Most of us know the moment. A patient has failed two, sometimes three, adequate antidepressant trials, maybe an augmentation agent too. They are still depressed, often demoralized, and now asking, sometimes skeptically, what comes next.
For two decades, the honest answer was “another medication,” with modest expectations. In STAR*D, fewer than 15 percent of patients reached remission with a third medication trial. Two FDA-authorized options have changed that conversation: transcranial magnetic stimulation (TMS), including the deep TMS (dTMS) H1 coil, and intranasal esketamine (Spravato), approved in 2019. An individual participant data analysis found that at four weeks, both repetitive TMS (rTMS) and esketamine reduced symptoms significantly more than starting a new antidepressant. The authors argue for moving interventional psychiatry earlier in treatment algorithms.
So the useful question is usually not whether to offer one of these treatments, but which to offer first, and for whom.
Similar efficacy, different speed
In the pivotal H1-coil trial (n=212), response and remission at week five were 37.0 and 30.4 percent with active treatment, versus 27.8 and 15.8 percent with sham, with no seizures. For esketamine, the most clinically useful trial is probably ESCAPE-TRD. In 676 patients continuing an SSRI or SNRI, esketamine beat extended-release quetiapine for remission at week eight (27.1 vs. 17.6 percent) and for staying relapse-free through week 32 (21.7 vs. 14.1 percent).
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No randomized trial has compared the two head to head, but the comparative data suggest broadly similar effectiveness:
- In the individual participant data analysis, rTMS produced numerically larger symptom reduction at four weeks, though the difference was not statistically significant.
- In a UC San Diego cohort of 372 patients, esketamine produced response sooner (median 36 vs. 49 days), but cumulative response converged by about 90 days (68.8 vs. 59.4 percent).
Speed is where they differ most. In that same cohort, suicidal ideation improved in a median of 9 days with esketamine, versus 26 days with TMS. A target trial emulation that matched 1,690 patients per arm found broadly similar suicide-related outcomes overall. Esketamine had an advantage in the 30- to 90-day window, which the authors advise interpreting cautiously.
TMS is also getting faster. An accelerated theta-burst protocol on the H1 coil matched standard treatment and reached remission sooner (21 vs. 28 days), at the cost of more site discomfort and headache.
When the clinical clock is pressing, esketamine’s faster trajectory is a real advantage. That means prominent suicidal ideation, a job at risk, or a patient too exhausted to wait six weeks. For a stable, chronically depressed patient, tolerability and durability matter more.
Different burdens, not lighter ones
Esketamine is available only through a Risk Evaluation and Mitigation Strategy (REMS) program, with on-site dosing, blood pressure checks, and at least two hours of monitoring. Patients cannot drive until the next day. Blood pressure can rise by more than 40 mm Hg, peaking around 40 minutes after the dose. Across nearly 1.5 million U.S. treatment sessions, sedation was reported in 34.7 percent, dissociation in 41.0 percent, and increased blood pressure in 0.9 percent. Serious adverse events were rare. Cardiovascular risk, pregnancy planning, and a history of substance misuse often decide the choice before efficacy does.
TMS requires no monitoring, and patients drive themselves. The cost is time: daily weekday sessions for about four weeks, then twice weekly. In the matched cohort, rTMS was associated with fewer hospitalizations, arrhythmias, and injuries over the first year.
The two treatments also follow different durability models. ESCAPE-TRD’s advantages held through 32 weeks, and in a secondary analysis, remission reached 55.7 versus 36.3 percent. But many responders stay on clinic-based dosing. TMS is usually a finite course. In the pivotal dTMS trial, benefit held through 16 weeks with twice-weekly continuation. Relapse after TMS does occur, and maintenance strategies are less standardized and less consistently covered. Many patients weigh these differences more heavily than we expect. Some prefer a finite course to open-ended clinic visits, while others prefer a treatment they can taper gradually.
Real-world barriers
Most payers require documented failure of a specified number of antidepressant trials for both treatments, often along with a psychotherapy trial. Many cover figure-8 TMS more readily than dTMS or accelerated protocols. Documenting each failed trial’s dose, duration, and adherence from the first visit saves weeks later.
REMS-certified sites and TMS centers also cluster in metropolitan areas, and FDA advisory committee members specifically flagged travel burden as a risk to esketamine access. Preference matters too, because it predicts adherence. Some patients fear dissociation or the “ketamine” association. Others are put off by daily appointments or scalp discomfort.
Anxiety and OCD
Anxiety is the rule in treatment-resistant depression, and both treatments appear to reduce it. But in the UC San Diego cohort, comorbid anxiety (hazard ratio 0.69) and benzodiazepine use (hazard ratio 0.73) predicted slower TMS response, while no predictors emerged for esketamine. This is a single retrospective cohort, but it argues for setting realistic timelines with anxious patients and considering a careful benzodiazepine taper where feasible.
Obsessive-compulsive disorder (OCD) features push toward deep TMS. The H7 coil is FDA-cleared for OCD after a sham-controlled trial showing 38.1 versus 11.1 percent response after treatment, and 45.2 versus 17.8 percent at one month. Esketamine has no comparable evidence for OCD. The H1 and H7 coils performed comparably for depression in a 169-patient randomized comparison, which makes H7 especially attractive when depression and obsessional symptoms travel together.
A practical framework
The evidence does not support a universal “TMS first” or “esketamine first” rule. Instead, match the treatment to the clinical picture.
- Favor esketamine for: Urgency, including prominent suicidal ideation; need for faster response; inability to attend daily sessions; prior TMS failure; patient preference.
- Favor deep TMS for: Comorbid OCD; cardiovascular or cerebrovascular risk; a history of substance misuse; pregnancy planning; no reliable ride home after dosing; preference for a finite course.
- For both: Address chronic benzodiazepine use, document prior trials thoroughly for payers, and agree in advance on measurement-based endpoints such as the PHQ-9 or MADRS.
Sequencing is a legitimate strategy. The mechanisms differ, so failing one does not predict failing the other. For patients who have run out of good medication options, the most important message is that they have options. Choosing among them is a clinical judgment shaped by urgency, comorbidity, medical risk, logistics, and the patient’s own priorities.
Ravi Singareddy is the founder and medical director of Empower Psychiatry & Sleep in north metro Atlanta, where he leads an interventional psychiatry practice offering transcranial magnetic stimulation (TMS) and Spravato (esketamine) for treatment-resistant depression. Double board-certified in psychiatry and sleep medicine, he brings more than two decades of clinical and academic experience to patients who haven’t found relief with medications alone. He is affiliated with Emory Healthcare.
His interest in neuromodulation dates back to his years as associate professor of psychiatry at Penn State College of Medicine. There, he taught annually on vagus nerve stimulation and novel depression therapies, and he published on long-term combined electroconvulsive therapy and vagus nerve stimulation in the American Journal of Psychiatry. He has authored numerous peer-reviewed papers on sleep disorders, insomnia, anxiety, and depression, with work appearing in Sleep, the Journal of Clinical Sleep Medicine, and Psychiatry Research.
Singareddy is a Fellow of the American Psychiatric Association and the American Academy of Sleep Medicine and practices measurement-based care, tracking outcomes to guide every treatment decision. He shares updates on Instagram.
