direct head-to-head randomized clinical trial comparing rTMS and esketamine. Future studies should also explore which type of patients benefit most from each treatment, whether the benefits last over time, and how best to sequence or combine these options. Research into long-term outcomes, safety, cost-effectiveness, and accessibility will be key to making these treatments more widely available. In our view, this work provides an important foundation for future studies that will generate knowledge supporting the shared decision-making process between physicians and patients suffering from tough-to-treat depression.  

What is the major take home message for the public? 

The key message is one of hope: for people struggling with depression that hasn’t improved with standard treatments, there are now effective alternatives. This study shows that both rTMS (a non-drug brain stimulation therapy) and intranasal esketamine (a fast-acting nasal spray) can both help where typical antidepressants have failed. They appear to work equally well, giving patients and doctors two strong options. These findings reassure the public that treatment-resistant depression is not the end of the road—new, effective therapies are available and making a real difference for many individuals suffering from resistant depression. 

Are there any Departmental faculty or learners you would like to acknowledge?

Daniel Blumberger and Jonathan Downar are Departmental Faculty involved in the original rTMS clinical trial and also contributed to this study.