Can I do SPRAVATO and TMS at the same time?

A patient sat in my office on a Tuesday afternoon and asked me, almost apologetically, if she was allowed to want both.

She had been on her fourth antidepressant. She had read about SPRAVATO. She had a friend who had done TMS and was, in her words, “weirdly fine now, like a different person.” Her own psychiatrist had told her, gently, that she would have to “pick a lane.” She wanted to know whether picking was actually the right answer, or whether two treatments designed to do different things in the same exhausted brain might work better together than either one alone.

It is one of the most clinically interesting questions in treatment-resistant depression right now. And the honest answer is: yes, in many cases you can — and increasingly we are starting to think you maybe should.

This piece walks through what the evidence actually says, where it stops, how the two treatments fit together mechanistically, what the safety data look like, and how we sequence them in real practice at Exxceed. If you are sitting where my patient sat — already aware of both options, already past the second or third antidepressant trial, already tired — this is for you.

The short answer first

For most patients with treatment-resistant depression, SPRAVATO and TMS can be used in combination or in close sequence. The published evidence is small but consistent: combining them tends to produce larger reductions in depressive symptoms than either alone, and the side effect profile so far has been mild and transient [3]. There are no absolute contraindications between the two when each is appropriately delivered. The question is rarely “is this allowed” — it is “what is the right order, the right spacing, and the right protocol for your depression.”

That last question is where a real psychiatric specialist earns their keep. Read on.

What each treatment is actually doing

To understand why combining them is interesting, you have to understand that SPRAVATO and TMS work on the same disease through completely different doors.

SPRAVATO is the FDA-approved nasal spray form of esketamine, the S-enantiomer of ketamine. It is a glutamate-system drug. It works at the NMDA receptor — a fast, excitatory receptor that has nothing to do with the serotonin and norepinephrine systems that traditional antidepressants target [1]. By transiently blocking NMDA receptors, esketamine sets off a cascade that ends in a surge of synaptic plasticity, increased BDNF (brain-derived neurotrophic factor), and the rapid regrowth of dendritic spines in mood-regulating cortical circuits [1][2]. That is the mechanism behind the now-familiar observation that ketamine and esketamine can lift severe depression within hours, where conventional medications take weeks. SPRAVATO was approved in the United States in 2019 as an adjunctive treatment for TRD and was approved as monotherapy on January 21, 2025 — the first medication ever to be approved as a standalone treatment for treatment-resistant depression [13][14].

TMS — transcranial magnetic stimulation — is the entirely non-pharmacologic cousin. A focused magnetic coil sits over the scalp and induces small electrical currents in the cortex, most often the left dorsolateral prefrontal cortex (DLPFC), a region that is consistently underactive in depression. Repeated sessions reshape activity in the cortical-limbic circuits underlying mood. The newer accelerated theta-burst protocols — including the Stanford Neuromodulation Therapy (SNT) protocol, formerly called SAINT — compress what was a six-week course into five days of multiple daily sessions, with functional MRI guiding the coil to the precise spot in each individual’s prefrontal cortex most anticorrelated with the subgenual cingulate, a deep emotional regulation hub [6][7]. SNT produced 86.4% remission in its open-label study and a 52.5% MADRS reduction versus 11.1% for sham in the double-blind randomized trial [6][7].

So one treatment is a chemistry intervention into the brain’s fast-glutamate signaling system. The other is a physics intervention into the brain’s underactive cortical control of mood. They are not competing for the same receptor. They are not competing for the same network node. That is exactly why combining them has been on the table.

Why combining is even a question

For decades, the standard “what next” after two failed antidepressants was: add a second-generation antipsychotic, switch classes, augment with lithium, or refer for ECT. Those algorithms still hold [1][2]. But two things shifted in the last five years.

First, both SPRAVATO and TMS moved from “novel” to “established.” Major treatment guidelines now name both as evidence-supported interventions for TRD [1][2][12]. They are no longer experimental. They are no longer rare. They are mainstream, and most academic centers and a growing number of community psychiatric specialty practices offer one or both.

Second, mechanistic research started pointing at a shared downstream story. Both rTMS and ketamine/esketamine, despite working through entirely different upstream mechanisms, appear to converge on common final pathways involving cortical excitability, BDNF-mediated synaptic plasticity, and the endocannabinoid system [5]. In animal models and human studies, both treatments raise endocannabinoid levels (anandamide and 2-arachidonoylglycerol) in ways that correlate with clinical improvement [5]. The implication: you may be hitting the same final circuit twice — once chemically, once electrically — and the brain may not mind.

Third, the clinical evidence on the actual combination started to accumulate. A 2024 systematic review by Arubuolawe and colleagues pulled together six published studies — three case reports, one retrospective study, one pilot study, and one prior review — examining TMS combined with ketamine in TRD [3]. Across studies, the combination produced “substantial and sustained improvement” in depressive symptoms, with efficacy higher than either treatment alone and adverse effects that were “generally mild and transient, with no severe adverse events reported in most studies” [3]. A separate 2024 analysis of clinical trial activity over the past decade noted that combinatorial treatment with rTMS, ECT, psychotherapy, and other non-pharmacologic interventions has become explicitly common in ketamine and esketamine research [4].

This is still small. Six studies is not a phase III randomized trial. The Arubuolawe review explicitly notes the heterogeneity of designs and the small sample sizes — what we have is signal, not certainty [3]. But it is a consistent signal, in the same direction, with no offsetting safety alarm. That is more than we had in 2019.

What the evidence actually says about each — and where the limits are

Let’s be honest about the numbers.

SPRAVATO, in real-world practice. The REAL-ESK study followed 116 TRD patients across multiple Italian mental health services using the FDA/EMA-approved nasal spray protocol. At three months, 64.2% had a clinical response (≥50% reduction in depressive symptom scores), and 40.6% met remission criteria. Side effects in real-world use matched what was seen in pivotal trials [8]. A separate REAL-ESK sub-analysis of older adults (≥65 years) showed comparable effectiveness — 53.3% response and 33.3% remission at three months — though with higher rates of dizziness, dissociation, and sedation [9]. The long-term SUSTAIN-2 open-label study tracked over 800 patients on esketamine plus an oral antidepressant for up to a year and showed sustained effect with a stable safety profile [10].

That said, a 2025 individual-patient-data meta-analysis of the pivotal randomized trials found that the effect size of esketamine added to an antidepressant, while statistically significant, was clinically modest — a roughly 3-point greater reduction on the MADRS depression scale than placebo at four weeks [11]. The authors of that meta-analysis were transparent: the magnitude of benefit, particularly for the originally approved combination indication, is smaller than is sometimes implied [11]. The monotherapy data — the basis for the January 2025 approval — looked larger, but had its own design concerns [11][13].

The patient takeaway is not that SPRAVATO does not work. It does. The takeaway is that SPRAVATO is a real treatment with a real but moderate effect size, which is exactly the kind of treatment for which augmentation strategies — including combining with TMS — make clinical sense.

TMS, especially accelerated TMS. The conventional FDA-cleared rTMS course (six weeks, daily sessions) has been around since 2008 and has well-established efficacy in TRD [1][12]. The accelerated theta-burst protocols are newer and considerably more powerful. SNT/SAINT in its open-label proof-of-concept study produced 86.4% remission in 22 TRD patients [6]. The follow-up double-blind randomized sham-controlled trial published in the American Journal of Psychiatry in 2022 confirmed it — a 52.5% reduction in MADRS scores after five days of active SNT versus 11.1% for sham [7]. This is the most powerful antidepressant intervention with the shortest treatment duration we have ever had outside of ECT.

The honest limit on TMS, including SNT, is durability. Many patients relapse over six to twelve months and need maintenance sessions or another intervention to hold the gain. This is one of the cleanest clinical reasons to consider combining TMS with a maintenance esketamine course — a topic the field is actively exploring.

The safety question

The reasonable patient question is some version of: “If SPRAVATO causes dissociation and TMS stimulates my brain, isn’t combining them risky?” It is the right question to ask. The answer, based on what we have so far, is reassuring but not absolute.

The combination has not produced unexpected serious adverse events in any of the published studies in the Arubuolawe systematic review [3]. The safety theory of why this is true: the two treatments do not overlap in their primary side-effect profiles. SPRAVATO’s main side effects — dissociation, transient blood pressure elevation, sedation, dizziness — happen during and shortly after dosing and resolve within two hours [8][14]. TMS’s main side effects — scalp discomfort at the coil site, occasional transient headache, the rare risk of seizure — are entirely unrelated and do not stack onto SPRAVATO’s profile.

The seizure question is worth addressing directly. Standard FDA-cleared TMS protocols carry a seizure risk on the order of 1 in 30,000 sessions in patients without other risk factors. Ketamine and esketamine, at sub-anesthetic doses used psychiatrically, are not associated with lowered seizure threshold in clinical use. The combined published case series have not reported induced seizures from the combination [3]. This is reassuring but is built on small numbers, and your prescribing clinician’s judgment about your specific seizure history, current medications, and any history of head injury matters enormously here.

The other practical concern is timing. SPRAVATO requires a two-hour observation period after each dose for blood pressure and dissociation monitoring [14]. TMS sessions are typically 3-20 minutes for standard protocols and can run longer for accelerated protocols. Same-day combinations are usually scheduled with TMS first and SPRAVATO second, or on alternating days, to keep observation periods clean and to avoid driving or transportation issues for patients.

How we actually sequence at Exxceed

Every treatment-resistant depression patient is different, and there is no single right protocol. But here is the sequencing logic we use in practice when both treatments are on the table.

Start with the question of urgency. If you are in a severe depressive episode, particularly with active suicidality, SPRAVATO’s rapid onset — clinical effect often within 24 hours — makes it the right first-line interventional treatment [1][8][13]. Get the depression off the floor first. Once you are stable enough to plan, we layer in TMS.

If you are not in crisis but have failed multiple medication trials, the order is often reversed. A five-day SNT/SAINT course can produce a 52.5% MADRS reduction with no medication side effects, no dissociation, no observation period, and no controlled-substance scheduling [7]. For many patients who want to feel like themselves first and then decide, leading with accelerated TMS is the cleaner path. SPRAVATO becomes the maintenance arm if remission is not full or if relapse begins.

If you are already responding partially to antidepressants and the question is augmentation, we will often combine. SPRAVATO twice weekly (the standard induction phase) running alongside a course of TMS — either standard 6-week rTMS or accelerated theta-burst — is the most common combined protocol we see in the published literature and in our own practice [3][4]. The two treatments are timed on different days, or sequenced on the same day with TMS in the morning and SPRAVATO in the afternoon.

Maintenance is the longest stretch. Once a patient has reached remission, the question becomes how to keep it. The 2025 review of innovative TRD approaches notes that long-term maintenance increasingly involves periodic TMS booster sessions paired with weekly or biweekly SPRAVATO — neither alone, both together — to hold the response [12]. This is the part of the algorithm where the combination strategy is doing the most work, because relapse is the central problem of TRD, and we now have two complementary tools to fight it instead of one.

Who is — and isn’t — a candidate for both

Patient candidacy for the combination overlaps with candidacy for each individually. Broadly speaking, you may be a candidate if:

• You have a diagnosis of major depressive disorder and have not responded adequately to at least two antidepressant trials of adequate dose and duration (the standard TRD definition) [1].
• You do not have a history of psychosis, mania, or active substance use disorder that would contraindicate ketamine.
• You do not have implanted ferromagnetic devices in the head, a history of seizure disorder unrelated to depression, or specific neurologic conditions that would contraindicate TMS.
• You are stable enough medically to tolerate SPRAVATO’s transient blood pressure elevation and the time commitment of TMS sessions (especially accelerated protocols).
• You have insurance coverage or financial planning for both, since both treatments require pre-authorization, and the combination protocol is not yet a single billable bundle.

You are likely not a candidate if you have uncontrolled hypertension, a recent cardiovascular event, an aneurysm or AV malformation, an implanted neurostimulator, or an active psychotic disorder. And patients with bipolar disorder require especially careful evaluation — both SPRAVATO and TMS have evidence in bipolar depression but require mood stabilization first.

The decision is never algorithmic. It is a clinical conversation with someone who knows the literature, knows your medical history, knows your previous medication trials, and knows the limits of what we are doing. If you are getting a “yes” or a “no” without that conversation, get a second opinion.

The honest limits of what we know

The biggest weakness in the combination story right now is that we do not have a large randomized trial of SPRAVATO plus TMS versus either alone. The Arubuolawe systematic review explicitly calls for one [3]. Until that trial exists, what we have is convergent mechanism, real-world observational data, and a small case series literature.

Several other questions remain open:

• The optimal order of induction. Does TMS first then SPRAVATO outperform SPRAVATO first then TMS, or vice versa?
• The optimal timing of same-day combinations. Should they be hours apart, half a day apart, or interleaved on alternating days?
• The optimal maintenance schedule. How often do you need TMS boosters? How often do you taper SPRAVATO?
• Whether the response durability of the combination outperforms the response durability of either alone over 12 to 24 months.

A clinician who tells you they have all of these answers is overstating the science. A clinician who tells you the combination cannot work, or that you must pick one, is understating it.

What this means for the patient on a Tuesday

The patient I started with — fourth antidepressant, friend who did TMS, lane to pick — left that visit with a treatment plan that involved both. We started with five days of accelerated theta-burst TMS, monitored her response over three weeks, then began SPRAVATO induction as the second arm to extend and consolidate the response. She is in maintenance now. She is not “weirdly fine.” She is, as she put it last visit, “fine in the boring way I forgot was possible.”

That is the goal. Boring relief from a disease that has stolen years.

If you are at the point where you are reading articles about combining advanced depression treatments, you are far enough into this to know that nothing will be a single magic bullet and that the question is how to assemble the right combination of tools for your depression. SPRAVATO and TMS, used together with intention and good clinical sequencing, are increasingly that combination. The evidence is small but real, the safety is good so far, and the mechanistic story is coherent enough to make sense even to a tired patient on a Tuesday afternoon.

You do not have to pick a lane. You have to pick the right path through both.