For individuals struggling with treatment-resistant Depression (TRD), the journey to recovery can be long and discouraging. Many patients have tried multiple antidepressants, psychotherapy, and augmentation strategies without achieving meaningful relief. Two of the most important advances in modern psychiatric treatment, repetitive Transcranial Magnetic Stimulation (rTMS) and intranasal esketamine (Spravato®), have transformed the treatment landscape.
Both are U.S. Food and Drug Administration (FDA) treatments for treatment-resistant Depression, with TMS FDA-cleared and Spravato FDA-approved, and both are offered at Mid City TMS. But patients and clinicians often ask the same question about Spravato vs. TMS for Depression: which treatment is more effective?
Key Points at a Glance
- A 2025 analysis compared TMS, Spravato, and starting a new antidepressant, using data from two earlier clinical trials of people with hard-to-treat Depression.
- After four weeks, both TMS and Spravato lowered Depression symptoms more than a new antidepressant did.
- TMS lowered symptoms slightly more than Spravato on average, but the difference was small enough that it could be due to chance.
- More Spravato patients were in remission at week four (33% compared with about 6% with TMS). TMS courses usually run at least six weeks, so a four-week snapshot may not show the full effect of TMS.
- The study pulled data from two separate trials rather than testing the treatments side by side, so the researchers call for direct trials before drawing firm conclusions.
Spravato vs. TMS for Depression: Which Treatment Is More Effective?
A 2025 study published in eClinicalMedicine, a journal in The Lancet family, provides the most direct comparison to date. Rather than relying on indirect comparisons or small observational studies, the investigators performed an individual participant data analysis using data from two major randomized clinical trials. Their conclusion was clear: both TMS and intranasal esketamine are significantly more effective than simply switching to another antidepressant, and TMS performed at least as well as esketamine, with a trend toward greater symptom improvement.
For patients considering advanced treatments, this study offers powerful reassurance that TMS and Spravato are both evidence-based options, and that TMS may offer unique advantages as a non-medication treatment. The authors also note that remission rates at four weeks favored esketamine and that the analysis was exploratory, so the details below matter.
Why Treatment-Resistant Depression Requires a Different Approach
Treatment-resistant Depression is typically defined as major depressive disorder (MDD) that does not respond adequately to at least two antidepressant trials of sufficient dose and duration. The 2025 study used a broader definition: participants had not responded to between one and three adequate antidepressant trials.
This is a common and serious problem. Data from the Sequenced Treatment Alternatives to Relieve Depression (STARD) trial showed that remission becomes less likely with each additional medication trial. As the study authors summarize, fewer than 15% of individuals reached remission with a third medication trial.
When this occurs, continuing to try one medication after another may not be the most effective strategy. Instead, patients may benefit from interventional treatments that work through entirely different mechanisms.
What Is TMS?
Transcranial Magnetic Stimulation uses focused magnetic pulses to stimulate brain regions involved in mood regulation, particularly the left dorsolateral prefrontal cortex (DLPFC). For a fuller explanation, see How Does TMS Work?
TMS is:
- FDA-cleared for major depressive disorder
- Noninvasive
- Drug-free
- Performed in an outpatient setting
- Associated with minimal systemic side effects
- Compatible with ongoing medications
Because TMS is thought to work by stimulating cortical targets that modulate brain networks involved in Depression, it can be effective even when multiple medications have failed.
What Is Spravato?
Spravato (esketamine) is an FDA-approved nasal spray for adults with treatment-resistant Depression. Learn more on our Spravato services page.
Esketamine is thought to act primarily by blocking the N-methyl-D-aspartate (NMDA) glutamate receptor, a different mechanism from both TMS and conventional antidepressants.
Key features include:
- Administration in a certified medical office
- At least two hours of post-treatment medical monitoring
- Twice-weekly sessions during the first four weeks of treatment
- Potential side effects that the study authors describe as transient psychiatric, hemodynamic (blood pressure), and neurologic effects
Spravato has become an important option for many patients with treatment-resistant Depression.
Study Title and Publication Details
The study was titled:
It was authored by Tyler S. Kaster and colleagues, a team of Canadian and U.S. researchers, and published online in eClinicalMedicine on October 30, 2025.
To the authors’ knowledge, this was the first analysis to directly compare once-daily rTMS with intranasal esketamine using patient-level data.
How the Researchers Conducted the Study
Rather than launching a brand-new randomized trial, the investigators combined individual-level data from two large clinical trials:
- The THREE-D trial, which compared two forms of rTMS (high-frequency 10 Hz stimulation and intermittent theta burst stimulation, or iTBS) in adults with treatment-resistant Depression.
- The TRANSFORM-2 trial, which evaluated intranasal esketamine plus a newly initiated oral antidepressant, compared with a placebo nasal spray plus a new antidepressant.
Number of Participants
After restricting both trials to participants with one to three failed antidepressant trials and using propensity-score matching to balance baseline Depression severity, the analysis included 282 participants, creating three matched groups of 94 patients each:
- rTMS
- Intranasal esketamine
- Control group receiving a new antidepressant medication (with placebo nasal spray)
Participant Characteristics
Participants were:
- Adults, with average ages of 42 to 47 years across the three groups
- Diagnosed with treatment-resistant Depression
- Balanced on baseline Depression severity after matching
- Resistant to one to three prior antidepressant trials
Treatment Protocols Used in the Analysis
rTMS Protocol
The rTMS arm combined both THREE-D treatment groups, since the trial found the two protocols equally effective:
- High-frequency 10 Hz stimulation or intermittent theta burst stimulation
- Left dorsolateral prefrontal cortex
- Once-daily sessions
- Four to six weeks of treatment, with outcomes compared at week four
Spravato Protocol
The esketamine arm followed the standard induction schedule:
- Flexibly dosed intranasal esketamine
- Twice weekly
- Four weeks
- Administered with a newly initiated oral antidepressant
Primary Outcome: Change in Depression Severity
The primary endpoint was Depression severity after four weeks, measured using the 17-item Hamilton Depression Rating Scale (HDRS-17). Scores from the Montgomery-Åsberg Depression Rating Scale (MADRS) used in TRANSFORM-2 were converted to HDRS-17 scores to allow direct comparison.
Main Result
rTMS produced a numerically greater reduction in depressive symptoms than esketamine, with an estimated mean difference of −2.46 points, but the confidence interval crossed zero, meaning the difference was not statistically significant.
In practical terms:
- Both treatments reduced symptoms more than a new antidepressant.
- Neither treatment clearly outperformed the other.
- TMS trended toward slightly greater improvement.
Both Treatments Outperformed Another Antidepressant Trial
One of the most clinically meaningful findings was that both rTMS and Spravato were superior to simply starting another antidepressant medication in reducing Depression severity. Compared with the new medication, rTMS lowered HDRS-17 scores by an estimated 5.35 points and esketamine by 2.89 points.
This is particularly important because many patients with treatment-resistant Depression spend months or years trying additional medications with diminishing returns. For patients researching Spravato vs. TMS for Depression, this comparison with a new antidepressant may matter as much as the comparison between the two treatments. Mid City TMS discusses this further in Lamictal vs. TMS and Esketamine for Treatment-Resistant Depression.
The authors write that the findings add to evidence that interventional psychiatry treatments are superior to additional medication trials, and suggest the need for new treatment algorithms for Depression.
Esketamine vs. TMS: Response and Remission Rates
Although the study’s primary analysis focused on continuous symptom reduction rather than categorical outcomes, adjusted response and remission estimates demonstrated that both treatments led to substantial clinical improvement.
Unadjusted rates at week four were:
- rTMS: response 47.9%, remission 6.4%
- Spravato: response 62.8%, remission 33%
- New antidepressant: response 50%, remission 22.3%
Why TMS Offers Distinct Advantages
Because efficacy was broadly comparable in this analysis, treatment choice between TMS vs Spravato can be based on practical considerations.
TMS Is Completely Drug-Free
No medication is administered, avoiding concerns about drug interactions or the side effects the authors associate with esketamine, which include potential long-term hepatobiliary and genitourinary effects and potential for misuse.
No Dissociation or Sedation
Patients remain fully alert and can drive immediately after treatment.
No Mandatory Observation Period
Unlike Spravato, which requires at least two hours of monitoring, TMS sessions are brief and patients return directly to work or daily activities.
No Blood Pressure Surges
TMS does not typically cause transient hypertension.
Excellent Long-Term Tolerability
The most common side effects are mild scalp discomfort and headache early in treatment.
When Spravato May Be Especially Helpful
Spravato may be particularly attractive when:
- Rapid symptom relief is a priority
- A patient prefers medication-based treatment
- Prior TMS has been ineffective
- The patient is comfortable with in-office monitoring
At Mid City TMS, Spravato is an important option, and many patients achieve remarkable improvement. For a comparison of Spravato with psilocybin, see Why TMS and Spravato Are Better Than Psilocybin.
Why Mid City TMS Offers Both TMS and Spravato
At Mid City TMS, we believe treatment-resistant Depression should be approached with personalized, evidence-based care.
We offer:
- FDA-cleared rTMS
- Spravato therapy
- Accelerated TMS protocols when appropriate
- Maintenance TMS
- Comprehensive psychiatric evaluation and ongoing monitoring
Because both treatments are highly effective, we work with each patient to determine which option best fits their symptoms, medical history, preferences, and practical needs. When weighing Spravato vs. TMS for Depression, there is no single right answer for every patient.
Key Takeaways From This Landmark Study
The 2025 Lancet EClinicalMedicine analysis of Spravato vs. TMS for Depression provides several important lessons:
- Both rTMS and Spravato reduced Depression symptoms more than starting a new antidepressant over four weeks.
- Both had higher odds of response than a new antidepressant, though neither had significantly higher odds of remission at week four.
- TMS performed at least as well as esketamine and showed a nonsignificant trend toward greater symptom reduction.
- Treatment selection should be individualized based on tolerability, convenience, and patient preference.
- Because the study combined data from two separate trials, randomized head-to-head trials are still needed.
Get In Touch About Spravato or TMS for Depression Today
For patients with Depression that has not responded to traditional medications, the message from this study is highly encouraging: there is more than one evidence-based path forward.
The 2025 EClinicalMedicine study confirms that both TMS and Spravato reduce symptoms more than another antidepressant trial, and that TMS may offer equal or potentially slightly greater symptom improvement while remaining noninvasive and drug-free. For anyone comparing Spravato vs. TMS for Depression, it is the best direct evidence available until randomized trials are completed.
At Mid City TMS, we are proud to offer both treatments and to individualize care for each patient.
If you have tried multiple medications without sufficient relief, contact us today or call us today at 212-517-1867 to learn whether TMS, Spravato, or a personalized combination strategy may help you.
Sources
Kaster, T. S., Dai, Y., Vila-Rodriguez, F., Downar, J., Daskalakis, Z. J., Blumberger, D. M., & Rhee, T. G. Efficacy of intranasal esketamine versus rTMS for treatment-resistant depression: Analysis of individual participant data from two clinical trials. eClinicalMedicine. 2025;90:103609. https://doi.org/10.1016/j.eclinm.2025.103609